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1.  Factors Associated with Loss-to-Follow-Up during Behavioral Interventions and HIV Testing Cohort among Men Who Have Sex with Men in Nanjing, China 
PLoS ONE  2015;10(1):e115691.
Background
Behavioral interventions (BIs) remained the cornerstone of HIV prevention in resource-limited settings. One of the major concerns for such efforts is the loss-to-follow-up (LTFU) that threatens almost every HIV control program involving high-risk population groups.
Methods
To evaluate the factors associated with LTFU during BIs and HIV testing among men who have sex with men (MSM), 410 HIV sero-negatives MSM were recruited using respondent driven sampling (RDS) in Nanjing, China during 2008, they were further followed for 18 months. At baseline and each follow-up visits, each participant was counseled about various HIV risk-reductions BIs at a designated sexually transmitted infection (STI) clinic.
Results
Among 410 participants recruited at baseline, altogether 221 (53.9%) were LTFU at the 18-month follow-up visit. Overall, 46 participants were found to be positive for syphilis infection at baseline while 13 participants were HIV sero-converted during the follow-up period. Increasing age was less (Adjusted Odds Ratio(aOR) of 0.90, 95% confidence Interval (CI) 0.86–0.94) and official residency of provinces other than Nanjing (AOR of 2.49, 95%CI 1.32–4.71), lower level of education (AOR of 2.01, 95%CI 1.10–3.66) and small social network size (AOR of 1.75, 95%CI 1.09–2.80) were more likely to be associated with higher odds of LTFU.
Conclusion
To improve retention in the programs for HIV control, counseling and testing among MSM in Nanjing, focused intensified intervention targeting those who were more likely to be LTFU, especially the young, less educated, unofficial residents of Nanjing who had smaller social network size, might be helpful.
doi:10.1371/journal.pone.0115691
PMCID: PMC4283967  PMID: 25559678
2.  Emerging Disparity in HIV/AIDS Disease Progression and Mortality for Men Who Have Sex with Men, Jiangsu Province, China 
AIDS and behavior  2014;18(0 1):10.1007/s10461-013-0520-2.
Few data exist on HIV disease progression and antiretroviral treatment (ART) impact among men who have sex with men (MSM) in China. Using data from the national case reporting system from 2004 to 2010, we describe changes in CD4 cell count before and after ART initiation, disease progression, and mortality among MSM in Jiangsu province compared with other persons living with HIV/AIDS. Median CD4 cell count among MSM at HIV diagnosis was 432 and decreased rapidly in 12 months to below the level of heterosexuals (slope: MSM −38.0, heterosexuals −15.5, injection drug users [IDU] −8.0, blood donors −10.5). Among those initiating ART, median CD4 cell count among MSM was 157, yet the increase in count was slower than for other groups (slope: MSM 26.9, heterosexuals 31.9, IDU 29.0, blood donors 35.0). Progression to AIDS was faster among MSM than heterosexuals and IDU. For the present, the mortality rate was lower for MSM compared with heterosexuals and blood donors; however, against a backdrop of more recent infection (ie, MSM had younger age, and 93.8 % were diagnosed after 2008), findings suggest a survival rate for MSM that will fall behind other groups. Improved medical and psychosocial supportive care is needed for this stigmatized population lest disparities become greater.
doi:10.1007/s10461-013-0520-2
PMCID: PMC3864630  PMID: 23695520
China; Gay men; Surveillance; Disease progression; Mortality; HIV
3.  System-Level Insights into the Cellular Interactome of a Non-Model Organism: Inferring, Modelling and Analysing Functional Gene Network of Soybean (Glycine max) 
PLoS ONE  2014;9(11):e113907.
