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1.  Surface-Chemistry Effect on Cellular Response of Luminescent Plasmonic Silver Nanoparticles 
Bioconjugate Chemistry  2014;25(3):453-459.
Cellular response of inorganic nanoparticles (NPs) is strongly dependent on their surface chemistry. By taking advantage of robust single-particle fluorescence and giant Raman enhancements of unique polycrystalline silver NPs (AgNPs), we quantitatively investigated effects of two well-known surface chemistries, passive PEGylation and active c-RGD peptide conjugation, on in vitro behaviors of AgNPs at high temporal and spatial resolution as well as chemical level using fluorescence and Raman microscopy. The results show that specific c-RGD peptide−αvβ3 integrin interactions not only induced endosome formation more rapidly, enhanced constrained diffusion, but also minimized nonspecific chemical interactions between the NPs and intracellular biomolecules than passive PEGylation chemistry; as a result, surface enhanced Raman scattering (SERS) signals of c-RGD peptides were well resolved inside endosomes in the live cells, while Raman signals of PEGylated AgNPs remained unresolvable due to interference of surrounding biomolecules, opening up an opportunity to investigate specific ligand–receptor interactions in real time at the chemical level.
doi:10.1021/bc500008a
PMCID: PMC3983130  PMID: 24559325
2.  Elucidation of the RamA Regulon in Klebsiella pneumoniae Reveals a Role in LPS Regulation 
PLoS Pathogens  2015;11(1):e1004627.
Klebsiella pneumoniae is a significant human pathogen, in part due to high rates of multidrug resistance. RamA is an intrinsic regulator in K. pneumoniae established to be important for the bacterial response to antimicrobial challenge; however, little is known about its possible wider regulatory role in this organism during infection. In this work, we demonstrate that RamA is a global transcriptional regulator that significantly perturbs the transcriptional landscape of K. pneumoniae, resulting in altered microbe-drug or microbe-host response. This is largely due to the direct regulation of 68 genes associated with a myriad of cellular functions. Importantly, RamA directly binds and activates the lpxC, lpxL-2 and lpxO genes associated with lipid A biosynthesis, thus resulting in modifications within the lipid A moiety of the lipopolysaccharide. RamA-mediated alterations decrease susceptibility to colistin E, polymyxin B and human cationic antimicrobial peptide LL-37. Increased RamA levels reduce K. pneumoniae adhesion and uptake into macrophages, which is supported by in vivo infection studies, that demonstrate increased systemic dissemination of ramA overexpressing K. pneumoniae. These data establish that RamA-mediated regulation directly perturbs microbial surface properties, including lipid A biosynthesis, which facilitate evasion from the innate host response. This highlights RamA as a global regulator that confers pathoadaptive phenotypes with implications for our understanding of the pathogenesis of Enterobacter, Salmonella and Citrobacter spp. that express orthologous RamA proteins.
Author Summary
Bacteria can rapidly evolve under antibiotic pressure to develop resistance, which occurs when target genes mutate, or when resistance-encoding genes are transferred. Alternatively, microbes can simply alter the levels of intrinsic proteins that allow the organism to “buy” time to resist antibiotic pressure. Klebsiella pneumoniae is a pathogen that causes significant blood stream or respiratory infections, but more importantly is a bacterium that is increasingly being reported as multidrug resistant. Our data demonstrate that RamA can trigger changes on the bacterial surface that allow Klebsiella to survive both antibiotic challenge, degradation by host immune peptides and resist phagocytosis. We demonstrate that the molecular basis of increased survival of ramA overexpressing K. pneumoniae, against host-derived factors is associated with RamA-driven alterations of the lipid A moiety of Klebsiella LPS. This modification is likely to be linked to Klebsiella’s ability to resist the host response so that it remains undetected by the immune system. The relevance of our work extends beyond RamA in Klebsiella as other pathogens such as Enterobacter spp and Salmonella spp. also produce this protein. Thus our overarching conclusion is that the intrinsic regulator, RamA perturbs host-microbe and microbe-drug interactions.
doi:10.1371/journal.ppat.1004627
PMCID: PMC4310594  PMID: 25633080
3.  Efficacy and Safety of Corneal Transplantation Using Corneas from Foreign Donors versus Domestic Donors: A Prospective, Randomized, Controlled Trial 
Journal of Ophthalmology  2015;2015:178289.
