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1.  The validation of the standard Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) in pre-operative patients with brain tumor in China 
Background
Health related quality of life (HRQOL) has increasingly emphasized on cancer patients. The psychometric properties of the standard Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30, version 3.0) in brain tumor patients wasn't proven, and there was no baseline HRQOL in brain tumor patients prior to surgery.
Methods
The questionnaire EORTC QLQ-C30 (version 3.0) was administered at three time points: T1, the first or the second day that patients were hospitalized after the brain tumor suspected or diagnosed by MRI or CT; T2, 1 to 2 days after T1, (T1 and T2 were both before surgery); T3, the day before discharge. Clinical variables included disease histologic types, cognitive function, and Karnofsky Performance Status.
Results
Cronbach's alpha coefficients for multi-item scales were greater than .70 and multitrait scaling analysis showed that most of the item-scale correlation coefficients met the standards of convergent and discriminant validity, except for the cognitive functioning scale. All scales and items exhibited construct validity. Score changes over peri-operation were observed in physical and role functioning scales. Compared with mixed cancer patients assessed after surgery but before adjuvant treatment, brain tumor patients assessed pre-surgery presented better function and fewer symptoms.
Conclusions
The standard Chinese version of the EORTC QLQ-C30 was overall a valid instrument to assess HRQOL in brain tumor patients in China. The baseline HRQOL in brain tumor patients pre-surgery was better than that in mixed cancer patients post-surgery. Future study should modify cognitive functioning scale and examine test-retest reliability and response validity.
doi:10.1186/1471-2288-11-56
PMCID: PMC3112193  PMID: 21513533
2.  Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improves outcomes in a rat glioma model 
The blood-brain-barrier (BBB) prevents the transport of most anticancer agents to the central nervous system and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels, along with several other factors, creates additional barriers for drug treatment for brain tumors. Focused ultrasound (FUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and the “blood-tumor barrier”. Here, we tested the impact of three weekly sessions of FUS and liposomal doxorubicin (DOX) in 9L rat glioma tumors. Animals that received FUS + DOX (N = 8) had a median survival time that was increased significantly (P < 0.001) compared to animals who received DOX only (N = 6), FUS only (N = 8), or no treatment (N = 7). Median survival for animals that received FUS + DOX was increased by 100% relative to untreated controls, whereas animals who received DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS + DOX group, and in two animals, only a few tumor cells were detected. Adverse events in the treatment group included skin toxicity, impaired activity, damage to surrounding brain tissue, and tissue loss at the tumor site. In one animal, intratumoral hemorrhage was observed. These events are largely consistent with known side effects of doxorubicin and with an extensive tumor burden. Overall this work demonstrates that multiple sessions using this FUS technique to enhance the delivery of liposomal doxorubicin has a pronounced therapeutic effect in this rat glioma model.
doi:10.1016/j.jconrel.2013.04.007
PMCID: PMC3952428  PMID: 23603615
Focused ultrasound; brain; drug delivery; glioma; blood-brain barrier; chemotherapy
3.  Pulmonary Permeability Assessed by Fluorescent-Labeled Dextran Instilled Intranasally into Mice with LPS-Induced Acute Lung Injury 
PLoS ONE  2014;9(7):e101925.
Background
Several different methods have been used to assess pulmonary permeability in response to acute lung injury (ALI). However, these methods often involve complicated procedures and algorithms that are difficult to precisely control. The purpose of the current study is to establish a feasible method to evaluate alterations in lung permeability by instilling fluorescently labeled dextran (FITC-Dextran) intranasally.
Methods/Principal Findings
For the mouse model of direct ALI, lipopolysaccharide (LPS) was administered intranasally. FITC-Dextran was instilled intranasally one hour before the mice were euthanized. Plasma fluorescence intensities from the LPS group were significantly higher than in the control group. To determine the reliability and reproducibility of the procedure, we also measured the lung wet-to-dry weight ratio, the protein concentration of the bronchoalveolar lavage fluid, tight and adherens junction markers and pathological changes. Consistent results were observed when the LPS group was compared with the control group. Simultaneously, we found that the concentration of plasma FITC-Dextran was LPS dose-dependent. The concentration of plasma FITC-Dextran also increased with initial intranasal FITC-Dextran doses. Furthermore, increased fluorescence intensity of plasma FITC-Dextran was found in the intraperitoneally LPS-induced ALI model.
