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1.  Solution-processed small-molecule solar cells: breaking the 10% power conversion efficiency 
Scientific Reports  2013;3:3356.
A two-dimensional conjugated small molecule (SMPV1) was designed and synthesized for high performance solution-processed organic solar cells. This study explores the photovoltaic properties of this molecule as a donor, with a fullerene derivative as an acceptor, using solution processing in single junction and double junction tandem solar cells. The single junction solar cells based on SMPV1 exhibited a certified power conversion efficiency of 8.02% under AM 1.5 G irradiation (100 mW cm−2). A homo-tandem solar cell based on SMPV1 was constructed with a novel interlayer (or tunnel junction) consisting of bilayer conjugated polyelectrolyte, demonstrating an unprecedented PCE of 10.1%. These results strongly suggest solution-processed small molecular materials are excellent candidates for organic solar cells.
doi:10.1038/srep03356
PMCID: PMC3842540  PMID: 24285006
2.  Crystal Structure of the Receptor-Binding Domain from Newly Emerged Middle East Respiratory Syndrome Coronavirus 
Journal of Virology  2013;87(19):10777-10783.
The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) has infected at least 77 people, with a fatality rate of more than 50%. Alarmingly, the virus demonstrates the capability of human-to-human transmission, raising the possibility of global spread and endangering world health and economy. Here we have identified the receptor-binding domain (RBD) from the MERS-CoV spike protein and determined its crystal structure. This study also presents a structural comparison of MERS-CoV RBD with other coronavirus RBDs, successfully positioning MERS-CoV on the landscape of coronavirus evolution and providing insights into receptor binding by MERS-CoV. Furthermore, we found that MERS-CoV RBD functions as an effective entry inhibitor of MERS-CoV. The identified MERS-CoV RBD may also serve as a potential candidate for MERS-CoV subunit vaccines. Overall, this study enhances our understanding of the evolution of coronavirus RBDs, provides insights into receptor recognition by MERS-CoV, and may help control the transmission of MERS-CoV in humans.
doi:10.1128/JVI.01756-13
PMCID: PMC3807420  PMID: 23903833
3.  HIV-, HCV-, and Co-Infections and Associated Risk Factors among Drug Users in Southwestern China: A Township-Level Ecological Study Incorporating Spatial Regression 
PLoS ONE  2014;9(3):e93157.
Background
The human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are major public health problems. Many studies have been performed to investigate the association between demographic and behavioral factors and HIV or HCV infection. However, some of the results of these studies have been in conflict.
Methodology/Principal Findings
The data of all entrants in the 11 national methadone clinics in the Yi Autonomous Prefecture from March 2004 to December 2012 were collected from the national database. Several spatial regression models were used to analyze specific community characteristics associated with the prevalence of HIV and HCV infection at the township level. The study enrolled 6,417 adult patients. The prevalence of HIV infection, HCV infection and co-infection was 25.4%, 30.9%, and 11.0%, respectively. Prevalence exhibited stark geographical variations in the area studied. The four regression models showed Yi ethnicity to be associated with both the prevalence of HIV and of HIV/HCV co-infection. The male drug users in some northwestern counties had greater odds of being infected with HIV than female drug users, but the opposite was observed in some eastern counties. The ‘being in drug rehabilitation variable was found to be positively associated with prevalence of HCV infection in some southern townships, however, it was found to be negatively associated with it in some northern townships.
Conclusions/Significance
The spatial modeling creates better representations of data such that public health interventions must focus on areas with high frequency of HIV/HCV to prevent further transmission of both HIV and HCV.
doi:10.1371/journal.pone.0093157
PMCID: PMC3970964  PMID: 24687006
4.  Nanoparticle-assisted high photoconductive gain in polymer/fullerene matrix 
Nature nanotechnology  2008;3(9):543-547.