Purpose. To assess the efficacy and safety of corneal transplantation using corneas from foreign donors. Methods. One hundred and eight patients needing therapeutic penetrating keratoplasty were randomly divided into 2 groups (54 cases/group): foreign group using foreign donor corneas and domestic group using domestic donor corneas. Clinical outcome and incidence of postoperative complications were compared between groups. Results. No significant difference with respect to the therapeutic outcome and postoperative Best Corrected Visual Acuity (BCVA) and neovascularization by final follow-up was observed between the two groups. The graft thickness in the foreign group was statistically higher than the domestic group at 1 month postoperatively, but not at 3, 6, and 12 months postoperatively. Corneal endothelial cell density in the domestic group was statistically higher than in the foreign group at 3, 6, and 12 months postoperatively. Corneal epithelial abnormalities in the foreign group were significantly higher than that in domestic group. The primary graft failure, incidence of graft survival, and postoperative complications such as immunologic rejection, graft infection, and secondary glaucoma were not significantly different between the two groups. Conclusions. Corneal transplantations using foreign donor corneas are as effective and safe as those using domestic donor corneas.
doi:10.1155/2015/178289
PMCID: PMC4324957
4.  Variations among Primary Care Physicians in Exercise Advice, Imaging, and Analgesics for Musculoskeletal Pain: Results from a Factorial Experiment 
Arthritis care & research  2014;66(1):147-156.
Objective
To examine whether medical decisions regarding evaluation and management of musculoskeletal pain conditions varied systematically by characteristics of the patient or provider.
Methods
We conducted a balanced factorial experiment among primary care physicians in the U.S. Physicians (N=192) viewed two videos of different patients (actors) presenting with pain: (1) undiagnosed sciatica symptoms or (2) diagnosed knee osteoarthritis. Systematic variations in patient gender, socioeconomic status (SES), race, physician gender and experience (<20 vs. ≥20 years in practice) permitted estimation of unconfounded effects. Analysis of variance was used to evaluate associations between patient or provider attributes and clinical decisions. Quality of decisions was defined based on the current recommendations of the ACR, American Pain Society, and clinical expert consensus.
Results
Despite current recommendations, under one-third of physicians would provide exercise advice (30.2% for osteoarthritis, 32.8% for sciatica). Physicians with fewer years in practice were more likely to provide advice on lifestyle changes, particularly exercise (P<0.01), and to prescribe NSAIDs for pain relief, both of which were appropriate and consistent with current recommendations for care. Newer physicians ordered fewer tests, particularly basic laboratory investigations or urinalysis. Test ordering decreased as organizational emphasis on business or profits increased. Patient factors and physician gender had no consistent effects on pain evaluation or treatment.
Conclusion
Physician education on disease management recommendations regarding exercise and analgesics, and implementation of quality measures may be useful, particularly for physicians with more years in practice.
doi:10.1002/acr.22143
PMCID: PMC4067704  PMID: 24376249
5.  Multiple species of wild tree peonies gave rise to the ‘king of flowers’, Paeonia suffruticosa Andrews 
The origin of cultivated tree peonies, known as the ‘king of flowers' in China for more than 1000 years, has attracted considerable interest, but remained unsolved. Here, we conducted phylogenetic analyses of explicitly sampled traditional cultivars of tree peonies and all wild species from the shrubby section Moutan of the genus Paeonia based on sequences of 14 fast-evolved chloroplast regions and 25 presumably single-copy nuclear markers identified from RNA-seq data. The phylogeny of the wild species inferred from the nuclear markers was fully resolved and largely congruent with morphology and classification. The incongruence between the nuclear and chloroplast trees suggested that there had been gene flow between the wild species. The comparison of nuclear and chloroplast phylogenies including cultivars showed that the cultivated tree peonies originated from homoploid hybridization among five wild species. Since the origin, thousands of cultivated varieties have spread worldwide, whereas four parental species are currently endangered or on the verge of extinction. The documentation of extensive homoploid hybridization involved in tree peony domestication provides new insights into the mechanisms underlying the origins of garden ornamentals and the way of preserving natural genetic resources through domestication.