Conclusion/Significance
In conclusion, the measurement of FITC-Dextran in plasma after intranasal instillation is a simple, reliable, and reproducible method to evaluate lung permeability alterations in vivo. The concentration of FITC-Dextran in the plasma may be useful as a potential peripheral biomarker of ALI in experimental clinical studies.
doi:10.1371/journal.pone.0101925
PMCID: PMC4090205  PMID: 25007191
4.  Metal centre effects on HNO binding in porphyrins and the electronic origin: Metal’s electronic configuration, position in the periodic table, and oxidation state 
HNO binds with many different metals in organometallic and bioinorganic chemistry. To help understand experimentally observed metal centre effects, a quantum chemical investigation was performed, revealing clear general binding trends with respect to metal centre characteristics and the electronic origin for the first time.
doi:10.1039/c2cc31016c
PMCID: PMC4084929  PMID: 22437041
5.  Melatonin Enhances the Anti-Tumor Effect of Fisetin by Inhibiting COX-2/iNOS and NF-κB/p300 Signaling Pathways 
PLoS ONE  2014;9(7):e99943.
Melatonin is a hormone identified in plants and pineal glands of mammals and possesses diverse physiological functions. Fisetin is a bio-flavonoid widely found in plants and exerts antitumor activity in several types of human cancers. However, the combinational effect of melatonin and fisetin on antitumor activity, especially in melanoma treatment, remains unclear. Here, we tested the hypothesis that melatonin could enhance the antitumor activity of fisetin in melanoma cells and identified the underlying molecular mechanisms. The combinational treatment of melanoma cells with fisetin and melatonin significantly enhanced the inhibitions of cell viability, cell migration and clone formation, and the induction of apoptosis when compared with the treatment of fisetin alone. Moreover, such enhancement of antitumor effect by melatonin was found to be mediated through the modulation of the multiply signaling pathways in melanoma cells. The combinational treatment of fisetin with melatonin increased the cleavage of PARP proteins, triggered more release of cytochrome-c from the mitochondrial inter-membrane, enhanced the inhibition of COX-2 and iNOS expression, repressed the nuclear localization of p300 and NF-κB proteins, and abrogated the binding of NF-κB on COX-2 promoter. Thus, these results demonstrated that melatonin potentiated the anti-tumor effect of fisetin in melanoma cells by activating cytochrome-c-dependent apoptotic pathway and inhibiting COX-2/iNOS and NF-κB/p300 signaling pathways, and our study suggests the potential of such a combinational treatment of natural products in melanoma therapy.
doi:10.1371/journal.pone.0099943
PMCID: PMC4085069  PMID: 25000190
6.  Sero-Survey of Polio Antibodies during Wild Poliovirus Outbreak in Southern Xinjiang Uygur Autonomous Region, China 
PLoS ONE  2014;9(7):e80069.
Background
After being polio free for more than 10 years, an outbreak following importation of wild poliovirus (WPV) was confirmed in Xinjiang Uygur Autonomous Region, China, in 2011.
Methods
A cross-sectional study was conducted prior to supplementary immunization activities (SIAs), immediately after the confirmation of the WPV outbreak. In selected prefectures, participants aged ≤60 years old who visited hospitals at county-level or above to have their blood drawn for reasons not related to the study, were invited to participate in our study. Antibody titers ≥8 were considered positive.
Results
Among the 2,611 participants enrolled, 2,253 (86.3%), 2,283 (87.4%), and 1,989 (76.2%) were seropositive to P1, P2 and P3 respectively, and 1744 (66.8%) participants were seropositive to all the three serotypes. Lower antibody seropositivities and geometric mean titers were observed in children <1 year of age and in adults aged 15–39 years.
Conclusion
Serosurveys to estimate population immunity in districts at high risk of polio importation might be useful to gauge underlying population immunity gaps to polio and possibly to guide preparedness and response planning. Consideration should be given to older children and adults during polio risk assessment planning and outbreak response.
doi:10.1371/journal.pone.0080069
PMCID: PMC4081020  PMID: 24991811
7.  A role for Drosophila ATX2 in activation of PER translation and circadian behavior 
Science (New York, N.Y.)  2013;340(6134):879-882.
