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1.  Application of Clinico-Radiologic-Pathologic Diagnosis of Diffuse Parenchymal Lung Diseases in Children in China 
PLoS ONE  2015;10(1):e0116930.
Diffuse parenchymal lung diseases in children (chDPLD) or interstitial lung diseases in children (chILD) represent a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality. However, the incidence of chDPLD is so low that most pediatricians lack sufficient knowledge of chDPLD, especially in China. Based on the clinico- radiologic- pathologic (CRP) diagnosis, we tried to describe (1) the characteristics of chDPLD and (2) the ratio of each constituent of chDPLD in China. Data were evaluated, including clinical, radiographic, and pathologic results from lung biopsies. We collected 25 cases of chDPLD, 18 boys and 7 girls with a median age of 6.0 years, from 16 hospitals in China. The most common manifestations included cough (n = 24), dyspnea (n = 21), and fever (n = 4). There were three cases of exposure-related interstitial lung disease (ILD), three cases of systemic disease-associated ILD, nineteen cases of alveolar structure disorder-associated ILD, and no cases of ILD specific to infancy. Non-specific interstitial pneumonia (n = 9) was the two largest groups. Conclusion: Non-specific interstitial pneumonia is the main categories of chDPLD in China. Lung biopsy is always a crucial step in the final diagnosis. However, clinical and imaging studies should be carefully evaluated for their value in indicating a specific chDPLD.
doi:10.1371/journal.pone.0116930
PMCID: PMC4287620  PMID: 25569558
2.  Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis 
Science (New York, N.Y.)  2014;345(6192):98-101.
Protein folding by the endoplasmic reticulum (ER) is physiologically critical, while its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here we find that unmitigated ER stress promotes apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, allowing time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.
doi:10.1126/science.1254312
PMCID: PMC4284148  PMID: 24994655
3.  A Novel Controlled-Release System for Antibacterial Enzyme Lysostaphin Delivery Using Hydroxyapatite/Chitosan Composite Bone Cement 
PLoS ONE  2014;9(12):e113797.
In this work, a lysostaphin-loaded, control-released, self-setting and injectable porous bone cement with efficient protein delivery was prepared by a novel setting method using hydroxyapatite/chitosan (HA/CS) composite scaffold. The cement samples were made through cementitious reactions by mixing solid powder, a mixture of HA/CS composite particles, lysostaphin, Ca(OH)2, CaCO3 and NaHCO3, with setting liquid containing citric acid, acetic acid, NaH2PO4, CaCl2 and poloxamer. The setting parameters of the cement samples were determined. The results showed that the final setting time was 96.6±5.2 min and the pH value increased from approximately 6.2 to nearly 10 during the setting process and the porosity was 34% at the end. And the microstructure and composition were detected by scanning electron microscopy (SEM), x-ray diffraction and Fourier transform-infrared spectroscopy. For the release behavior of lysostaphin loaded in the cement sample, the in vitro cement extract experiment indicated that about 94.2±10.9% of the loaded protein was released before day 8 and the in vivo Qdot 625 fluorescence tracking experiment showed that the loaded protein released slower than the free one. Then the biocompatibility of the cement samples was evaluated using the methylthiazol tetrazolium assay, SEM and hematoxylin-eosin staining, which suggested good biocompatibility of cement samples with MC 3T3-E1 cells and subcutaneous tissues of mice. Finally the antibacterial activity assay indicated that the loaded lysostaphin had good release ability and strong antibacterial enzymatic activity against methicillin-resistant Staphylococcus aureus. Collectively, all the results suggested that the lysostaphin-loaded self-setting injectable porous bone cement released the protein in a controlled and effective way and the protein activity was well retained during the setting and releasing process. Thus this bone cement can be potentially applied as a combination of artificial bone substitute and controlled-release system for delivery of lysostaphin to treat bone defects and infections.
doi:10.1371/journal.pone.0113797
PMCID: PMC4252040  PMID: 25464506
4.  Recognizing Objects in 3D Point Clouds with Multi-Scale Local Features 
Sensors (Basel, Switzerland)  2014;14(12):24156-24173.