doi:10.1098/rspb.2014.1687
PMCID: PMC4240985  PMID: 25377453
conservation; hybridization; Paeonia; RNA-seq; species tree
6.  Tetrahydrobiopterin Improves Endothelial Function in Cardiovascular Disease: A Systematic Review 
Background. Tetrahydrobiopterin (BH4) is a cofactor of nitric oxide synthase (NOS). Nitric oxide (NO) bioavailability is reduced during the early stage of vascular diseases, such as coronary artery disease, hypercholesterolemia, hypertension, and diabetic vasculopathy, and even throughout the entire progression of atherosclerosis. Methods. A literature search was performed using electronic databases (up to January 31, 2014), including MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL), using an established strategy. Results. Fourteen articles were selected with a total of 370 patients. Ten of the fourteen studies showed a significant improvement in the endothelial dysfunction of various cardiovascular disease groups with BH4 supplementation compared with the control groups or placebos. Three studies showed no positive outcome, and one study showed that low-dose BH4 had no effect but that high-dose BH4 did have a significantly different result. Conclusions. This review concludes that supplementation with BH4 and/or augmentation of the endogenous levels of BH4 will be a novel approach to improve the endothelial dysfunction observed in various cardiovascular diseases. BH4 might be considered to be a new therapeutic agent to prevent the initiation and progression of cardiovascular disease.
doi:10.1155/2014/850312
PMCID: PMC4273464  PMID: 25548592
7.  Characterization of a novel orthoreovirus isolated from fruit bat, China 
BMC Microbiology  2014;14(1):293.
Background
In recent years novel human respiratory disease agents have been described for Southeast Asia and Australia. The causative pathogens were classified as pteropine orthoreoviruses with a strong phylogenetic relationship to orthoreoviruses of bat origin.
Results
In this report, we isolated a novel Melaka-like reovirus (named “Cangyuan virus”) from intestinal content samples of one fruit bat residing in China’s Yunnan province. Phylogenetic analysis of the whole Cangyuan virus genome sequences of segments L, M and S demonstrated the genetic diversity of the Cangyuan virus. In contrast to the L and M segments, the phylogenetic trees for the S segments of Cangyuan virus demonstrated a greater degree of heterogeneity.
Conclusions
Phylogenetic analysis indicated that the Cangyuan virus was a novel orthoreovirus and substantially different from currently known members of Pteropine orthoreovirus (PRV) species group.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0293-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0293-4
PMCID: PMC4264558  PMID: 25433675
Bat Orthoreovirus; Prevalence; Viral genome reassortment
8.  Global View of the Functional Molecular Organization of the Avian Cerebrum: Mirror Images and Functional Columns 
The Journal of comparative neurology  2013;521(16):3614-3665.
Based on quantitative cluster analyses of 52 constitutively expressed or behaviorally regulated genes in 23 brain regions, we present a global view of telencephalic organization of birds. The patterns of constitutively expressed genes revealed a partial mirror image organization of three major cell populations that wrap above, around, and below the ventricle and adjacent lamina through the mesopallium. The patterns of behaviorally regulated genes revealed functional columns of activation across boundaries of these cell populations, reminiscent of columns through layers of the mammalian cortex. The avian functionally regulated columns were of two types: those above the ventricle and associated mesopallial lamina, formed by our revised dorsal mesopallium, hyperpallium, and intercalated hyperpallium; and those below the ventricle, formed by our revised ventral mesopallium, nidopallium, and intercalated nidopallium. Based on these findings and known connectivity, we propose that the avian pallium has four major cell populations similar to those in mammalian cortex and some parts of the amygdala: 1) a primary sensory input population (intercalated pallium); 2) a secondary intrapallial population (nidopallium/hyperpallium); 3) a tertiary intrapallial population (mesopallium); and 4) a quaternary output population (the arcopallium). Each population contributes portions to columns that control different sensory or motor systems. We suggest that this organization of cell groups forms by expansion of contiguous developmental cell domains that wrap around the lateral ventricle and its extension through the middle of the mesopallium. We believe that the position of the lateral ventricle and its associated mesopallium lamina has resulted in a conceptual barrier to recognizing related cell groups across its border, thereby confounding our understanding of homologies with mammals.
doi:10.1002/cne.23404
PMCID: PMC4145244  PMID: 23818122
forebrain; brain pathways; brain organization; neural activity; motor behavior; primary sensory; brain evolution; neurotransmitter receptors; immediate early genes; pallium; cortex; striatum; pallidum; basal ganglia; amygdala; claustrum
9.  Efficient non-doped phosphorescent orange, blue and white organic light-emitting devices 
Scientific Reports  2014;4:6754.