A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of Ataxin-2 (ATX2) – an RNA binding protein implicated in human neurodegenerative diseases - was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons, and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. Indeed, ATX2 formed a complex with TYF, and promoted its interaction with Poly-A binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing, and reveals that this protein functions as an activator of PER translation in circadian neurons.
doi:10.1126/science.1234746
PMCID: PMC4078874  PMID: 23687048
9.  Migration Patterns of Hepatitis C Virus in China Characterized for Five Major Subtypes Based on Samples from 411 Volunteer Blood Donors from 17 Provinces and Municipalities 
Journal of Virology  2014;88(13):7120-7129.
ABSTRACT
We investigated the migration patterns of hepatitis C virus (HCV) in China. Partial E1 and/or NS5B sequences from 411 volunteer blood donors sampled in 17 provinces and municipalities located in five large regions, the north-northeast, northwest, southwest, central south, and southeast, were characterized. The sequences were classified into eight subtypes (1a, n = 3; 1b, n = 183; 2a, n = 83; 3a, n = 30; 3b, n = 44; 6a, n = 55; 6n, n = 10; 6v, n = 1) and a new subtype candidate. Bayesian evolutionary analysis by sampling trees of the E1 sequences of the five major subtypes revealed distinct migration patterns. Subtype 1b showed four groups: one is prevalent nationwide with possible origins in the north-northeast; two are locally epidemic in the central south and northwest, respectively, and have spread sporadically to other regions; and the fourth one is likely linked to the long-distance dispersion among intravenous drug users from the northwest. Subtype 2a showed two groups: the larger one was mainly restricted to the northwest and seemed to show a trend toward migration via the Silk Road; the smaller one was geographically mixed and may represent descendants of those that spread widely during the contaminated plasma campaign in the 1990s. Subtype 3a exhibited three well-separated geographic groups that may be epidemically unrelated: one showed origins in the northwest, one showed origins in the southwest, and the other showed origins in the central south. In contrast, subtype 3b had a mixture of geographic origins, suggesting migrations from the southwest to the northwest and sporadically to other regions. Structurally resembling the tree for subtype 3a, the tree for subtype 6a showed four groups that may indicate migrations from the central south to southeast, southwest, and northwest. Strikingly, no subtype 6a strain was identified in the north-northeast.
IMPORTANCE With a population of greater than 1.3 billion and a territory of >9.6 million square kilometers, China has a total of 34 provinces and municipalities. In such a vast country, the epidemic history and migration trends of HCV are thought to be unique and complex but variable among regions and are unlikely to be represented by those observed in only one or at best a few provinces and municipalities. However, due to the difficulties in recruiting patients, all previous studies for this purpose have been based only on data from limited regions, and therefore, geographical biases were unavoidable. In this study, such biases were greatly reduced because we utilized samples collected from volunteer blood donors in 17 provinces and municipalities. To our knowledge, this is the first study in which the HCV isolates represented such a large portion of the country, and thus, the results should shed light on the current understanding of HCV molecular epidemiology.
doi:10.1128/JVI.00414-14
PMCID: PMC4054444  PMID: 24719413
10.  Genome-Wide Linkage Study Suggests a Susceptibility Locus for Isolated Bilateral Microtia on 4p15.32–4p16.2 
PLoS ONE  2014;9(7):e101152.
Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32–4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean) of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively). Haplotype reconstruction analysis of the 4p15.32–4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65–30.24 cM; 5.54–15.58 Mb). Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.