Polymer/inorganic nanocrystal composites1–10 offer an attractive means to combine the merits of organic and inorganic materials into novel electronic and photonic systems. However, many applications of these composites are limited by the solubility11 and distribution of nanocrystals (NCs) in polymer matrices. Here, a high photoconductive gain has been achieved by blending cadmium telluride (CdTe) nanoparticles (NPs) into a polymer/fullerene matrix followed by a solvent annealing12 process. The NP surface capping ligand, N-phenyl-N’-methyldithiocarbamate, renders the NPs highly soluble in the polymer blend thereby enabling high nanocrystal loadings. An external quantum efficiency (EQE) as high as ~8000% (at 350nm) is reached at −4.5V. Hole-dominant devices coupled with AFM images are studied to uncover the probable mechanism. We observe a higher concentration of CdTe NPs is located near the cathode/polymer interface. These NPs with trapped electrons assist hole injection into the polymer under reverse bias, which contributes to greater than 100% EQE.
doi:10.1038/nnano.2008.206
PMCID: PMC3966304  PMID: 18772915
CdTe; nanoparticles; quantum dots; polymer photodetector; photoconductive gain; nanocrystal composites
5.  The Relationship between Seven Common Polymorphisms from Five DNA Repair Genes and the Risk for Breast Cancer in Northern Chinese Women 
PLoS ONE  2014;9(3):e92083.
Background
Converging evidence supports the central role of DNA damage in progression to breast cancer. We therefore in this study aimed to assess the potential interactions of seven common polymorphisms from five DNA repair genes (XRCC1, XRCC2, XRCC3, XPA and APEX1) in association with breast cancer among Han Chinese women.
Methodology/Principal Findings
This was a case-control study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched cancer-free controls. The polymerase chain reaction - ligase detection reaction method was used to determine genotypes. All seven polymorphisms were in accordance with Hardy-Weinberg equilibrium in controls. Differences in the genotypes and alleles of XRCC1 gene rs25487 and XPA gene rs1800975 were statistically significant between patients and controls, even after the Bonferroni correction (P<0.05/7). Accordingly, the risk for breast cancer was remarkably increased for rs25487 (OR = 1.28; 95% CI: 1.07–1.51; P = 0.006), but decreased for rs1800975 (OR = 0.77; 95% CI: 0.67–0.90; P = 0.001) under an additive model at a Bonferroni corrected alpha of 0.05/7. Allele combination analysis showed higher frequencies of the most common combination C-G-G-C-G-G-G (alleles in order of rs1799782, rs25487, rs3218536, rs861539, rs1800975, rs1760944 and rs1130409) in controls than in patients (PSim = 0.002). In further interaction analysis, two-locus model including rs1800975 and rs25487 was deemed as the overall best model with the maximal testing accuracy of 0.654 and the cross-validation consistency of 10 out of 10 (P = 0.001).
Conclusion
Our findings provide clear evidence that XRCC1 gene rs25487 and XPA gene rs1800975 might exert both independent and interactive effects on the development of breast cancer among northern Chinese women.
doi:10.1371/journal.pone.0092083
PMCID: PMC3958445  PMID: 24642895
6.  Effects of THAP11 on Erythroid Differentiation and Megakaryocytic Differentiation of K562 Cells 
PLoS ONE  2014;9(3):e91557.
Hematopoiesis is a complex process regulated by sets of transcription factors in a stage-specific and context-dependent manner. THAP11 is a transcription factor involved in cell growth, ES cell pluripotency, and embryogenesis. Here we showed that THAP11 was down-regulated during erythroid differentiation but up-regulated during megakaryocytic differentiation of cord blood CD34+ cells. Overexpression of THAP11 in K562 cells inhibited the erythroid differentiation induced by hemin with decreased numbers of benzidine-positive cells and decreased mRNA levels of α-globin (HBA) and glycophorin A (GPA), and knockdown of THAP11 enhanced the erythroid differentiation. Conversely, THAP11 overexpression accelerated the megakaryocytic differentiation induced by phorbol myristate acetate (PMA) with increased percentage of CD41+ cells, increased numbers of 4N cells, and elevated CD61 mRNA levels, and THAP11 knockdown attenuated the megakaryocytic differentiation. The expression levels of transcription factors such as c-Myc, c-Myb, GATA-2, and Fli1 were changed by THAP11 overexpression. In this way, our results suggested that THAP11 reversibly regulated erythroid and megakaryocytic differentiation.
doi:10.1371/journal.pone.0091557
PMCID: PMC3956667  PMID: 24637716
7.  P-Selectin-Mediated Platelet Adhesion Promotes the Metastasis of Murine Melanoma Cells 
PLoS ONE  2014;9(3):e91320.