Efficient phosphorescent orange, blue and white organic light-emitting devices (OLEDs) with non-doped emissive layers were successfully fabricated. Conventional blue phosphorescent emitters bis [4,6-di-fluorophenyl]-pyridinato-N,C2′] picolinate (Firpic) and Bis(2,4-difluorophenylpyridinato) (Fir6) were adopted to fabricate non-doped blue OLEDs, which exhibited maximum current efficiency of 7.6 and 4.6 cd/A for Firpic and Fir6 based devices, respectively. Non-doped orange OLED was fabricated utilizing the newly reported phosphorescent material iridium (III) (pbi)2Ir(biq), of which manifested maximum current and power efficiency of 8.2 cd/A and 7.8 lm/W. The non-doped white OLEDs were achieved by simply combining Firpic or Fir6 with a 2-nm (pbi)2Ir(biq). The maximum current and power efficiency of the Firpic and (pbi)2Ir(biq) based white OLED were 14.8 cd/A and 17.9 lm/W.
doi:10.1038/srep06754
PMCID: PMC4208040  PMID: 25341698
10.  Mammary Fat of Breast Cancer: Gene Expression Profiling and Functional Characterization 
PLoS ONE  2014;9(10):e109742.
Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.
doi:10.1371/journal.pone.0109742
PMCID: PMC4188628  PMID: 25291184
11.  Steady-State Equilibrium Phase Inversion Recovery ON-resonant Water Suppression (IRON) Magnetic Resonance Angiography in Conjunction with Superparamagnetic Nanoparticles. A Robust Technique for Imaging within a Wide Range of Contrast Agent Dosages 
Objectives
To investigate the ability of inversion recovery ON-resonant water suppression (IRON) in conjunction with P904 (superparamagnetic nanoparticles which consisting of a maghemite core coated with a low-molecular-weight amino-alcohol derivative of glucose) to perform steady-state equilibrium phase magnetic resonance angiography (MRA) over a wide dose range.
Materials and Methods
Experiments were approved by the institutional animal care committee. Rabbits (n=12) were imaged at baseline and serially after the administration of 10 incremental dosages of 0.57–5.7 mgFe/Kg P904. Conventional T1-weighted and IRON MRA were obtained on a clinical 1.5-T scanner to image the thoracic and abdominal aorta, and peripheral vessels. Contrast-to-noise ratios (CNR) and vessel sharpness were quantified.
Results
Using IRON MRA, CNR and vessel sharpness progressively increased with incremental dosages of the contrast agent P904, exhibiting constantly higher contrast values than T1-weighted MRA over a very wide range of contrast agent doses (CNR of 18.8±5.6 for IRON versus 11.1±2.8 for T1-weighted MRA at 1.71 mgFe/kg, p=0.02 and 19.8±5.9 for IRON versus −0.8±1.4 for T1-weighted MRA at 3.99 mgFe/kg, p=0.0002). Similar results were obtained for vessel sharpness in peripheral vessels, (Vessel sharpness of 46.76±6.48% for IRON versus 33.20±3.53% for T1-weighted MRA at 1.71 mgFe/Kg, p=0.002, and of 48.66±5.50% for IRON versus 19.00±7.41% for T1-weighted MRA at 3.99 mgFe/Kg, p=0.003).
Conclusion
Our study suggests that quantitative CNR and vessel sharpness after the injection of P904 are consistently higher for IRON MRA when compared to conventional T1-weighted MRA. These findings apply for a wide range of contrast agent dosages.
doi:10.1002/jmri.24043
PMCID: PMC3657577  PMID: 23418107
12.  Relationship between homocysteine level and diabetic retinopathy: a systematic review and meta-analysis 
Diagnostic Pathology  2014;9(1):167.
Background
The relationship between homocysteine (Hcy) and diabetic retinopathy (DR) remains unclear to date. Therefore, a systematic review and meta-analysis was performed on the relationship between Hcy level and DR.
Methods
Studies were identified by searching PubMed, Embase, and Web of Science databases until 5 May, 2014.
Results
A total of 31 studies involving 6,394 participants were included in the meta-analysis. After pooling the data from each included study, the blood Hcy concentration in the DR group was observed to be higher than that in the control group [WMD = 2.55; 95% confidence interval (CI), 1.70–3.40], and diabetes mellitus (DM) patients with hyperhomocysteinemia were at a risk for DR [odds ratio (OR) = 1.93; 95% CI, 1.46–2.53]. Considering the different DM types, hyperhomocysteinemia in T1DM (OR = 1.83, 95% CI, 1.28–2.62) was associated with DR rather than in T2DM (OR = 1.59, 95% CI, 0.72–3.51). Considerable statistical heterogeneity in the overall summary estimates was partly explained by the geographical differences.