Recognizing 3D objects from point clouds in the presence of significant clutter and occlusion is a highly challenging task. In this paper, we present a coarse-to-fine 3D object recognition algorithm. During the phase of offline training, each model is represented with a set of multi-scale local surface features. During the phase of online recognition, a set of keypoints are first detected from each scene. The local surfaces around these keypoints are further encoded with multi-scale feature descriptors. These scene features are then matched against all model features to generate recognition hypotheses, which include model hypotheses and pose hypotheses. Finally, these hypotheses are verified to produce recognition results. The proposed algorithm was tested on two standard datasets, with rigorous comparisons to the state-of-the-art algorithms. Experimental results show that our algorithm was fully automatic and highly effective. It was also very robust to occlusion and clutter. It achieved the best recognition performance on all of these datasets, showing its superiority compared to existing algorithms.
doi:10.3390/s141224156
PMCID: PMC4299104  PMID: 25517694
object recognition; point cloud; local feature; clutter; occlusion
5.  NCoR REPRESSION OF LXRs RESTRICTS MACROPHAGE BIOSYNTHESIS OF INSULIN-SENSITIZING OMEGA 3 FATTY ACIDS 
Cell  2013;155(1):200-214.
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The co-repressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that de-repression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for pro-inflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin sensitizing therapies.
doi:10.1016/j.cell.2013.08.054
PMCID: PMC4131699  PMID: 24074869
nuclear co-repressor; insulin resistance; obesity; macrophage; inflammation
6.  The Wedelolactone Derivative Inhibits Estrogen Receptor-Mediated Breast, Endometrial, and Ovarian Cancer Cells Growth 
BioMed Research International  2014;2014:713263.
Estrogen and estrogen receptor (ER)-mediated signaling pathways play important roles in the etiology and progression of human breast, endometrial, and ovarian cancers. Attenuating ER activities by natural products and their derivatives is a relatively practical strategy to control and reduce breast, endometrial, and ovarian cancer risk. Here, we found 3-butoxy-1,8,9-trihydroxy-6H-benzofuro[3,2-c]benzopyran-6-one (BTB), a new derivative of wedelolactone, could effectively inhibit the 17-estradiol (E2)-induced ER transactivation and suppress the growth of breast cancer as well as endometrial and ovarian cancer cells. Our results indicate that 2.5 μM BTB effectively suppresses ER-positive, but not ER-negative, breast, endometrial, and ovarian cancer cells. Furthermore, our data indicate that BTB can modulate ER transactivation and suppress the expression of E2-mediated ER target genes (Cyclin D1, E2F1, and TERT) in the ER-positive MCF-7, Ishikawa, and SKOV-3 cells. Importantly, this BTB mediated inhibition of ER activity is selective since BTB does not suppress the activities of other nuclear receptors, including glucocorticoid receptor and progesterone receptor, suggesting that BTB functions as a selective ER signaling inhibitor with the potential to treat breast, endometrial, and ovarian cancers.