Studies have indicated that the aggregation of activated platelets with cancer cells facilitates tumor metastasis; the adhesion molecule P-selectin may be an important mediator of this process, but the detailed mechanism is unclear. In the current study, we established a B16F10 (B16) cell metastatic model in P-selectin knockout (P-sel−/−) mice to determine the effect of P-selectin-mediated platelet adhesion on metastasis. Compared with C57 mice, P-sel−/− mice developed fewer metastatic foci, and cell proliferation within the metastatic tumors was inhibited by P-selectin deficiency. The platelet refusion assay demonstrated that mice with P-sel−/− platelets developed fewer lung metastatic foci (P<0.01) with a lower microvascular density (MVD) than mice with wild-type platelets. A co-culture model of platelets and B16 cells was utilized to determine the difference in VEGF concentration in the supernatants. The results demonstrated that the supernatant from the P-sel−/− platelet/B16 co-culture had a lower concentration of VEGF. Therefore, our findings indicated that P-selectin deficiency inhibited the metastasis of B16 cells and that wild-type platelet refusion reversed this inhibition. The P-selectin-mediated interaction between platelets and B16 cells promoted angiogenesis by up-regulating VEGF.
doi:10.1371/journal.pone.0091320
PMCID: PMC3954694  PMID: 24632801
8.  Chemoprevention of dietary digitoflavone on colitis-associated colon tumorigenesis through inducing Nrf2 signaling pathway and inhibition of inflammation 
Molecular Cancer  2014;13:48.
Background
Nuclear factor-erythroid 2-related factor 2 (Nrf2) has emerged as a novel target for the prevention of colorectal cancer (CRC). Many chemopreventive compounds associated with Nrf2 activation are effective in preclinical systems and many on-going clinical trials are showing promising findings. In present study we evaluated the cytoprotective effect and chemopreventive properties of dietary digitoflavone.
Method
A cell based Antioxidant Response Element (ARE)-driven luciferase reporter system was applied to screen potential Nrf2 activators. Activation of Nrf2 by digitoflavone was confirmed through mRNA, protein and GSH level assay in Caco-2 cell line. The cytoprotective effect of digitoflavone was evaluated in H2O2-induced oxidative stress model and further signaling pathways analysis was used to determine the target of digitoflavone induced Nrf2 activation. An AOM-DSS induced colorectal cancer model was used to assess the chemopreventive effect of digitoflavone.
Result
Micromolarity (10 μM) level of digitoflavone increased Nrf2 expressing, nuclear translocation and expression of downstream phase II antioxidant enzymes. Furthermore, digitoflavone decreased H2O2-induced oxidative stress and cell death via p38 MAPK-Nrf2/ARE pathway. In vivo study, 50 mg/kg digitoflavone significantly reduced AOM-DSS induced tumor incidence, number and size.
Conclusion
These observations suggest that digitoflavone is a novel Nrf2 pathway activator, and protects against oxidative stress-induced cell injury. The results of the present study add further evidence of the molecular mechanisms that allow digitoflavone to exert protective effects and reaffirm its potential role as a chemopreventive agent in colorectal carcinogenesis.
doi:10.1186/1476-4598-13-48
PMCID: PMC3973863  PMID: 24602443
Digitoflavone; Luteolin; Reactive oxygen species (ROS); Nrf2; p38 MAPK; Chemoprevention
9.  A Topic Clustering Approach to Finding Similar Questions from Large Question and Answer Archives 
PLoS ONE  2014;9(3):e71511.
With the blooming of Web 2.0, Community Question Answering (CQA) services such as Yahoo! Answers (http://answers.yahoo.com), WikiAnswer (http://wiki.answers.com), and Baidu Zhidao (http://zhidao.baidu.com), etc., have emerged as alternatives for knowledge and information acquisition. Over time, a large number of question and answer (Q&A) pairs with high quality devoted by human intelligence have been accumulated as a comprehensive knowledge base. Unlike the search engines, which return long lists of results, searching in the CQA services can obtain the correct answers to the question queries by automatically finding similar questions that have already been answered by other users. Hence, it greatly improves the efficiency of the online information retrieval. However, given a question query, finding the similar and well-answered questions is a non-trivial task. The main challenge is the word mismatch between question query (query) and candidate question for retrieval (question). To investigate this problem, in this study, we capture the word semantic similarity between query and question by introducing the topic modeling approach. We then propose an unsupervised machine-learning approach to finding similar questions on CQA Q&A archives. The experimental results show that our proposed approach significantly outperforms the state-of-the-art methods.
doi:10.1371/journal.pone.0071511
PMCID: PMC3942313  PMID: 24595052
10.  Dynamic Characterization of the CT Angiographic ‘Spot Sign’ 
PLoS ONE  2014;9(3):e90431.