doi:10.1371/journal.pone.0101152
PMCID: PMC4077761  PMID: 24983964
11.  Effects of Dietary Alpha-lipoic Acid and Acetyl-L-carnitine on Growth Performance and Meat Quality in Arbor Acres Broilers 
An experiment was conducted to evaluate the effects of dietary alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC) on growth performance, carcass characteristics and meat quality in Arbor Acres broilers. A total of 486 1-d-old male Arbor Acres broilers were randomly allocated to 9 dietary treatments, 9 treatments were group A (0 mg/kg LA and 0 mg/kg ALC), group B (50 mg/kg LA and 0 mg/kg ALC), group C (100 mg/kg LA and 0 mg/kg ALC), group D (0 mg/kg LA and 50 mg/kg ALC), group E (50 mg/kg LA and 50 mg/kg ALC), group F (100 mg/kg LA and 50 mg/kg ALC), group G (0 mg/kg LA and 100 mg/kg ALC), group H (50 mg/kg LA and 100 mg/kg ALC), group I (100 mg/kg LA and 100 mg/kg ALC). Birds were slaughtered at 42 days old. Average daily gain (ADG), average feed intake (AFI), feed conversion rate (FCR), eviscerated rate, breast muscle percentage, thigh muscle percentage, abdominal fat percentage, liver weight, muscle color (L* value, a* value, b* value), pH values at 45 min and 24 h postmortem were measured. Results showed that there existed an interaction between LA and ALC in growth performance of broilers, carcass traits and meat quality. The overall result is that high level of LA and ALC led to lower AFI, ADG (p<0.01), lower abdominal fat percentage, liver weight (p<0.01), lower L* value, a* value, and b* value of breast muscle, L* value of thigh muscle (p<0.05), and higher FCR (p<0.01), eviscerated rate (p<0.01), breast muscle percentage, thigh muscle percentage (p<0.05), a* value, pH 45 min and pH 24 h of thigh muscle (p<0.01). These results suggested that dietary LA and ALC contributed to the improvement of meat quality in broilers.
doi:10.5713/ajas.2013.13436
PMCID: PMC4093565  PMID: 25050042
Alpha-lipoic Acid; Acetyl-L-carnitine; Carcass Traits; Meat Quality; Broiler
12.  Infection of Beet necrotic yellow vein virus with RNA4-encoded P31 specifically up-regulates pathogenesis-related protein 10 in Nicotiana benthamiana 
Virology Journal  2014;11:118.
Background
Beet necrotic yellow vein virus (BNYVV) is the infectious agent of sugar beet rhizomania, which consists of four or five plus-sense RNAs. RNA4 of BNYVV is not essential for virus propagation in Nicotiana benthamiana but has a major effect on symptom expression. Early reports showed that RNA4-encoded P31 was associated with severe symptoms, such as curling and dwarfing, in N. benthamiana.
Results
We discovered that the pathogenesis-related protein 10 (PR-10) gene can be up-regulated in BNYVV-infected N. benthamiana in the presence of RNA4 and that it had a close link with symptom development. Our frame-shift, deletion and substitution analysis showed that only the entire P31 could induce PR-10 up-regulation during BNYVV infection and that all the tryptophans and six cysteines (C174, C183, C186, C190, C197 and C199) in the cysteine-rich P31 had significant effects on PR-10 expression. However, P31 could not interact directly with PR-10 in yeast.
Conclusions
Our data demonstrated that only integrated P31 specifically induced PR-10 transcription, which coincided closely with the appearance of severe symptoms in BNYVV-infected N. benthamiana, although they could not interact directly with each other in yeast.
doi:10.1186/1743-422X-11-118
PMCID: PMC4078943  PMID: 24961274
Beet necrotic yellow vein virus; RNA4; P31; Pathogenesis-related protein 10; Nicotiana benthamiana
13.  Isoprenoid Biosynthesis: Ferraoxetane or Allyl Anion Mechanism for IspH Catalysis?** 
Angewandte Chemie (International ed. in English)  2013;52(25):10.1002/anie.201302343.
doi:10.1002/anie.201302343
PMCID: PMC3821072  PMID: 23649534
terpene; biosynthesis; enzyme catalysis; iron-sulfur cluster; metalloprotein
14.  Efficacy and safety of flurbiprofen axetil in the prevention of pain on propofol injection: A systematic review and meta-analysis 
Background
Pain on injection is an acknowledged adverse effect (AE) of propofol administration for the induction of general anesthesia. Flurbiprofen axetil has been reported to reduce the pain of injection. However, results of published papers on the efficacy of flurbiprofen axetil in managing pain on injection of propofol are inconsistent.
Material/Methods
We conducted a comprehensive meta-analysis of studies to appraise the efficacy and safety of flurbiprofen axetil for controlling pain induced by propofol injection. The pooled risk ratio (RR) with corresponding 95% confidence intervals (CI) was calculated employing fixed- or random-effects models, depending upon the heterogeneity of the included trials.