doi:10.1155/2014/713263
PMCID: PMC4157183  PMID: 25221777
7.  Assessment of left ventricular twist mechanics by speckle tracking echocardiography reveals association between LV twist and myocardial fibrosis in patients with hypertrophic cardiomyopathy 
We aimed to investigate whether left ventricular (LV) twist analysis can detect the extent of myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). This prospective case–control study recruited 81 consecutive patients with HCM examined between January 2012 and April 2013. Data of 76 patients were analyzed after excluding 5 patients whose echocardiographic images were of poor quality. Healthy volunteers (n = 46) served as controls. Both groups underwent comprehensive echocardiographic examination (i.e., Bas-Rotation, AP-Rotation, LVEF, LADs, IVST, LAVi, E/Em, LVMI, advanced LV-twist analysis by speckle tracking echocardiography) and magnetic resonance imaging. Between-group differences were analyzed by independent t test; logistic regression analysis was performed to identify effect factors. No significant differences were found between baseline characteristics of HCM and control groups (all p > 0.05). HCM patients had significantly higher Bas-Rotation, AP-Rotation, LV Twist, LVEF, LADs, IVST, LAVi, E/Em and LVMI than controls (all p < 0.0001) and significantly lower LVDd and E/A (both p < 0.001). Bas-Rotation, AP-Rotation, LV-Twist, LADs, IVST, LAVi, E/Em and LVMI were significantly higher in HCM patients with fibrosis than in those without fibrosis (p < 0.001), but no significant differences in other echocardiographic parameters were found between those with and without fibrosis. Age, Bas-Rotation, AP-Rotation, LV twist, LADs, IVST, LAVi, E/A, E/Em, and LVMI were significant effect factors for fibrosis. AUROC analysis showed that LV twist had high discriminatory power to detect extent of myocardial fibrosis (AUC 0.996, 95 % CI 0.989–1.004, p < 0.001). Left ventricular twist mechanics are associated with the extent of myocardial fibrosis. LV-twist assessment by STE may be clinically useful.
Electronic supplementary material
The online version of this article (doi:10.1007/s10554-014-0509-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s10554-014-0509-6
PMCID: PMC4232740  PMID: 25106760
Hypertrophic cardiomyopathy; Cardiac magnetic resonance; Speckle tracking echocardiography; Myocardial fibrosis
8.  Antibiotic management of complicated intra-abdominal infections in adults: The Asian perspective 
Regional epidemiological data and resistance profiles are essential for selecting appropriate antibiotic therapy for intra-abdominal infections (IAIs). However, such information may not be readily available in many areas of Asia and current international guidelines on antibiotic therapy for IAIs are for Western countries, with the most recent guidance for the Asian region dating from 2007. Therefore, the Asian Consensus Taskforce on Complicated Intra-Abdominal Infections (ACT-cIAI) was convened to develop updated recommendations for antibiotic management of complicated IAIs (cIAIs) in Asia. This review article is based on a thorough literature review of Asian and international publications related to clinical management, epidemiology, microbiology, and bacterial resistance patterns in cIAIs, combined with the expert consensus of the Taskforce members. The microbiological profiles of IAIs in the Asian region are outlined and compared with Western data, and the latest available data on antimicrobial resistance in key pathogens causing IAIs in Asia is presented. From this information, antimicrobial therapies suitable for treating cIAIs in patients in Asian settings are proposed in the hope that guidance relevant to Asian practices will prove beneficial to local physicians managing IAIs.
Highlights
•We propose updated recommendations for antibiotic management of cIAIs in Asia.•Literature from Asian and international publications are reviewed and compared.•Antimicrobial resistance in key pathogens causing IAIs in Asia is presented.•Expert consensus of the Asian Taskforce members is also included.
doi:10.1016/j.amsu.2014.06.005
PMCID: PMC4284456  PMID: 25568794
Epidemiology; Intra-abdominal infection; Antibiotics; Asia; Microbiology; Resistance
9.  SREBP2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility 
Circulation  2013;128(6):632-642.
Background
The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells (ECs) via sterol regulatory element binding protein 2 (SREBP2).
Methods and Results
Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in ECs. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 (NOX2) and NLRP3. Consistently, SREBP2, NOX2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, EC-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.
Conclusions
Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographic distribution of atherosclerotic lesions.
doi:10.1161/CIRCULATIONAHA.113.002714
PMCID: PMC3798034  PMID: 23838163
shear stress; endothelial cell; atherosclerosis; inflammasome; SREBP
10.  Immunogenicity and safety of three 2010–2011 seasonal trivalent influenza vaccines in Chinese toddlers, children and older adults 
Human Vaccines & Immunotherapeutics  2013;9(8):1725-1734.