Background and purpose
Standard (static) CT angiography is used to identify the intracerebral hemorrhage (ICH) spot sign. We used dynamic CT-angiography to describe spot sign characteristics and measurement parameters over 60-seconds of image acquisition.
Methods
We prospectively identified consecutive patients presenting with acute ICH within 4.5 hours of symptom onset, and collected whole brain dynamic CT-angiography (dCTA). Spot parameters (earliest appearance, duration, maximum Hounsfield unit (HU), time to maximum HU, time to spot diagnostic definition, spot volume and hematoma volumes) were measured using volumetric analysis software.
Result
We enrolled 34 patients: three were excluded due to secondary causes of ICH. Of the remaining 31 patients there were 18 females (58%) with median age 70 (range 47–86) and baseline hematoma volume 33 ml (range 0.7–103 ml). Positive dCTA spot sign was present in 13 patients (42%) visualized as an expanding 3-dimensional structure temporally evolving its morphology over the scan period. Median time to spot appearance was 21 s (range 15–35 seconds). This method allowed tracking of spots evolution until the end of venous phase (active extravasation) with median duration of 39 s (range 25–45 seconds). The average density and time to maximum density was 204HU and 30.8 s (range 23–31 s) respectively. Median time to spot diagnosis was 20.8 s using either 100 or 120HU definitions.
Conclusion
Dynamic CTA allows a 3-dimensional assessment of spot sign formation during acute ICH, and captured higher spot sign prevalence than previously reported. This is the first study to describe and quantify spot sign characteristics using dCTA; these can be used in ongoing and upcoming ICH studies.
doi:10.1371/journal.pone.0090431
PMCID: PMC3940908  PMID: 24594897
11.  A One-Step, Solvothermal Reduction Method for Producing Reduced Graphene Oxide Dispersions in Organic Solvents 
ACS nano  2010;4(7):3845-3852.
Refluxing graphene oxide (GO) in N-methyl-2-pyrrolidinone (NMP) results in deoxygenation and reduction to yield a stable colloidal dispersion. The solvothermal reduction is accompanied by a color change from light brown to black. Atomic force microscopy (AFM) and scanning electron microscopy (SEM) images of the product confirm the presence of single sheets of the solvothermally reduced graphene oxide (SRGO). X-ray photoelectron spectroscopy (XPS) of SRGO indicates a significant increase in intensity of the C=C bond character, while the oxygen content decreases markedly after the reduction is complete. X-ray diffraction analysis of SRGO shows a single broad peak at 26.24° 2θ (3.4 Å), confirming the presence of graphitic stacking of reduced sheets. SRGO sheets are redispersible in a variety of organic solvents, which may hold promise as an acceptor material for bulk heterojunction photovoltaic cells, or electromagnetic interference shielding applications.
doi:10.1021/nn100511a
PMCID: PMC3939021  PMID: 20586422
graphene; graphite oxide; solvothermal; reduced graphene oxide; composite; solar cell; reduction
12.  A methodological, systematic review of evidence-based independent risk factors for surgical site infections after spinal surgery 
European Spine Journal  2012;22(3):605-615.
Objective
To identify the independent risk factors, based on available evidence in the literature, for patients developing surgical site infections (SSI) after spinal surgery.
Methods
Non-interventional studies evaluating the independent risk factors for patients developing SSI following spinal surgery were searched in Medline, Embase, Sciencedirect and OVID. The quality of the included studies was assessed by a modified quality assessment tool that had been previously designed for observational studies. The effects of studies were combined with the study quality score using a best-evidence synthesis model.