Conclusions
Results from this current meta-analysis indicate that hyperhomocysteinemia is a risk factor for DR, especially proliferative DR. Differences between geographical regions were observed in the relationship between hyperhomocysteinemia with T1DM risk. Given the heterogeneous results, the relationship between high Hcy and DR needs further investigation.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_167
doi:10.1186/s13000-014-0167-y
PMCID: PMC4207897  PMID: 25257241
Hyperhomocysteinemia; Homocysteine; Diabetic retinopathy (DR)
13.  Direct in vitro comparison of six 3D positive contrast methods for susceptibility marker imaging 
Purpose
To compare different techniques for positive contrast imaging of susceptibility markers with MRI for 3D visualization. As several different techniques have been reported, the choice of the suitable method depends on its properties with regard to the amount of positive contrast and the desired background suppression, as well as other imaging constraints needed for a specific application.
Materials and methods
Six different positive contrast techniques are investigated for their ability to image at 3T a single susceptibility marker in vitro. The white marker method (WM), susceptibility gradient mapping (SGM), inversion recovery with on-resonant water suppression (IRON), frequency selective excitation (FSX), fast low flip-angle positive contrast SSFP (FLAPS), and iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) were implemented and investigated.
Results
The different methods were compared with respect to the volume of positive contrast, the product of volume and signal intensity, imaging time, and the level of background suppression. Quantitative results are provided and strengths and weaknesses of the different approaches are discussed.
Conclusion
The appropriate choice of positive contrast imaging technique depends on the desired level of background suppression, acquisition speed, and robustness against artifacts, for which in vitro comparative data is now available.
doi:10.1002/jmri.23976
PMCID: PMC3620818  PMID: 23281151
susceptibility imaging; off resonance; positive contrast
14.  Facilitating Cytokine-Mediated Cancer Cell Death by Proteobacterial N-Acylhomoserine Lactones 
ACS chemical biology  2013;8(6):1117-1120.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in cancer cells over normal cells; however, tumor cells may develop TRAIL resistance. Here we demonstrate that this resistance can be overcome in the presence of bacterial acylhomoserine lactones (AHLs) or AHL-producing bacteria through the combined effect of TRAIL-induced apoptosis and AHL-mediated inhibition of inflammation regulated by NF-κB signaling. This discovery unveils a previously unrecognized symbiotic link between bacteria and host immunosurveillance.
doi:10.1021/cb4000184
PMCID: PMC3755046  PMID: 23517377
15.  Protein Phosphatase 2A Catalytic Subunit α (PP2Ac) Plays a MyD88-dependent, Central Role in the Gene-Specific Regulation of Endotoxin Tolerance (ET) 
Cell reports  2013;3(3):678-688.
SUMMARY
MyD88, the intracellular adaptor of most TLRs, mediates either pro-inflammatory or immunosuppressive signaling that contributes to chronic inflammation-associated diseases. Although gene-specific chromatin modifications regulate inflammation, the role of MyD88 signaling in establishing such epigenetic landscapes under different inflammatory states remains elusive. Using quantitative proteomics to enumerate the inflammation-phenotypic constituents of MyD88 interactome, we found that in endotoxin-tolerant macrophages PP2Ac enhances its association with MyD88, and is constitutively activated. Knockdown of PP2Ac prevents suppression of pro-inflammatory genes and resistance to apoptosis. Through sitespecific dephosphorylation constitutively active PP2Ac disrupts the signal-promoting TLR4-MyD88 complex, and broadly suppresses the activities of multiple pro-inflammatory/proapoptotic pathways as well, shifting pro-inflammatory MyD88 signaling to a pro-survival mode. Constitutively active PP2Ac translocated with MyD88 into the nuclei of tolerant macrophages establishes the immunosuppressive pattern of chromatin modifications and represses chromatin remodeling to selectively silence pro-inflammatory genes, coordinating the MyD88-dependent inflammation control at both signaling and epigenetic levels under endotoxin-tolerant conditions.
doi:10.1016/j.celrep.2013.01.029
PMCID: PMC4060247  PMID: 23434512
16.  MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers 
Cell Cycle  2013;12(9):1385-1394.