Cellular interactome, in which genes and/or their products interact on several levels, forming transcriptional regulatory-, protein interaction-, metabolic-, signal transduction networks, etc., has attracted decades of research focuses. However, such a specific type of network alone can hardly explain the various interactive activities among genes. These networks characterize different interaction relationships, implying their unique intrinsic properties and defects, and covering different slices of biological information. Functional gene network (FGN), a consolidated interaction network that models fuzzy and more generalized notion of gene-gene relations, have been proposed to combine heterogeneous networks with the goal of identifying functional modules supported by multiple interaction types. There are yet no successful precedents of FGNs on sparsely studied non-model organisms, such as soybean (Glycine max), due to the absence of sufficient heterogeneous interaction data. We present an alternative solution for inferring the FGNs of soybean (SoyFGNs), in a pioneering study on the soybean interactome, which is also applicable to other organisms. SoyFGNs exhibit the typical characteristics of biological networks: scale-free, small-world architecture and modularization. Verified by co-expression and KEGG pathways, SoyFGNs are more extensive and accurate than an orthology network derived from Arabidopsis. As a case study, network-guided disease-resistance gene discovery indicates that SoyFGNs can provide system-level studies on gene functions and interactions. This work suggests that inferring and modelling the interactome of a non-model plant are feasible. It will speed up the discovery and definition of the functions and interactions of other genes that control important functions, such as nitrogen fixation and protein or lipid synthesis. The efforts of the study are the basis of our further comprehensive studies on the soybean functional interactome at the genome and microRNome levels. Additionally, a web tool for information retrieval and analysis of SoyFGNs can be accessed at SoyFN: http://nclab.hit.edu.cn/SoyFN.
doi:10.1371/journal.pone.0113907
PMCID: PMC4244207  PMID: 25423109
4.  Short Laminin Peptide for Improved Neural Stem Cell Growth 
The authors developed a novel peptide sequence with only 12 amino acids based on the Ile-Lys-Val-Ala-Val sequence. This novel short peptide shows great promise in artificial niche development for supporting human neural stem/progenitor cell culture in vitro and in vivo and for promoting human neural stem/progenitor cell transplantation in future clinical therapy.
Human neural stem/progenitor cells (hNSCs) are very difficult to culture and require human or animal source extracellular matrix molecules, such as laminin or collagen type IV, to support attachment and to regulate their survival and proliferation. These extracellular matrix molecules are difficult to purify from human or animal tissues, have high batch-to-batch variability, and may cause an immune response if used in clinical applications. Although several laminin- and collagen IV-derived peptides are commercially available, they do not support long-term hNSC attachment and growth. To solve this problem, we developed a novel peptide sequence with only 12 amino acids based on the Ile-Lys-Val-Ala-Val, or IKVAV, sequence: Ac-Cys-Cys-Arg-Arg-Ile-Lys-Val-Ala-Val-Trp-Leu-Cys. This short peptide sequence, similar to tissue-derived full laminin molecules, supported hNSCs to attach and proliferate to confluence for continuous passage and subculture. This short peptide also directed hNSCs to differentiate into neurons. When conjugated to poly(ethylene glycol) hydrogels, this short peptide benefited hNSC attachment and proliferation on the surface of hydrogels and promoted cell migration inside the hydrogels with maximum enhancement at a peptide density of 10 μM. This novel short peptide shows great promise in artificial niche development for supporting hNSC culture in vitro and in vivo and for promoting hNSC transplantation in future clinical therapy.
doi:10.5966/sctm.2013-0015
PMCID: PMC4006481  PMID: 24692587
Neural stem/progenitor cells; Peptide; Attachment; Migration; Hydrogel
5.  Highly Compact (4F2) and Well Behaved Nano-Pillar Transistor Controlled Resistive Switching Cell for Neuromorphic System Application 
Scientific Reports  2014;4:6863.
To simplify the architecture of a neuromorphic system, it is extremely desirable to develop synaptic cells with the capacity of low operation power, high density integration, and well controlled synaptic behaviors. In this study, we develop a resistive switching device (ReRAM)-based synaptic cell, fabricated by the CMOS compatible nano-fabrication technology. The developed synaptic cell consists of one vertical gate-all-around Si nano-pillar transistor (1T) and one transition metal-oxide based resistive switching device (1R) stacked on top of the vertical transistor directly. Thanks to the vertical architecture and excellent controllability on the ON/OFF performance of the nano-pillar transistor, the 1T1R synaptic cell shows excellent characteristics such as extremely high-density integration ability with 4F2 footprint, ultra-low operation current (<2 nA), fast switching speed (<10 ns), multilevel data storage and controllable synaptic switching, which are extremely desirable for simplifying the architecture of neuromorphic system.
doi:10.1038/srep06863
PMCID: PMC4215303  PMID: 25359219
6.  A Least Square Method Based Model for Identifying Protein Complexes in Protein-Protein Interaction Network 
BioMed Research International  2014;2014:720960.