Results
Thirty-six observational studies involving 2,439 patients with SSI after spinal surgery were identified. The included studies covered a wide range of indications and surgical procedures. These articles were published between 1998 and 2012. According to the quality assessment criteria for included studies, 15 studies were deemed to be high-quality studies, 5 were moderate-quality studies, and 16 were low-quality studies. A total of 46 independent factors were evaluated for risk of SSI. There was strong evidence for six factors, including obesity/BMI, longer operation times, diabetes, smoking, history of previous SSI and type of surgical procedure. We also identified 8 moderate-evidence, 31 limited-evidence and 1 conflicting-evidence factors.
Conclusion
Although there is no conclusive evidence for why postoperative SSI occurs, these data provide evidence to guide clinicians in admitting patients who will have spinal operations and to choose an optimal prophylactic strategy. Further research is still required to evaluate the effects of these above risk factors.
doi:10.1007/s00586-012-2514-6
PMCID: PMC3585628  PMID: 23001381
Surgical site infection; Spinal surgery; Postoperative infection; Risk factors; Systematic review
13.  Molecular basis of host specificity in human pathogenic bacteria 
Pathogenic bacteria display various levels of host specificity or tropism. While many bacteria can infect a wide range of hosts, certain bacteria have strict host selectivity for humans as obligate human pathogens. Understanding the genetic and molecular basis of host specificity in pathogenic bacteria is important for understanding pathogenic mechanisms, developing better animal models and designing new strategies and therapeutics for the control of microbial diseases. The molecular mechanisms of bacterial host specificity are much less understood than those of viral pathogens, in part due to the complexity of the molecular composition and cellular structure of bacterial cells. However, important progress has been made in identifying and characterizing molecular determinants of bacterial host specificity in the last two decades. It is now clear that the host specificity of bacterial pathogens is determined by multiple molecular interactions between the pathogens and their hosts. Furthermore, certain basic principles regarding the host specificity of bacterial pathogens have emerged from the existing literature. This review focuses on selected human pathogenic bacteria and our current understanding of their host specificity.
doi:10.1038/emi.2014.23
PMCID: PMC3974339
host specificity; immune evasion; molecular mechanisms; pathogen–host interactions; pathogenic bacteria; tropism
14.  Polysaccharide-Gold Nanocluster Supramolecular Conjugates as a Versatile Platform for the Targeted Delivery of Anticancer Drugs 
Scientific Reports  2014;4:4164.
Through the high affinity of the β-cyclodextrin (β-CD) cavity for adamantane moieties, novel polysaccharide-gold nanocluster supramolecular conjugates (HACD-AuNPs) were successfully constructed from gold nanoparticles (AuNPs) bearing adamantane moieties and cyclodextrin-grafted hyaluronic acid (HACD). Due to their porous structure, the supramolecular conjugates could serve as a versatile and biocompatible platform for the loading and delivery of various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT), by taking advantage of the controlled association/dissociation of drug molecules from the cavities formed by the HACD skeletons and AuNPs cores as well as by harnessing the efficient targeting of cancer cells by hyaluronic acid. Significantly, the release of anticancer drugs from the drug@HACD-AuNPs system was pH-responsive, with more efficient release occurring under a mildly acidic environment, such as that in a cancer cell. Taking the anticancer drug DOX as an example, cell viability experiments revealed that the DOX@HACD-AuNPs system exhibited similar tumor cell inhibition abilities but lower toxicity than free DOX due to the hyaluronic acid reporter-mediated endocytosis. Therefore, the HACD-AuNPs supramolecular conjugates may possess great potential for the targeted delivery of anticancer drugs.
doi:10.1038/srep04164
PMCID: PMC3933908  PMID: 24566666
15.  Spinal Changes of a Newly Isolated Neuropeptide Endomorphin-2 Concomitant with Vincristine-Induced Allodynia 
PLoS ONE  2014;9(2):e89583.
Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain unclear. There is increasing evidence implicating the involvement of spinal endomorphin-2 (EM2) in neuropathic pain. In this study, we used a vincristine-evoked rat CNP model displaying mechanical allodynia and central sensitization, and observed a significant decrease in the expression of spinal EM2 in CNP. Also, while intrathecal administration of exogenous EM2 attenuated allodynia and central sensitization, the mu-opioid receptor antagonist β-funaltrexamine facilitated these events. We found that the reduction in spinal EM2 was mediated by increased activity of dipeptidylpeptidase IV, possibly as a consequence of chemotherapy-induced oxidative stress. Taken together, our findings suggest that a decrease in spinal EM2 expression causes the loss of endogenous analgesia and leads to enhanced pain sensation in CNP.
doi:10.1371/journal.pone.0089583
PMCID: PMC3933549  PMID: 24586889
16.  NMDA Receptors Subserve Persistent Neuronal Firing During Working Memory In Dorsolateral Prefrontal Cortex 
Neuron  2013;77(4):736-749.