The 2009 influenza A(H1N1) pandemic strain was for the first time included in the 2010–2011 seasonal trivalent influenza vaccine (TIV). We conducted a double-blind, randomized trial in Chinese population to assess the immunogenicity and safety of the 2010–2011 TIV manufactured by GlaxoSmithKline and compared it with the counterpart vaccines manufactured by Sanofi Pasteur and Sinovac Biotech. Healthy toddlers (6–36 mo), children (6–12 y) and older adults (≥60 y) with 300 participants in each age group were enrolled to randomly receive two doses (toddlers, 28 d apart) or one dose (children and older adults). The immunogenicity was assessed by hemagglutination-inhibition (HI) assay. The solicited injection-site and systemic adverse events (AEs) were collected within 7 d after vaccination. All the three TIVs were well-tolerated with 15.1% of participants reporting AEs, most of which were mild. No serious AEs and unusual AEs were reported. Fever and pain were the most common systemic and injection-site AEs, respectively. The three TIVs showed good immunogenicity. The seroprotection rates against both H1N1 and H3N2 strains were more than 87% in toddlers after two doses and more than 95% in children and more than 86% in older adults after one dose. The seroprotection rates against B strain were 68–71% in toddlers after two doses, 70–74% in children and 69–72% in older adults after one dose. In conclusion, the three 2010–2011 TIVs had good immunogenicity and safety in Chinese toddlers, children and older adults and were generally comparable in immunogenicity and reactogenicity.
doi:10.4161/hv.24832
PMCID: PMC3906273  PMID: 23896581
influenza; vaccine; seasonal trivalent influenza vaccine; influenza A (H1N1); immunogenicity; safety
11.  Behavior of the Edible Seaweed Sargassum fusiforme to Copper Pollution: Short-Term Acclimation and Long-Term Adaptation 
PLoS ONE  2014;9(7):e101960.
Aquatic agriculture in heavy-metal-polluted coastal areas faces major problems due to heavy metal transfer into aquatic organisms, leading to various unexpected changes in nutrition and primary and/or secondary metabolism. In the present study, the dual role of heavy metal copper (Cu) played in the metabolism of photosynthetic organism, the edible seaweed Sargassum fusiforme, was evaluated by characterization of biochemical and metabolic responses using both 1H NMR and GC-MS techniques under acute (47 µM, 1 day) and chronic stress (8 µM, 7 days). Consequently, photosynthesis may be seriously inhibited by acute Cu exposure, resulting in decreasing levels of carbohydrates, e.g., mannitol, the main products of photosynthesis. Ascorbate may play important roles in the antioxidant system, whose content was much more seriously decreased under acute than that under chronic Cu stress. Overall, these results showed differential toxicological responses on metabolite profiles of S. fusiforme subjected to acute and chronic Cu exposures that allowed assessment of impact of Cu on marine organisms.
doi:10.1371/journal.pone.0101960
PMCID: PMC4098904  PMID: 25025229
12.  Content determination of the flavonoids in the different parts and different species of Abelmoschus esculentus L. by reversed phase-high performance liquid chromatograph and colorimetric method 
Pharmacognosy Magazine  2014;10(39):278-284.
Background:
This research will establish the ultraviolet colorimetric method to determine the total flavonoid content in different species and different parts of Abelmoschus esculentus L.
Materials and Methods:
We establish the reversed-phase high-performance liquid chromatograph (RP-HPLC) method to determine the content of the three flavonoid glycosides in different species and different parts of the A. esculentus. Adopt the NaNO2-Al (NO3)3-NaOH colorimetric method to determine the total flavonoid content; at the same time, adopt the RP-HPLC method to determine the contents of the three flavonoid glycosides. Using the methods of ultraviolet colorimetry and RP-HPLC, we determined and analyzed the total flavonoid content and the content of the three flavonoid glycosides in different species and different parts of A. esculentus.