Protein complex formed by a group of physical interacting proteins plays a crucial role in cell activities. Great effort has been made to computationally identify protein complexes from protein-protein interaction (PPI) network. However, the accuracy of the prediction is still far from being satisfactory, because the topological structures of protein complexes in the PPI network are too complicated. This paper proposes a novel optimization framework to detect complexes from PPI network, named PLSMC. The method is on the basis of the fact that if two proteins are in a common complex, they are likely to be interacting. PLSMC employs this relation to determine complexes by a penalized least squares method. PLSMC is applied to several public yeast PPI networks, and compared with several state-of-the-art methods. The results indicate that PLSMC outperforms other methods. In particular, complexes predicted by PLSMC can match known complexes with a higher accuracy than other methods. Furthermore, the predicted complexes have high functional homogeneity.
doi:10.1155/2014/720960
PMCID: PMC4227386  PMID: 25405206
7.  Correlation of EGFR mutation and histological subtype according to the IASLC/ATS/ERS classification of lung adenocarcinoma 
Objective: To evaluate the correlation of EGFR mutation and histological subtypes of lung adenocarcinoma based on the IASLC/ATS/ERS classification. Methods: EGFR exons 18-21 of 206 resected lung adenocarcinoma specimens were analyzed with pyrosequecing, then the differences between histological subtypes and EGFR mutation were compared. Results: EGFR mutation was detected in 123 specmens, most of which were papillary and acinar predominant adenocarcinoma. EGFR mutation rate of the specimens with papillary, acinar or lepidic component was higher than without these components (P < 0.05), and with solid or mucinous component was lower than that without the component (P < 0.05). EGFR mutation in solid predominant mixed other subtypes was more commonly found than that of pure solid component (P=0.018). Conclusions: The presence of well-differentiated components in lung adenocarcinoma, such as lepidic, papillary and acinar, indicates a higher EGFR mutation rate, while the solid and mucinous component indicate a lower EGFR mutation rate. There is heterogeneity of EGFR mutation in lung adenocarcinoma.
PMCID: PMC4270542  PMID: 25550848
Lung neoplasms; adenocarcinoma; receptor; epidermal growth factor
8.  Thuringiensin: A Thermostable Secondary Metabolite from Bacillus thuringiensis with Insecticidal Activity against a Wide Range of Insects 
Toxins  2014;6(8):2229-2238.
Thuringiensin (Thu), also known as β-exotoxin, is a thermostable secondary metabolite secreted by Bacillus thuringiensis. It has insecticidal activity against a wide range of insects, including species belonging to the orders Diptera, Coleoptera, Lepidoptera, Hymenoptera, Orthoptera, and Isoptera, and several nematode species. The chemical formula of Thu is C22H32O19N5P, and it is composed of adenosine, glucose, phosphoric acid, and gluconic diacid. In contrast to the more frequently studied insecticidal crystal protein, Thu is not a protein but a small molecule oligosaccharide. In this review, a detailed and updated description of the characteristics, structure, insecticidal mechanism, separation and purification technology, and genetic determinants of Thu is provided.
doi:10.3390/toxins6082229
PMCID: PMC4147579  PMID: 25068925
thuringiensin; Bacillus thuringiensis; insecticidal mechanism; genetic determinants
9.  Amniotic Fluid Embolism (AFE) in China: Are maternal mortality and morbidity preventable? 
Summary
A case of hospital-patient conflict has occurred in China that has lifted billows in the public and highlighted the lethality of amniotic fluid embolism (AFE). AFE is a rare but severe obstetric complication with high maternal mortality and morbidity. Globally, the incidence of AFE is estimated to be approximately 2 to 6 per 100,000 deliveries. The maternal mortality rate (MMR) attributable to AFE ranges between 0.5 to 1.7 deaths per 100,000 deliveries in the developed world and 1.9 to 5.9 deaths per 100,000 deliveries in the developing world. In developed countries, AFE often accounts for a leading cause of maternal mortality; whereas the proportion of maternal death caused by AFE tends to be not as dominant compared to common perinatal complications in developing countries. With the mechanism remaining to be elucidated, AFE can neither be predicted nor prevented even in developed countries. Treatment requires a set of highly intensive advanced emergency obstetric care, challenging obstetric care in developing countries. Although this complication is currently far from preventable, China has potential to improve the prognosis of AFE by strengthening the emergency obstetric care system.
doi:10.5582/irdr.2014.01016
PMCID: PMC4214245  PMID: 25364652
Amniotic Fluid Embolism (AFE); maternal mortality; obstetric complication; China
10.  Effective inhibition of melanoma tumorigenesis and growth via a new complex vaccine based on NY-ESO-1-alum-polysaccharide-HH2 
Molecular Cancer  2014;13:179.