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-143 (miR-143) has been observed in CRC tissues. Here in this study, we found that miR-143 expression was downregulated both in CRC patients’ blood samples and tumor specimens. MiR-143 expression levels were strongly correlated with clinical stages and lymph node metastasis. Furthermore, insulin-like growth factor-I receptor (IGF-IR), a known oncogene, was a novel direct target of miR-143, whose expression levels were inversely correlated with miR-143 expression in human CRC specimens. Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner. Taken together, these results revealed that miR-143 levels in human blood and tumor tissues are associated with CRC cancer occurrence, metastasis and drug resistance, and miR-143 levels may be used as a new diagnostic marker and therapeutic target for CRC in the future.
doi:10.4161/cc.24477
PMCID: PMC3674066  PMID: 23574723
microRNA-143; tumorigenesis; angiogenesis; IGF-IR; chemotherapy
17.  Analysis of Autoinducer-2 Quorum Sensing in Yersinia pestis 
Infection and Immunity  2013;81(11):4053-4062.
The autoinducer-2 (AI-2) quorum-sensing system has been linked to diverse phenotypes and regulatory changes in pathogenic bacteria. In the present study, we performed a molecular and biochemical characterization of the AI-2 system in Yersinia pestis, the causative agent of plague. In strain CO92, the AI-2 signal is produced in a luxS-dependent manner, reaching maximal levels of 2.5 μM in the late logarithmic growth phase, and both wild-type and pigmentation (pgm) mutant strains made equivalent levels of AI-2. Strain CO92 possesses a chromosomal lsr locus encoding factors involved in the binding and import of AI-2, and confirming this assignment, an lsr deletion mutant increased extracellular pools of AI-2. To assess the functional role of AI-2 sensing in Y. pestis, microarray studies were conducted by comparing Δpgm strain R88 to a Δpgm ΔluxS mutant or a quorum-sensing-null Δpgm ΔypeIR ΔyspIR ΔluxS mutant at 37°C. Our data suggest that AI-2 quorum sensing is associated with metabolic activities and oxidative stress genes that may help Y. pestis survive at the host temperature. This was confirmed by observing that the luxS mutant was more sensitive to killing by hydrogen peroxide, suggesting a potential requirement for AI-2 in evasion of oxidative damage. We also show that a large number of membrane protein genes are controlled by LuxS, suggesting a role for quorum sensing in membrane modeling. Altogether, this study provides the first global analysis of AI-2 signaling in Y. pestis and identifies potential roles for the system in controlling genes important to disease.
doi:10.1128/IAI.00880-13
PMCID: PMC3811820  PMID: 23959719
18.  A case of horizontal gene transfer from Wolbachia to Aedes albopictus C6/36 cell line 
Mobile Genetic Elements  2014;4:e28914.
Horizontal gene transfer plays an essential role in evolution and ecological adaptation, yet this phenomenon has remained controversial, particularly where it occurs between prokaryotes and eukaryotes. There are a handful of reported examples of horizontal gene transfer occurring between prokaryotes and eukaryotes in the literature, with most of these documented cases pertaining to invertebrates and endosymbionts. However, the vast majority of these horizontally transferred genes were either eventually excluded or rapidly became nonfunctional in the recipient genome. In this study, we report the discovery of a horizontal gene transfer from the endosymbiont Wolbachia in the C6/36 cell line derived from the mosquito Aedes albopictus. Moreover, we report that this horizontally transferred gene displayed high transcription level. This finding and the results of further experimentation strongly suggest this gene is functional and has been expressed and translated into a protein in the mosquito host cells.
doi:10.4161/mge.28914
PMCID: PMC4013104  PMID: 24812591
horizontal gene transfer; endosymbiont; Wolbachia; mosquito; Aedes Albopictus; C6/36 cell line
19.  Antagonism of a Zinc Metalloprotease Using a Unique Metal-Chelating Scaffold: Tropolones as Inhibitors of P. aeruginosa Elastase†‡ 
Tropolone emerged from the screening of a chelator fragment library (CFL) as an inhibitor of the Zn2+-dependent virulence factor, Pseudomonas aeruginosa elastase (LasB). Based on this initial hit, a series of substituted tropolone-based LasB inhibitors was prepared, and a compound displaying potent activity in vitro and in a bacterial swarming assay was identified. Importantly, this inhibitor was found to be specific for LasB over other metalloenzymes, validating the usage of tropolone as a viable scaffold for identifying first-in-class LasB inhibitors.
doi:10.1039/c3cc41191e
PMCID: PMC3618488  PMID: 23482955
20.  Ribosomal Protein S29 Regulates Metabolic Insecticide Resistance through Binding and Degradation of CYP6N3 
PLoS ONE  2014;9(4):e94611.