Summary
Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPAR) contributed background depolarization to sustain network firing. In contrast, many Response cells -which likely predominate in rodent PFC- were sensitive to AMPAR blockade and increased firing following systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer’s Disease profoundly impair cognition.
doi:10.1016/j.neuron.2012.12.032
PMCID: PMC3584418  PMID: 23439125
17.  Schistosoma japonicum Egg Specific Protein SjE16.7 Recruits Neutrophils and Induces Inflammatory Hepatic Granuloma Initiation 
Neutrophils are known to play a major role in the egg granulomatous lesions caused by Schistosoma japonicum, but the precise mechanism by which eggs recruit or active neutrophil is unknown. Here we report S. japonicum egg specific EF-hand protein-SjE16.7 is a potent neutrophil recruiter and initiates the egg associated inflammatory granuloma in schistosomiasis. We show that the expression of SjE16.7 at level of both mRNA and protein is restricted to the egg stage. It locates in the miracidium and subshell area of the egg and can be secreted by the egg. The antigenic properties of SjE16.7 strongly suggest a role for SjE16.7 as an egg-derived molecule involved in host-parasite interactions. To study SjE16.7 functions in vivo, we challenged murine air pouch with recombinant SjE16.7. The results showed SjE16.7 trigged more inflammatory cell infiltration than vehicle or control protein. Using peritoneal exudate neutrophils from mice, we found that SjE16.7 significantly induced neutrophil chemotaxis in vitro, and the observed phenotypes were associated with enhanced Rac GTPase activation in SjE16.7 treated cells. Finally, in vivo hepatic granuloma formation model showed SjE16.7 coupled beads recruited more inflammatory cell infiltration than control beads. Our findings suggest SjE16.7 is an important pathogenic factor derived from egg. By recruiting neutrophils and inducing local inflammation, SjE16.7 facilitates eggs to be excreted through gut tissues and also initiates pathology in the liver; therefore SjE16.7 is a possible target for the prevention and treatment of schistosomiasis.
Author Summary
As a neglected disease, schistosomiasis continues to be a significant cause of parasitic morbidity and mortality worldwide. Schistosoma japonicum is one of the major causative agents of human schistosomiasis. Trapped in the liver or intestinal tissue, S. japonicum eggs are the main cause of pathology following infection. They induce vigorous immune responses from the host, which facilitate the passage of the eggs from the tissue to the gut lumen and cause the pathology in liver. In this paper, we described, for the first time, S. japonicum egg specific EF-hand protein-SjE16.7 is a potent neutrophil recruiter and initiates the egg associated inflammatory granuloma in schistosomiasis. This study presents a precise mechanism by which eggs recruit neutrophil and induce inflammatory response. It furthers our understanding of the immunopathogenesis of human schistosomiasis. In addition, it provides a potential target for the prevention and treatment of this globally important parasite.
doi:10.1371/journal.pntd.0002703
PMCID: PMC3923719  PMID: 24551263
18.  Applications and Comparisons of Four Time Series Models in Epidemiological Surveillance Data 
PLoS ONE  2014;9(2):e88075.
Public health surveillance systems provide valuable data for reliable predication of future epidemic events. This paper describes a study that used nine types of infectious disease data collected through a national public health surveillance system in mainland China to evaluate and compare the performances of four time series methods, namely, two decomposition methods (regression and exponential smoothing), autoregressive integrated moving average (ARIMA) and support vector machine (SVM). The data obtained from 2005 to 2011 and in 2012 were used as modeling and forecasting samples, respectively. The performances were evaluated based on three metrics: mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE). The accuracy of the statistical models in forecasting future epidemic disease proved their effectiveness in epidemiological surveillance. Although the comparisons found that no single method is completely superior to the others, the present study indeed highlighted that the SVMs outperforms the ARIMA model and decomposition methods in most cases.
doi:10.1371/journal.pone.0088075
PMCID: PMC3914930  PMID: 24505382
19.  Clinical implications of high NQO1 expression in breast cancers 
Background
NAD (P) H: quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing enzyme that detoxifies chemical stressors and antioxidants, providing cytoprotection in normal tissues. However, high-level expression of NQO1 has been correlated with numerous human malignancies, suggesting a role in carcinogenesis and tumor progression. This study aimed to explore the clinicopathological significance of NQO1 and as a prognostic determinant in breast cancer.