Results:
There are great distribution differences of the total flavonoids and the three flavonoid glycosides in different species and parts of A. esculentus. Among them, the content of the effective constituents in the flower is relatively high, next is in the fruit. In the different species of A. esculentus, the content of the flavonoids of finger relatively high. The HPLC method established in this research is simple and convenient and its results are accurate and reliable. In addition, it has a very good repeatability.
Conclusion:
The results provided the reference data for the medicinal use of A. esculentus and it can be used in quality analyzing of its effective constituents.
doi:10.4103/0973-1296.137368
PMCID: PMC4159921  PMID: 25210315
Abelmoschus esculentus; flavonoid glycoside; reversed-phase high-performance liquid chromatograph; total flavonoids
13.  Expression of Recombinant Human FADD, Preparation of Its Polyclonal Antiserum and the Application in Immunoassays 
The wild-type human Fas-associated death domain (FADD) protein was expressed as a His-tag fusion protein in Escherichia coli. Recombinant FADD proteins were purified under the denatured condition. After denatured protein purification, it was refolded and obtained at a yield of about 23 mg/L. Purified FADD exhibited as a homogenous band corresponding to the molecular weight of 31 kDa. Immunization of rabbits against the refolded FADD protein was allowed the production of high titre polyclonal antiserum. This new polyclonal antibody could recognize recombinant FADD protein in Western blot. Immunoreactivity was also observed in immunofluorescence assay. The low cost polyclonal antiserum was applicable to extensive detection of FADD in various immunoassays.
doi:10.1038/cmi.2008.59
PMCID: PMC4073656  PMID: 19118514
FADD; His-tag fusion protein; polyclonal antibody; immunofluorescence assay
14.  Molecular Epidemiology and Antimicrobial Resistance of Methicillin-Resistant Staphylococcus aureus Bloodstream Isolates in Taiwan, 2010 
PLoS ONE  2014;9(6):e101184.
The information of molecular characteristics and antimicrobial susceptibility pattern of methicillin-resistant Staphylococcus aureus (MRSA) is essential for control and treatment of diseases caused by this medically important pathogen. A total of 577 clinical MRSA bloodstream isolates from six major hospitals in Taiwan were determined for molecular types, carriage of Panton-Valentine leukocidin (PVL) and sasX genes and susceptibilities to 9 non-beta-lactam antimicrobial agents. A total of 17 genotypes were identified in 577 strains by pulsotyping. Five major pulsotypes, which included type A (26.2%, belonging to sequence type (ST) 239, carrying type III staphylococcal chromosomal cassette mec (SCCmec), type F (18.9%, ST5-SCCmecII), type C (18.5%, ST59-SCCmecIV), type B (12.0%, ST239-SCCmecIII) and type D (10.9%, ST59-SCCmecVT/IV), prevailed in each of the six sampled hospitals. PVL and sasX genes were respectively carried by ST59-type D strains and ST239 strains with high frequencies (93.7% and 99.1%, respectively) but rarely detected in strains of other genotypes. Isolates of different genotypes and from different hospitals exhibited distinct antibiograms. Multi-resistance to ≥3 non-beta-lactams was more common in ST239 isolates (100%) than in ST5 isolates (97.2%, P = 0.0347) and ST59 isolates (8.2%, P<0.0001). Multivariate analysis further indicated that the genotype, but not the hospital, was an independent factor associated with muti-resistance of the MRSA strains. In conclusion, five common MRSA clones with distinct antibiograms prevailed in the major hospitals in Taiwan in 2010. The antimicrobial susceptibility pattern of invasive MRSA was mainly determined by the clonal distribution.
doi:10.1371/journal.pone.0101184
PMCID: PMC4072725  PMID: 24967822
15.  Genotoxic Klebsiella pneumoniae in Taiwan 
PLoS ONE  2014;9(5):e96292.