Background
Many diseases are transmitted by mosquitoes, including malaria, dengue fever, yellow fever, filariasis, and West Nile fever. Chemical control plays a major role in managing mosquito-borne diseases. However, excessive and continuous application of insecticides has caused the development of insecticide resistance in many species including mosquito, and this has become the major obstacle to controlling mosquito-borne diseases. Insecticide resistance is the result of complex polygenic inheritance, and the mechanisms are not well understood. Ribosomal protein RPS29 was found to be associated with DM resistance in our previous study. In this study, we aim to further investigate the involvement of RPS29 in deltamethrin resistance.
Methodology and Principal Findings
In this study, tandem affinity purification was used to identify proteins that can interact with RPS29. Among the candidate proteins, CYP6N3, a member of the CYP450 superfamily, was identified, and binding to RPS29 was confirmed in vitro and in vivo by GST pull-down and immunofluorescence. CCK-8 assay was used to investigate the RPS29-CTP6N3 interaction in relation to DM resistance. CYP6N3 overexpression significantly enhanced DM resistance and insect cell viability, but this was reversed by RPS29 overexpression. Western blot was used to study the mechanism of interaction between RPS29 and CYP6N3. RPS29 increases CYP6N3 protein degradation through the proteasome.
Conclusions and Significance
These observations indicate that CYP6N3, a novel RPS29-interacting partner, could stimulate deltamethrin resistance in mosquito cells and RPS29 overexpression targeted CYP6N3 for proteosomal degradation, abrogating the CYP6N3-associated resistence to deltamethrin. Our findings provide a novel mechanism associated with CYP450s mediated DM resistance.
doi:10.1371/journal.pone.0094611
PMCID: PMC3984272  PMID: 24728095
21.  The adhesion of mussel foot protein-3 to TiO2 surfaces: the effect of pH 
Biomacromolecules  2013;14(4):1072-1077.
The underwater adhesion of marine mussels relies on mussel foot proteins (mfps) rich in the catecholic amino acid 3, 4-dihydroxyphenylalanine (Dopa). As a side-chain, Dopa is capable of strong bidentate interactions with a variety of surfaces, including many minerals and metal oxides. Titanium is among the most widely used medical implant material and quickly forms a TiO2 passivation layer under physiological conditions. Understanding the binding mechanism of Dopa to TiO2 surfaces is therefore of considerable theoretical and practical interest. Using a surface forces apparatus, we explored the force-distance profiles and adhesion energies of mussel foot protein 3 (mfp-3) to TiO2 surfaces at three different pHs (pH3, 5.5 and 7.5). At pH3, mfp-3 showed the strongest adhesion force on TiO2, with an adhesion energy of ~ −7.0 mJ/m2. Increasing the pH gives rise to two opposing effects: (1) increased oxidation of Dopa, thus decreasing availability for the Dopa-mediated adhesion, and (2) increased bidentate Dopa-Ti coordination, leading to the further stabilization of the Dopa group and thus an increasing of adhesion force. Both effects were reflected in the resonance-enhanced Raman spectra obtained at the three deposition pHs. The two competing effects give rise to a higher adhesion force of mfp-3 on TiO2 surface at pH 7.5 than at pH 5.5. Our results suggest that Dopa-containing proteins and synthetic polymers have great potential as coating materials for medical implant materials, particularly if redox activity can be controlled.
doi:10.1021/bm301908y
PMCID: PMC3635841  PMID: 23452271
22.  Acupuncture for Essential Hypertension: A Meta-Analysis of Randomized Sham-Controlled Clinical Trials 
Background. Acupuncture is frequently advocated as an adjunct treatment for essential hypertension. The aim of this review was to assess its adjunct effectiveness in treating hypertension. Methods. We searched PubMed, the Cochrane Library, EMBASE, and the Chinese databases Sino-Med, CNKI, WanFang, and VIP through November, 2012, for eligible randomized controlled trials that compared acupuncture with sham acupuncture. Outcome measures were changes in diastolic (DBP) and systolic blood pressure (SBP). Results. A total of 4 randomized controlled trials were included. We found no evidence of an improvement with the fact that acupuncture relative to sham acupuncture in SBP change (n = 386; mean difference = −3.80 mmHg, 95% CI = −10.03–2.44 mmHg; I2 = 99%), and an insignificant improvement in DBP change (n = 386; mean difference = −2.82 mmHg, 95% CI = −5.22–(−0.43) mmHg; I2 = 97%). In subgroup analyses, acupuncture significantly improved both SBP and DBP in patients taking antihypertensive medications. Only minor acupuncture-related adverse events were reported. Conclusions. Our results are consistent with acupuncture significantly lowers blood pressure in patients taking antihypertensive medications. We did not find that acupuncture without antihypertensive medications significantly improves blood pressure in those hypertensive patients.