Methods
A total of 176 breast cancer patients with strict follow-up, 45 ductal carcinoma in situ (DCIS), 22 hyperplasia and 52 adjacent non-tumor breast tissues were selected for immunohistochemical staining of NQO1 protein. Immunofluorescence staining was also performed to detect the subcellular localization of NQO1 protein in MCF-7 breast cancer cells. Eight fresh breast cancers paired with adjacent non-tumor tissues were quantified using real time RT-PCR (qRT-PCR) and western blot. The correlations between NQO1 overexpression and the clinical features of breast cancer were evaluated using chi-square test and Fisher’s exact tests. The survival rate was calculated using the Kaplan–Meier method, and the relationship between prognostic factors and patient survival was also analyzed by the Cox proportional hazards models.
Results
NQO1 protein showed a mainly cytoplasmic staining pattern in breast cancer. The strongly positive rate of NQO1 protein was 61.9% (109/176) in breast cancer, and was significantly higher than in DCIS (31.1%, 14/45), hyperplasia tissues (13.6%, 3/22) and adjacent non-tumor tissues (13.5%, 7/52). High-level expression of NQO1 protein was correlated with late clinical stage, poor differentiation, lymph node metastasis, Her2 expression and disease-free and 10-year overall survival rates in breast cancer. Moreover, multivariate analysis suggested that NQO1 emerged as a significant independent prognostic factor along with clinical stage and Her2 expression status in patients with breast cancer.
Conclusions
High-level expression of NQO1 appears to be associated with breast cancer progression, and may be a potential biomarker for poor prognostic evaluation of breast cancers.
doi:10.1186/1756-9966-33-14
PMCID: PMC3944477  PMID: 24499631
Breast cancer; NQO1; Immunohistochemistry; Prognosis
20.  High Expression of Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Predicts Poor Prognosis in Head and Neck Squamous Cell Carcinoma 
BioMed Research International  2014;2014:850316.
Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher's exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC.
doi:10.1155/2014/850316
PMCID: PMC3933037
21.  Age-Related Decrease in the Mitochondrial Sirtuin Deacetylase Sirt3 Expression Associated with ROS Accumulation in the Auditory Cortex of the Mimetic Aging Rat Model 
PLoS ONE  2014;9(2):e88019.
Age-related dysfunction of the central auditory system, also known as central presbycusis, can affect speech perception and sound localization. Understanding the pathogenesis of central presbycusis will help to develop novel approaches to prevent or treat this disease. In this study, the mechanisms of central presbycusis were investigated using a mimetic aging rat model induced by chronic injection of D-galactose (D-Gal). We showed that malondialdehyde (MDA) levels were increased and manganese superoxide dismutase (SOD2) activity was reduced in the auditory cortex in natural aging and D-Gal-induced mimetic aging rats. Furthermore, mitochondrial DNA (mtDNA) 4834 bp deletion, abnormal ultrastructure and cell apoptosis in the auditory cortex were also found in natural aging and D-Gal mimetic aging rats. Sirt3, a mitochondrial NAD+-dependent deacetylase, has been shown to play a crucial role in controlling cellular reactive oxygen species (ROS) homeostasis. However, the role of Sirt3 in the pathogenesis of age-related central auditory cortex deterioration is still unclear. Here, we showed that decreased Sirt3 expression might be associated with increased SOD2 acetylation, which negatively regulates SOD2 activity. Oxidative stress accumulation was likely the result of low SOD2 activity and a decline in ROS clearance. Our findings indicate that Sirt3 might play an essential role, via the mediation of SOD2, in central presbycusis and that manipulation of Sirt3 expression might provide a new approach to combat aging and oxidative stress-related diseases.
doi:10.1371/journal.pone.0088019
PMCID: PMC3913718  PMID: 24505357
22.  Birth cohort effects on abdominal obesity in the United States: the Silent Generation, Baby Boomers, and Generation X 
Background
Abdominal obesity predicts a wide range of adverse health outcomes. Over the past several decades, prevalence of abdominal obesity has increased markedly in industrialized countries like the U.S. No previous analyses, however, have evaluated whether there are birth cohort effects for abdominal obesity. Estimating cohort effects is necessary to forecast future health trends and understand past population-level trends.