Background
Colibactin is a nonribosomal peptide-polyketide synthesized by multi-enzyme complexes encoded by the pks gene cluster. Colibactin-producing Escherichia coli have been demonstrated to induce host DNA damage and promote colorectal cancer (CRC) development. In Taiwan, the occurrence of pyogenic liver abscess (PLA) has been suggested to correlate with an increasing risk of CRC, and Klebsiella pneumoniae is the predominant PLA pathogen in Taiwan
Methodology/Principal Findings
At the asn tRNA loci of the newly sequenced K. pneumoniae 1084 genome, we identified a 208-kb genomic island, KPHPI208, of which a module identical to the E. coli pks colibactin gene cluster was recognized. KPHPI208 consists of eight modules, including the colibactin module and the modules predicted to be involved in integration, conjugation, yersiniabactin production, microcin production, and unknown functions. Transient infection of BALB/c normal liver cells with K. pneumoniae 1084 increased the phosphorylation of histone H2AX, indicating the induction of host DNA damage. Colibactin was required for the genotoxicity of K. pneumoniae 1084, as it was diminished by deletion of clbA gene and restored to the wild type level by trans-complementation with a clbA coding plasmid. Besides, BALB/c mice infected with K. pneumoniae 1084 exhibited enhanced DNA damage in the liver parenchymal cells when compared to the isogenic clbA deletion mutant. By PCR detection, the prevalence of pks-positive K. pneumoniae in Taiwan is 25.6%, which is higher than that reported in Europe (3.5%), and is significantly correlated with K1 type, which predominantly accounted for PLA in Taiwan.
Conclusions
Our knowledge regarding how bacteria contribute to carcinogenesis has just begun. The identification of genotoxic K. pneumoniae and its genetic components will facilitate future studies to elucidate the molecular basis underlying the link between K. pneumoniae, PLA, and CRC.
doi:10.1371/journal.pone.0096292
PMCID: PMC4031060  PMID: 24852749
16.  Immunization of Rabbits with Highly Purified, Soluble, Trimeric Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Induces a Vigorous B Cell Response and Broadly Cross-Reactive Neutralization 
PLoS ONE  2014;9(5):e98060.
Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env) in an adjuvant containing monophosphoryl lipid A (MPL) and QS21 (AS02A). Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4), gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L), also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D)) or monomer (gp140-L(M)). Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN) human monoclonal antibodies (mAbs) similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction.
doi:10.1371/journal.pone.0098060
PMCID: PMC4028264  PMID: 24846288
17.  Seroepidemiology of Toxocara Canis infection among primary schoolchildren in the capital area of the Republic of the Marshall Islands 
BMC Infectious Diseases  2014;14:261.
Background
Toxocariasis, which is predominantly caused by Toxocara canis (T. canis) infection, is a common zoonotic parasitosis worldwide; however, the status of toxocariasis endemicity in the Republic of the Marshall Islands (RMI) remains unknown.
Methods
A seroepidemiological investigation was conducted among 166 primary school children (PSC) aged 7–12 years from the capital area of the RMI. Western blots based the excretory-secretory antigens of larval T. canis (TcES) was employed, and children were considered seropositive if their serum reacted with TcES when diluted at a titer of 1:64. Information regarding demographic characteristics of and environmental risk factors affecting these children was collected using a structured questionnaire. A logistic regression model was applied to conduct a multivariate analysis.
Results
The overall seropositive rate of T. canis infection was 86.75% (144/166). In the univariate analysis, PSC who exhibited a history of feeding dogs at home (OR = 5.52, 95% CI = 1.15–26.61, p = 0.02) and whose parents were employed as nonskilled workers (OR = 2.86, 95% CI = 1.08–7.60, p = 0.03) demonstrated a statistically elevated risk of contracting T. canis infections. Cleaning dog huts with gloves might prevent infection, but yielded nonsignificant effects. The multivariate analysis indicated that parental occupation was the critical risk factor in this study because its effect remained significant after adjusting for other variables; by contrast, the effect of dog feeding became nonsignificant because of other potential confounding factors. No associations were observed among gender, age, consuming raw meat or vegetables, drinking unboiled water, cleaning dog huts with gloves, or touching soil.