Results
Compared with the placebo group, flurbiprofen axetil allows more patients to have no pain (RR 3.51, 95% CI 2.22–5.55, p=0.000), and decreases the cumulative number of patients with mild, moderate, and severe pain on injecting propofol (RR 0.70, 95% CI 0.58–0.86, p=0.000; RR 0.59, 95% CI 0.46–0.75, p=0.000; RR 0.25, 95% CI 0.16–0.38, p=0.000, respectively). In the stratified analysis by the doses, flurbiprofen axetil at a dose of over 50 mg was found to be effective in reducing propofol-induced pain on injection; however, there were no significant differences in relieving pain between treatment and placebo groups with flurbiprofen axetil at a dose of 25 mg. In terms of drug safety, there were no adverse effects (AEs) reported between flurbiprofen axetil-based regimens and placebo regimens.
Conclusions
Flurbiprofen axetil, an injectable prodrug of flurbiprofen, can significantly prevent or relieve the pain induced by propofol injection. More studies are required to assess its adverse effects.
doi:10.12659/MSM.890102
PMCID: PMC4070992  PMID: 24935068
Prevention; Injection Pain; Flurbiprofen; Meta-Analysis; Propofol
15.  High-throughput Genetic Screen for Synaptogenic Factors: Identification of LRP6 as Critical for Excitatory Synapse Development 
Cell reports  2013;5(5):1330-1341.
SUMMARY
Genetic screens in invertebrates have discovered many synaptogenic genes and pathways. However, similar genetic studies have not been possible in mammals. We have optimized an automated high-throughput platform that employs automated liquid handling and imaging of primary mammalian neurons. Using this platform we have screened 3200 shRNAs targeting 800 proteins. One of the hits identified was LRP6, a co-receptor for canonical Wnt ligands. LRP6 regulates excitatory synaptogenesis, and is selectively localized to excitatory synapses. In vivo knockdown of LRP6 leads to a reduction in the number of functional synapses. Moreover, we show that the canonical Wnt ligand, Wnt8A, promotes synaptogenesis via LRP6. These results provide a proof of principle for using a high content approach to screen for synaptogenic factors in the mammalian nervous system, and identify and characterize a Wnt ligand receptor complex that is critical for development of functional synapses in vivo.
doi:10.1016/j.celrep.2013.11.008
PMCID: PMC3924421  PMID: 24316074
16.  Fluorescence-Guided Surgery in Combination with UVC Irradiation Cures Metastatic Human Pancreatic Cancer in Orthotopic Mouse Models 
PLoS ONE  2014;9(6):e99977.
The aim of this study is to determine if ultraviolet light (UVC) irradiation in combination with fluorescence-guided surgery (FGS) can eradicate metastatic human pancreatic cancer in orthotopic nude–mouse models. Two weeks after orthotopic implantation of human MiaPaCa-2 pancreatic cancer cells, expressing green fluorescent protein (GFP), in nude mice, bright-light surgery (BLS) was performed on all tumor-bearing mice (n = 24). After BLS, mice were randomized into 3 treatment groups; BLS-only (n = 8) or FGS (n = 8) or FGS-UVC (n = 8). The residual tumors were resected using a hand-held portable imaging system under fluorescence navigation in mice treated with FGS and FGS-UVC. The surgical resection bed was irradiated with 2700 J/m2 UVC (254 nm) in the mice treated with FGS-UVC. The average residual tumor area after FGS (n = 16) was significantly smaller than after BLS only (n = 24) (0.135±0.137 mm2 and 3.338±2.929 mm2, respectively; p = 0.007). The BLS treated mice had significantly reduced survival compared to FGS- and FGS-UVC-treated mice for both relapse-free survival (RFS) (p<0.001 and p<0.001, respectively) and overall survival (OS) (p<0.001 and p<0.001, respectively). FGS-UVC-treated mice had increased RFS and OS compared to FGS-only treated mice (p = 0.008 and p = 0.025, respectively); with RFS lasting at least 150 days indicating the animals were cured. The results of the present study suggest that UVC irradiation in combination with FGS has clinical potential to increase survival.
doi:10.1371/journal.pone.0099977
PMCID: PMC4055701  PMID: 24924955
17.  Reshaping Antibody Diversity 
Cell  2013;153(6):1379-1393.