Background
A safe and effective adjuvant plays an important role in the development of a vaccine. However, adjuvants licensed for administration in humans remain limited. Here, for the first time, we developed a novel combination adjuvant alum-polysaccharide-HH2 (APH) with potent immunomodulating activities, consisting of alum, polysaccharide of Escherichia coli and the synthetic cationic innate defense regulator peptide HH2.
Methods
The adjuvant effects of APH were examined using NY-ESO-1 protein-based vaccines in prophylactic and therapeutic models. We further determined the immunogenicity and anti-tumor effect of NY-ESO-1-APH (NAPH) vaccine using adoptive cellular/serum therapy in C57/B6 and nude mice. Cell-mediated and antibody-mediated immune responses were evaluated.
Results
The APH complex significantly promoted antigen uptake, maturation and cross-presentation of dendritic cells and enhanced the secretion of TNF-α, MCP-1 and IFN-γ by human peripheral blood mononuclear cells compared with individual components. Vaccination of NAPH resulted in significant tumor regression or delayed tumor progression in prophylactic and therapeutic models. In addition, passive serum/cellular therapy potently inhibited tumor growth of NY-ESO-1-B16. Mice treated with NAPH vaccine produced higher antibody titers and greater antibody-dependent/independent cellular cytotoxicity. Therefore, NAPH vaccination effectively stimulated innate immunity, and boosted both arms of the adaptive humoral and cellular immune responses to suppress tumorigenesis and growth of melanoma.
Conclusions
Our study revealed the potential application of APH complex as a novel immunomodulatory agent for vaccines against tumor refractory and growth.
doi:10.1186/1476-4598-13-179
PMCID: PMC4120012  PMID: 25070035
Alum; Polysaccharide; HH2; Adjuvant complex; NY-ESO-1 protein-based vaccines; Melanoma; Cross-presentation
11.  On Some Nonclassical Algebraic Properties of Interval-Valued Fuzzy Soft Sets 
The Scientific World Journal  2014;2014:192957.
Interval-valued fuzzy soft sets realize a hybrid soft computing model in a general framework. Both Molodtsov's soft sets and interval-valued fuzzy sets can be seen as special cases of interval-valued fuzzy soft sets. In this study, we first compare four different types of interval-valued fuzzy soft subsets and reveal the relations among them. Then we concentrate on investigating some nonclassical algebraic properties of interval-valued fuzzy soft sets under the soft product operations. We show that some fundamental algebraic properties including the commutative and associative laws do not hold in the conventional sense, but hold in weaker forms characterized in terms of the relation =L. We obtain a number of algebraic inequalities of interval-valued fuzzy soft sets characterized by interval-valued fuzzy soft inclusions. We also establish the weak idempotent law and the weak absorptive law of interval-valued fuzzy soft sets using interval-valued fuzzy soft J-equal relations. It is revealed that the soft product operations ∧ and ∨ of interval-valued fuzzy soft sets do not always have similar algebraic properties. Moreover, we find that only distributive inequalities described by the interval-valued fuzzy soft L-inclusions hold for interval-valued fuzzy soft sets.
doi:10.1155/2014/192957
PMCID: PMC4131116  PMID: 25143964
12.  Melatonin facilitates extinction, but not acquisition or expression, of conditional cued fear in rats 
BMC Neuroscience  2014;15(1):86.
Background
Previous studies have shown that melatonin is involved in the processes that contribute to learning and memory. At present study, we tested the effects of exogenous melatonin (2.5 mg/kg) on the acquisition, expression and extinction of cued fear in rats.
Results
Results showed that a single afternoon administration 30 min before conditioning has no effect on the acquisition of cued fear. Compared to rats injected with vehicle, rats injected with melatonin 30 min before extinction training presented a significant lower freezing during both extinction training and extinction test phases, however, freezing response did not differ for the initial four trials during extinction training. Melatonin injected immediately after extinction training was ineffective on extinction learning.