Methods
This analysis evaluated whether there were birth cohort effects for abdominal obesity for the Silent Generation (born 1925-1945), children of the Great Depression; Baby Boomers (born 1946-1964); or Generation X (born 1965-1980). Cohort effects for prevalence of abdominal obesity were estimated using the median polish method with data collected from the National Health and Nutrition Examination Survey between 1988 and 2008. Respondents were aged 20-74 years.
Results
After taking into account age effects and ubiquitous secular changes, the Silent Generation and Generation X had higher cohort-specific prevalence of abdominal obesity than the Baby Boomers. Effects were more pronounced in women than men.
Conclusions
This work presents a novel finding: evidence that the birth cohorts of the post-World War II Baby Boom appeared to have uniquely low cohort effects on abdominal obesity. The growing prosperity of the post-World-War II U.S. may have exposed the Baby Boom generation to lower levels of psychosocial and socioeconomic stress than previous or subsequent generations. By identifying factors associated with the Baby Boomers’ low cohort-specific sensitivity to the obesogenic environment, the obesity prevention community can identify early-life factors that can protect future generations from excess weight gain.
doi:10.1038/ijo.2012.198
PMCID: PMC3604045  PMID: 23229734
age-period-cohort; obesity; abdominal obesity; demography; sex differences; United States
23.  Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model 
Multidrug-resistant breast cancers have limited and ineffective clinical treatment options. This study aimed to develop PLGA nanoparticles containing a synergistic combination of vincristine and verapamil to achieve less toxicity and enhanced efficacy on multidrug-resistant breast cancers. The 1:250 molar ratio of VCR/VRP showed strong synergism with the reversal index of approximately 130 in the multidrug-resistant MCF-7/ADR cells compared to drug-sensitive MCF-7 cells. The lyophilized nanoparticles could get dispersed quickly with the similar size distribution, zeta potential and encapsulation efficiency to the pre-lyophilized nanoparticles suspension, and maintain the synergistic in vitro release ratio of drugs. The co-encapsulated nanoparticle formulation had lower toxicity than free vincristine/verapamil combinations according to the acute-toxicity test. Furthermore, the most effective tumor growth inhibition in the MCF-7/ADR human breast tumor xenograft was observed in the co-delivery nanoparticle formulation group in comparison with saline control, free vincristine, free vincristine/verapamil combinations and single-drug nanoparticle combinations. All the data demonstrated that PLGANPs simultaneously loaded with chemotherapeutic drug and chemosensitizer might be one of the most potential formulations in the treatment of multidrug-resistant breast cancer in clinic.
doi:10.3390/ijms15022761
PMCID: PMC3958880  PMID: 24552875
multidrug-resistant breast cancer; vincristine; verapamil; PLGA nanoparticles; co-encapsulation
24.  Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects 
BMC Cancer  2014;14:48.
Background
Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival.
Methods
The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy.
Results
The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes.
Conclusions
These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.
doi:10.1186/1471-2407-14-48
PMCID: PMC3922726  PMID: 24475975
Cancer immunotherapy; IL-18; GM-CSF; Cell vaccine; Apoptosis
25.  In situ TEM Observation of Resistance Switching in Titanate Based Device 
Scientific Reports  2014;4:3890.
After decades of efforts, the research on resistance switching (RS) behavior in transition metal oxides has shifted to the stage of verifying the proposed models by direct experimental evidences. In this paper, RS behavior and oxygen content variation of La0.85Sr0.15TiO3/SrTiO3:Nb (LSTO/STON) were investigated by in situ transmission electron microscopy observation and in situ electron energy loss spectrum characterization under external electric field. The oxygen content fluctuation adjusted by applied bias has been investigated and the observed results imply the conductive channels should be formed by the oxygen vacancy at the Pt/LSTO interface. Moreover, in situ TEM characterization displays the advantage - to reveal the origin of various RS behaviors.
doi:10.1038/srep03890
PMCID: PMC3902442  PMID: 24463532

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