Summary
Unlike humans or mice, some species have limited genome encoded combinatorial diversity potential, yet mount a robust antibody response. Cows are unusual in having exceptionally long CDR H3 loops and few V-regions, but the mechanism for creating diversity is not understood. Deep sequencing revealed that ultralong CDR H3s contain a remarkable complexity of cysteines, suggesting that disulfide-bonded mini-domains may arise during repertoire development. Indeed, crystal structures of two cow antibodies reveal that these CDR H3s form a very unusual architecture composed of a β-strand “stalk” that supports a structurally diverse, disulfide-bonded, “knob” domain. Sequence analysis suggests that diversity arises from somatic hypermutation of an ultralong DH with a severe codon bias towards mutation to cysteine. These unusual antibodies can be elicited to recognize defined antigens through the knob domain. Thus, the bovine immune system produces an antibody repertoire composed of CDR H3s of unprecedented length that fold into a diversity of mini-domains generated through combinations of somatically generated disulfides.
doi:10.1016/j.cell.2013.04.049
PMCID: PMC4007204  PMID: 23746848
18.  Structural Insights into SraP-Mediated Staphylococcus aureus Adhesion to Host Cells 
PLoS Pathogens  2014;10(6):e1004169.
Staphylococcus aureus, a Gram-positive bacterium causes a number of devastating human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. S. aureus SraP, a surface-exposed serine-rich repeat glycoprotein (SRRP), is required for the pathogenesis of human infective endocarditis via its ligand-binding region (BR) adhering to human platelets. It remains unclear how SraP interacts with human host. Here we report the 2.05 Å crystal structure of the BR of SraP, revealing an extended rod-like architecture of four discrete modules. The N-terminal legume lectin-like module specifically binds to N-acetylneuraminic acid. The second module adopts a β-grasp fold similar to Ig-binding proteins, whereas the last two tandem repetitive modules resemble eukaryotic cadherins but differ in calcium coordination pattern. Under the conditions tested, small-angle X-ray scattering and molecular dynamic simulation indicated that the three C-terminal modules function as a relatively rigid stem to extend the N-terminal lectin module outwards. Structure-guided mutagenesis analyses, in addition to a recently identified trisaccharide ligand of SraP, enabled us to elucidate that SraP binding to sialylated receptors promotes S. aureus adhesion to and invasion into host epithelial cells. Our findings have thus provided novel structural and functional insights into the SraP-mediated host-pathogen interaction of S. aureus.
Author Summary
Staphylococcus aureus is an important pathogen that causes a range of human diseases, such as infective endocarditis, osteomyelitis, septic arthritis and sepsis. The increasing resistance of S. aureus to most of the current antibiotics emphasizes the need to develop new approaches to control staphylococcal infections. As a surface-exposed serine-rich repeat glycoprotein (SRRP), S. aureus SraP is involved in the pathogenesis of infective endocarditis via its ligand-binding region (BR) adhering to human platelets. However, little is known about how SraP interacts with its host receptor(s). Through structural and functional analyses of the BR domain, we have discovered a specific binding of SraP to N-acetylneuraminic acid (Neu5Ac), in agreement with a recent report of the trisaccharide ligand of SraP. Further mutagenesis analysis showed that SraP binding to Neu5Ac and the trisaccharide promotes S. aureus adhesion to and invasion into host epithelial cells. These findings increase our knowledge of surface protein mediated interaction of S. aureus with host epithelial cells.
doi:10.1371/journal.ppat.1004169
PMCID: PMC4047093  PMID: 24901708
19.  High density GaN/AlN quantum dots for deep UV LED with high quantum efficiency and temperature stability 
Scientific Reports  2014;4:5166.
High internal efficiency and high temperature stability ultraviolet (UV) light-emitting diodes (LEDs) at 308 nm were achieved using high density (2.5 × 109 cm−2) GaN/AlN quantum dots (QDs) grown by MOVPE. Photoluminescence shows the characteristic behaviors of QDs: nearly constant linewidth and emission energy, and linear dependence of the intensity with varying excitation power. More significantly, the radiative recombination was found to dominant from 15 to 300 K, with a high internal quantum efficiency of 62% even at room temperature.
doi:10.1038/srep05166
PMCID: PMC4046137  PMID: 24898569
20.  In situ Growth of NixCu1-x Alloy Nanocatalysts on Redox-reversible Rutile (Nb,Ti)O4 Towards High-Temperature Carbon Dioxide Electrolysis 
Scientific Reports  2014;4:5156.