Conclusions
These results suggest that melatonin, at the dose applied in this study, facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. These findings extend previous research on the melatonin effects on learning and memory and suggest that melatonin may serve as an agent for the treatment of anxiety disorders such as posttraumatic stress disorder (PTSD).
doi:10.1186/1471-2202-15-86
PMCID: PMC4111846  PMID: 25026909
Melatonin; Cued fear; Fear conditioning; Fear extinction; PTSD; Rats
13.  Neurotrophic Signaling Factors in Brain Ischemia/Reperfusion Rats: Differential Modulation Pattern between Single-Time and Multiple Electroacupuncture Stimulation 
Electroacupuncture (EA) treatment has been widely used for stroke-like disorders in traditional Chinese medicine. However, the underlying mechanisms remain unclear. Our previous studies showed that single-time EA stimulation at “Baihui” (GV 20) and “Shuigou” (GV 26) after the onset of ischemia can protect the brain against ischemic injury in rats with middle cerebral artery occlusion (MCAO). Here, we further investigated the differential effects between multiple EA and single-time EA stimulation on ischemic injury. In the present study, we found that both single-time EA and multiple EA stimulation significantly reduced MCAO-induced ischemic infarction, while only multiple EA attenuated sensorimotor dysfunctions. Also, with PCR array screening and ingenuity gene analysis, we revealed that multiple EA and single-time EA stimulation could differentially induce expression changes in neurotrophic signaling related genes. Meanwhile, with western blotting, we demonstrated that the level of glia maturation factor β (GMFβ) increased in the early stage (day 1) of reperfusion, and this upregulation was suppressed only by single-time EA stimulation. These findings suggest that the short-term effect of single-time EA stimulation differs from the cumulative effect of multiple EA, which possibly depends on their differential modulation on neurotrophic signaling molecules expression.
doi:10.1155/2014/625050
PMCID: PMC4122066  PMID: 25126102
14.  Ranibizumab versus Bevacizumab for Ophthalmic Diseases Related to Neovascularisation: A Meta-Analysis of Randomised Controlled Trials 
PLoS ONE  2014;9(7):e101253.
Background
Bevacizumab is believed to be as effective and safe as ranibizumab for ophthalmic diseases; however, its magnitude of effectiveness and safety profile remain controversial. Thus, a meta-analysis and systematic review appears necessary.
Methods
PubMed and EMBASE were systematically searched with no restrictions. All relevant citations comparing ranibizumab and bevacizumab were considered for inclusion. Pooled effect estimates were obtained using a fixed- and random-effects meta-analysis.
Results
Nine independent randomised-controlled clinical trials (RCTs) involving 2,289 participants were identified. Compared with bevacizumab, the overall combined weighted mean difference (WMD) of the mean change in visual acuity for ranibizumab was 0.52 letters (95% CI −0.11–1.14). The odds ratios (ORs) of gaining ≥15, gaining 5–14, losing 5–14 and losing ≤15 letters were 1.10 (95% CI 0.90–1.33), 0.93 (95% CI 0.77–1.11), 0.89 (95% CI 0.65–1.22) and 0.95 (95% CI 0.73–1.25), respectively. The risk of serious systemic events increased by 17% (95% CI 6%–27%, p = 0.0042) for bevacizumab treatment in comparison with ranibizumab. No statistically significant differences between the two treatments were found for the nonfatal arterial thrombotic events, ocular serious adverse, death from vascular and all causes events.
Conclusions
Bevacizumab is not inferior to ranibizumab as a treatment for achieving visual acuity. The use of bevacizumab was associated with an increased risk of developing serious systemic events. Weighing the costs and health outcomes is necessary when selecting between bevacizumab and ranibizumab for ophthalmic diseases. Due to the limitations of the available data, further research is needed.
doi:10.1371/journal.pone.0101253
PMCID: PMC4077727  PMID: 24983855
15.  Analyzing Association of the XRCC3 Gene Polymorphism with Ovarian Cancer Risk 
BioMed Research International  2014;2014:648137.