Conclusions
This is the first serological investigation of T. canis infection among PSC in the RMI. The high seroprevalence indicates the commonness of T. canis transmission and possible human risk. The fundamental information that the present study provides regarding T. canis epidemiology can facilitate developing strategies for disease prevention and control.
doi:10.1186/1471-2334-14-261
PMCID: PMC4024650  PMID: 24886153
Toxocara canis (T. canis); Western blotting; Primary school children (PSC); Republic of the marshall islands (RMI)
18.  Structural insights into H+-coupled multidrug extrusion by a MATE transporter 
Nature structural & molecular biology  2013;20(11):10.1038/nsmb.2687.
Multidrug and toxic compound extrusion (MATE) transporters contribute to multidrug resistance by coupling the efflux of drugs to the influx of Na+ or H+. Known structures of Na+-coupled, extracellular-facing MATE transporters from the NorM subfamily revealed twelve membrane-spanning segments related by a quasi-twofold rotational symmetry and a multidrug-binding cavity situated near the membrane surface. Here we report the crystal structure of an H+-coupled MATE transporter from Bacillus halodurans and the DinF subfamily at 3.2 Å-resolution, unveiling a surprisingly asymmetric arrangement of twelve transmembrane helices. We also identified a membrane-embedded substrate-binding chamber by combining crystallographic and biochemical analyses. Our studies further suggested a direct competition between H+ and substrate during DinF-mediated transport, and how a MATE transporter alternates between its extracellular- and intracellular-facing conformations to propel multidrug extrusion. Collectively, our results demonstrated hitherto unrecognized mechanistic diversity among MATE transporters.
doi:10.1038/nsmb.2687
PMCID: PMC3825517  PMID: 24141706
19.  A General Synthetic Approach to Functionalized Dihydrooxepines 
Organic letters  2013;15(8):1994-1997.
A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer–Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate.
doi:10.1021/ol4006689
PMCID: PMC3653422  PMID: 23550898
20.  Excision of viral reprogramming cassettes by Cre protein transduction enables rapid, robust and efficient derivation of transgene-free human induced pluripotent stem cells 
Integrating viruses represent robust tools for cellular reprogramming; however, the presence of viral transgenes in induced pluripotent stem cells (iPSCs) is deleterious because it holds the risk of insertional mutagenesis leading to malignant transformation. Here, we combine the robustness of lentiviral reprogramming with the efficacy of Cre recombinase protein transduction to derive iPSCs devoid of transgenes. By genome-wide analysis and targeted differentiation towards the cardiomyocyte lineage, we show that transgene-free iPSCs are superior to iPSCs before Cre transduction. Our study provides a simple, rapid and robust protocol for the generation of clinical-grade iPSCs suitable for disease modeling, tissue engineering and cell replacement therapies.
doi:10.1186/scrt435
PMCID: PMC4055111  PMID: 24713299
21.  Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor 
Nature  2013;500(7464):589-592.
SUMMARY
Co-development of the cardiovascular and pulmonary systems is a recent evolutionary adaption to terrestrial life that couples cardiac output with the gas exchange function of the lung 1. In this report, we show that the pulmonary vasculature develops even in the absence of lung development. We have identified a population of multi-potent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2/Gli1/Isl1. We show that CPPs arise from cardiac progenitors prior to lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Together, these studies identify a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung co-development that is required for adaptation to terrestrial existence.
doi:10.1038/nature12358
PMCID: PMC3758448  PMID: 23873040
22.  Development and regeneration of Sox2+ endoderm progenitors is regulated by a HDAC1/2-Bmp4/Rb1 regulatory pathway 
Developmental cell  2013;24(4):345-358.