In this paper, we report the in situ growth of NixCu1-x (x = 0, 0.25, 0.50, 0.75 and 1.0) alloy catalysts to anchor and decorate a redox-reversible Nb1.33Ti0.67O4 ceramic substrate with the aim of tailoring the electrocatalytic activity of the composite materials through direct exsolution of metal particles from the crystal lattice of a ceramic oxide in a reducing atmosphere at high temperatures. Combined analysis using XRD, SEM, EDS, TGA, TEM and XPS confirmed the completely reversible exsolution/dissolution of the NixCu1-x alloy particles during the redox cycling treatments. TEM results revealed that the alloy particles were exsolved to anchor onto the surface of highly electronically conducting Nb1.33Ti0.67O4 in the form of heterojunctions. The electrical properties of the nanosized NixCu1-x/Nb1.33Ti0.67O4 were systematically investigated and correlated to the electrochemical performance of the composite electrodes. A strong dependence of the improved electrode activity on the alloy compositions was observed in reducing atmospheres at high temperatures. Direct electrolysis of CO2 at the NixCu1-x/Nb1.33Ti0.67O4 composite cathodes was investigated in solid-oxide electrolysers. The CO2 splitting rates were observed to be positively correlated with the Ni composition; however, the Ni0.75Cu0.25 combined the advantages of metallic nickel and copper and therefore maximised the current efficiencies.
doi:10.1038/srep05156
PMCID: PMC4042123  PMID: 24889679
21.  Hydrogels Formed by Oxo-ester Mediated Native Chemical Ligation 
Biomaterials science  2013;1(6):603-613.
Oxo-ester mediated native chemical ligation (OMNCL) is a variation of the more general native chemical ligation (NCL) reaction that is widely employed for chemoselective ligation of peptide fragments. While OMNCL has been used for a variety of peptide ligations and for biomolecular modification of surfaces, it is typically practiced under harsh conditions that are unsuitable for use in a biological context. In this report we describe the use of OMNCL for polymer hydrogel formation, in-vitro cell encapsulation, and in-vivo implantation. Multivalent polymer precursors containing N-hydroxysuccinimide (NHS) activated oxo-esters and N-cysteine (N-Cys) endgroups were chemically synthesized from branched poly(ethylene glycol) (PEG). Hydrogels formed rapidly at physiologic pH upon mixing of aqueous solutions of NHS and N-Cys functionalized PEGs. Quantitative 1H NMR experiments showed that the reaction proceeds through an OMNCL pathway involving thiol capture to form a thioester intermediate, followed by an S-to-N acyl rearrangement to yield an amide cross-link. pH and temperature were found to influence gelation rate, allowing tailoring of gelation times from a few seconds to a few minutes. OMNCL hydrogels initially swelled before contracting to reach an equilibrium increase in relative wet weight of 0%. This unique behavior impacted the gel stiffness and was attributed to latent formation of disulfide cross-links between network-bound Cys residues. OMNCL hydrogels were adhesive to hydrated tissue, generating a lap shear adhesion strength of 46 kPa. Cells encapsulated in OMNCL hydrogels maintained high viability, and in-situ formation of OMNCL hydrogel by subcutaneous injection in mice generated a minimal acute inflammatory response. OMNCL represents a promising strategy for chemical cross-linking of hydrogels in a biological context and is an attractive candidate for in-vivo applications such as wound healing, tissue repair, drug delivery, and tissue engineering.
doi:10.1039/C3BM00201B
PMCID: PMC3719992  PMID: 23894696
22.  Prevalence of Nonpolio Enteroviruses in the Sewage of Guangzhou City, China, from 2009 to 2012 
Applied and Environmental Microbiology  2013;79(24):7679-7683.