doi:10.1155/2014/279478
PMCID: PMC3960742  PMID: 24723957
23.  Immunomodulation and the quorum sensing molecule 3-oxo-C12-homoserine lactone: The importance of chemical scaffolding for probe development† 
As a guide for chemical probe design, focused analogue synthetic studies were undertaken upon the lactone ring of 3-oxo-C12-homoserine lactone. We have concluded that hydrolytic instability of the heterocyclic ring is pivotal for its ability to modulate immune signaling and probe preparation was aligned with these findings.
doi:10.1039/c3cc38851d
PMCID: PMC3566768  PMID: 23328974
24.  Expression of IGFBP-6 in a proliferative vitreoretinopathy rat model and its effects on retinal pigment epithelial cell proliferation and migration 
AIM
To investigate the expression of insulin-like growth factor binding protein-6 (IGFBP-6) in a proliferative vitreoretinopathy (PVR) model and its effects on proliferation and migration in retinal pigment epithelial (RPE) cells.
METHODS
A PVR Wistar rat model was established by the intravitreal injection of RPE-J cells combined with platelet-rich plasma (PRP). The expression levels of IGFBP-6 were tested by ELISA. ARPE-19 cell proliferation was evaluated by the MTS method, and cell migration was evaluated by wound healing assays.
RESULTS
The success rate of the PVR model was 89.3% (25/28). IGFBP-6 was expressed at higher levels in the vitreous, serum and retina of rats experiencing advanced PVR (grade 3) than in the control group (vitreous: 152.80±15.08ng/mL vs 105.44±24.81ng/mL, P>0.05; serum: 93.48±9.27ng/mL vs 80.59±5.20ng/mL, P<0.05; retina: 3.02±0.38ng/mg vs 2.05±0.53ng/mg, P<0.05). In vitro, IGFBP-6 (500ng/mL) inhibited the IGF-II (50ng/mL) induced ARPE-19 cell proliferation (OD value at 24h: from 1.38±0.05 to 1.30±0.02; 48h: from 1.44±0.06 to 1.35±0.05). However, it did not affect basal or VEGF-, TGF-β- and PDGF-induced cell proliferation. IGFBP-6 (500ng/mL) reduced the IGF-II (50ng/mL)-induced would healing rate [24h: from (43.91±3.85)% to (29.76±2.49)%; 48 h: from (66.09±1.67)% to (59.88±3.43)%].
CONCLUSION
Concentrations of IGFBP-6 increased in the vitreous, serum, and retinas only in advanced PVR in vivo. IGFBP-6 also inhibited IGF-II-induced cell proliferation in a not dose or time dependent manner and migration. IGFBP-6 participates in the development of PVR and might play a protective role in PVR.
doi:10.3980/j.issn.2222-3959.2014.01.05
PMCID: PMC3949454  PMID: 24634859
insulin-like growth factor binding protein-6; proliferative vitreoretinopathy; retinal pigment epithelial cells
25.  Prediction of Early Response to Chemotherapy in Lung Cancer by Using Diffusion-Weighted MR Imaging 
The Scientific World Journal  2014;2014:135841.
Purpose. To determine whether change of apparent diffusion coefficient (ADC) value could predict early response to chemotherapy in lung cancer. Materials and Methods. Twenty-five patients with advanced non-small cell lung cancer underwent chest MR imaging including DWI before and at the end of the first cycle of chemotherapy. The tumor's mean ADC value and diameters on MR images were calculated and compared. The grouping reference was based on serial CT scans according to Response Evaluation Criteria in Solid Tumors. Logistic regression was applied to assess treatment response prediction ability of ADC value and diameters. Results. The change of ADC value in partial response group was higher than that in stable disease group (P = 0.004). ROC curve showed that ADC value could predict treatment response with 100% sensitivity, 64.71% specificity, 57.14% positive predictive value, 100% negative predictive value, and 82.7% accuracy. The area under the curve for combination of ADC value and longest diameter change was higher than any parameter alone (P ≤ 0.01). Conclusions. The change of ADC value may be a sensitive indicator to predict early response to chemotherapy in lung cancer. Prediction ability could be improved by combining the change of ADC value and longest diameter.
doi:10.1155/2014/135841
PMCID: PMC3943194  PMID: 24688359

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