The mechanisms that govern the maintenance and differentiation of tissue specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by de-repression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue specific progenitor activity during development and regeneration.
doi:10.1016/j.devcel.2013.01.012
PMCID: PMC3586315  PMID: 23449471
23.  Saccharide-mediated antagonistic effects of bark beetle fungal associates on larvae 
Biology Letters  2013;9(1):20120787.
Bark beetles are among the most destructive of pine forest pests and they form close symbiotic relationships with ophiostomatoid fungi. Although some fungi are considered to be mutualistic symbionts of bark beetles with respect to the supply of nutrients, detrimental effects of fungal symbionts on larval growth have also been frequently reported. The mechanisms of such antagonistic effects are hypothesized to be a decrease in nutritional resources caused by competition for saccharides by the fungi. Here, we provide experimental evidence that three beetle-associated fungi modify the nutritional content of an artificial phloem diet, leading to a detrimental effect on the growth of Dendroctonus valens larvae. When larvae were fed a diet of pine phloem in agar medium colonized with any of these fungi, feeding activity was not affected but weight significantly decreased. Additional analysis showed that fungi depleted the fructose and glucose concentrations in the phloem media. Furthermore, these detrimental effects were neutralized by supplementing the media with fructose or glucose, suggesting that fungi may affect larval growth by modifying diet saccharide contents. These data indicate that fungus-induced nutritional changes in bark beetle diet can affect larval growth, and that the mechanism involves fungus-induced saccharide depletion from the larval diet.
doi:10.1098/rsbl.2012.0787
PMCID: PMC3565487  PMID: 23193043
bark beetle; symbiosis; ophiostomatoid; antagonism; saccharide; nutrition
24.  Effects of Multimicronutrient Supplementation during Pregnancy on Postnatal Growth of Children under 5 Years of Age: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(2):e88496.
Background
The beneficial effect of antenatal multiple micronutrients supplementation on infant birth outcomes has been proposed by previous meta-analyses. However, their benefits on postnatal health of children have not been summarized. A meta-analysis of randomized controlled trials was conducted to evaluate the effect of maternal multimicronutrient supplementation on postnatal growth of children under 5 years of age.
Methods
We searched both published and ongoing trials through the PubMed, EMBASE, CENTRAL (OVID platform), Web of Science, BIOSIS Previews, Chinese Science Citation Database, Scopus, ProQuest, ClinicalTrials.gov, Chinese Biomedical Database, and WANFANG database for randomized controlled trials. Reference lists of included studies and relevant reviews were also reviewed for eligible studies. Standard mean difference (SMD) was employed as the index for continuous variables by using fixed effects models. Trend analysis by visual inspection was applied to evaluate the change of mean difference of weight and height between the groups over time.
Results
Nine trials (12 titles) from nine different countries were retrieved for analysis. Pooled results showed that antenatal multimicronutrient supplementation increased child head circumference (SMD = 0.08, 95% CI: 0.00–0.15) compared with supplementation with two micronutrient or less. No evidence was found for the benefits of antenatal multimicronutrient supplementation on weight (P = 0.11), height (P = 0.66), weight-for-age z scores (WAZ) (P = 0.34), height-for-age z scores (HAZ) (P = 0.81) and weight-for-height z scores (WHZ) (P = 0.22). A positive effect was found on chest circumference based on two included studies.
Conclusions
Antenatal multimicronutrient supplementation has a significant positive effect on head circumference of children under 5 years. No impact of the supplementation was found on weight, height, WAZ, HAZ and WHZ.
doi:10.1371/journal.pone.0088496
PMCID: PMC3930526  PMID: 24586335
25.  Characterization of a Novel Glucokinase Activator in Rat and Mouse Models 
PLoS ONE  2014;9(2):e88431.
Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
doi:10.1371/journal.pone.0088431
PMCID: PMC3922816  PMID: 24533087

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