The human-pathogenic viruses in urban sewage have been extensively monitored to obtain information on circulating viruses in human communities. Enteroviruses (EVs) excreted by patients who present with diverse clinical syndromes can remain infectious in the environment for several weeks, and limited data on circulating environmental EVs are available. A 4-year (2009 to 2012) surveillance study was conducted to detect nonpolio enteroviruses (NPEVs) in the urban sewage of Guangzhou city, China. After the viruses in the sewage samples were concentrated and isolated, molecular identification was used to detect and type the NPEVs. During the 4-year study, 17 different NPEV serotypes were identified in the sewage of Guangzhou city. The most common serotypes were echovirus 11 (ECHO11), ECHO6, ECHO7, and ECHO12 and coxsackie group B viruses 5 (CVB5) and CVB3. The predominant serotypes were influenced by spatial and temporal factors and differed each year. CVB5 was commonly detected in 2009 and 2010 but was rarely isolated in 2011 and 2012. In contrast, CVB3 was not observed in 2009 and 2010 but was increasingly detected in 2011 and 2012. Our study provides an overview of the serotype distribution and circulation patterns of NPEVs in the sewage of Guangzhou, China. In the absence of a systematic EV disease surveillance system, the detection and characterization of sewage-borne NPEVs will help us better understand the changes in EV disease trends and the epidemic background of circulating EVs, which could help interpret the EV trends and warn of future outbreaks in this area.
doi:10.1128/AEM.02058-13
PMCID: PMC3837794  PMID: 24096418
23.  Immunogenicity, Safety, and Lot Consistency of a Novel Inactivated Enterovirus 71 Vaccine in Chinese Children Aged 6 to 59 Months 
Clinical and Vaccine Immunology : CVI  2013;20(12):1805-1811.
The determination of lot-to-lot consistency in the manufacturing process is a mandatory step in the clinical development of the novel enterovirus 71 (EV71) vaccine. A phase III, randomized, placebo-controlled, double-blind trial assessed the lot consistency, immunogenicity, and safety of the EV71 vaccine in children aged 6 to 59 months. Healthy children (n = 1,400) received one of three lots of the EV71 vaccine containing 400 U of EV71 antigen or a placebo at days 0 and 28. Blood samples were collected before dose 1 and at 28 days after dose 2 (day 56) for an anti-EV71 neutralizing antibody (NTAb) assay. The geometric mean titer (GMT) and the seropositivity rates (with titers of ≥1:8) were compared at day 56. After each dose, the solicited injection site and general adverse events (AEs) were recorded for 7 days, and unsolicited AEs were recorded for 28 days. At day 56, the seropositivity rates ranged from 99.7% to 100% for the vaccine groups. The NTAb GMTs for the vaccine were 140.3 (95% confidence interval [CI], 117.8 to 167.1), 141.5 (95% CI, 118.0 to 169.6), and 146.6 (95% CI, 122.5 to 175.3). The two-sided 95% CI of the log difference in GMTs between the pairs of lots were between −0.176 and 0.176, therefore meeting the predefined equivalence criteria. The percentages of subjects reporting any injection site AEs, general AEs, or serious AEs were similar across the four vaccination groups. In conclusion, the demonstration of consistency between the manufacturing lots confirms for the purposes of clinical development the reliability of the EV71 vaccine production process. (This study has been registered at ClinicalTrials.gov under registration no. NCT01636245.)
doi:10.1128/CVI.00491-13
PMCID: PMC3889509  PMID: 24108780
24.  Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study 
Background
Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents.
Methods
Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity.
Results
There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants.
Conclusions
Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.
doi:10.1186/1744-9081-10-20
PMCID: PMC4050412  PMID: 24885073
Internet addiction; Response inhibition; fMRI; Go/No-Go
25.  Evaluation of fatty liver fibrosis in rabbits using real-time shear wave elastography 
The aim of the present study was to detect the elastic modulus (stiffness) of the livers of rabbits with non-alcoholic and alcoholic fatty liver disease using real-time shear wave elastography (SWE), and to investigate the fibrosis development process in the formation of fatty liver. The stiffness of the fatty livers in rabbit models prepared via feeding with alcohol or a high-fat diet were measured using a real-time SWE ultrasound system and a 4–15-MHz linear array probe, and the liver stiffness was compared with the pathological staging of the disease. The stiffness of the liver was positively correlated with the degree of pathological change in fatty liver disease (P<0.01). The stiffness of the liver in the alcoholic fatty liver group was higher compared with that in the non-alcoholic fatty liver and control groups, and the stiffness in the non-alcoholic fatty liver group was higher than that in the control group (P<0.01). Real-time SWE objectively identified the trend in the changing stiffness of the liver and noninvasively detected the development of fibrosis in the progression of non-alcoholic and alcoholic fatty liver disease.
doi:10.3892/etm.2014.1749
PMCID: PMC4079399  PMID: 25009583
real-time shear wave elastography; rabbit; fatty liver; elasticity

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