This meta-analysis aims to examine whether the XRCC3 polymorphisms are associated with ovarian cancer risk. Eligible case-control studies were identified through search in PubMed. Pooled odds ratios (ORs) were appropriately derived from fixed effects models. We therefore performed a meta-analysis of 5,302 ovarian cancer cases and 8,075 controls from 4 published articles and 8 case-control studies for 3 SNPs of XRCC3. No statistically significant associations between XRCC3 rs861539 polymorphisms and ovarian cancer risk were observed in any genetic models. For XRCC3 rs1799794 polymorphisms, we observed a statistically significant correlation with ovarian cancer risk using the homozygote comparison (T2T2 versus T1T1: OR = 0.70, 95% CI = 0.54–0.90, P = 0.005), heterozygote comparison (T1T2 versus T1T1: OR = 1.10, 95% CI = 1.00–1.21, P = 0.04), and the recessive genetic model (T2T2 versus T1T1+T1T2: OR = 0.67, 95% CI = 0.52–0.87, P = 0.002). For XRCC3 rs1799796 polymorphisms, we also observed a statistically significant correlation with ovarian cancer risk using the heterozygote comparison (T1T2 versus T1T1: OR = 0.91, 95% CI = 0.83–0.99, P = 0.04). In conclusion, this meta-analysis shows that the XRCC3 were associated with ovarian cancer risk overall for Caucasians. Asian and African populations should be further studied.
doi:10.1155/2014/648137
PMCID: PMC4071988  PMID: 25006581
16.  Blocking the formation of radiation–induced breast cancer stem cells 
Oncotarget  2014;5(11):3743-3755.
The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer.
PMCID: PMC4116517  PMID: 25003837
Breast Cancer; Radiation; Cancer Stem Cells; NF-kappaB; Stemness genes
17.  Draft Genome Sequence of Bacillus thuringiensis NBIN-866 with High Nematocidal Activity 
Genome Announcements  2014;2(3):e00429-14.
Bacillus thuringiensis NBIN-866, a Gram-positive bacterium, was isolated from soil in China. We announce here the draft genome sequence of strain B. thuringiensis NBIN-866, which possesses highly nematocidal factors, such as proteins and small molecular peptides.
doi:10.1128/genomeA.00429-14
PMCID: PMC4031334  PMID: 24855295
18.  ATP1A3 Mutations and Genotype-Phenotype Correlation of Alternating Hemiplegia of Childhood in Chinese Patients 
PLoS ONE  2014;9(5):e97274.
Alternating hemiplegia of childhood (AHC) is a rare and severe neurological disorder. ATP1A3 was recently identified as the causative gene. Here we report the first genetic study in Chinese AHC cohort. We performed whole-exome sequencing on three trios and three unrelated patients, and screened additional 41 typical cases and 100 controls by PCR-Sanger sequencing. ATP1A3 mutations were detected in 95.7% of typical AHC patients. At least 93.3% were de novo. Four late onset, atypical AHC patients were also mutation positive, suggesting the need for testing ATP1A3 mutations in atypical cases. Totally, 13 novel missense mutations (T370N, G706R, L770R, T771N, T771I, S772R, L802P, D805H, M806K, P808L, I810N, L839P and G893R) were identified in our study. By homology modeling of the mutant protein structures and calculation of an extensive list of molecular features, we identified two statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. A logistic regression classifier achieved 92.9% accuracy by the average of 100 times of five-fold cross validations. Genotype-phenotype correlation analysis showed that patients with epilepsy were more likely to carry E815K mutation. In summary, ATP1A3 is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes.
doi:10.1371/journal.pone.0097274
PMCID: PMC4026576  PMID: 24842602
19.  Association of serum hemoglobin A1c, C-peptide and insulin-like growth factor-1 levels with the occurrence and development of lung cancer 
Molecular and Clinical Oncology  2014;2(4):506-508.
The present study aimed to investigate the correlation of the of hemoglobin A1c (HbA1c), C-peptide and insulin-like growth factor-1 (IGF-1) levels with the development and progression of lung cancer. The serum HbA1c, C-peptide and IGF-1 levels were measured and compared between 80 lung cancer patients and 80 healthy controls; furthermore, their correlation with histopathological type and tumor stage was analyzed in the 80 lung cancer patients. Our results suggested that the levels of HbA1c, C-peptide and IGF-1 were significantly increased in patients with lung cancer compared to those in the control group (P<0.05). In addition, the levels of C-peptide and IGF-1 were significantly higher in the small-cell lung cancer group (n=18), the stage III–IV (n=55) group and the lung cancer with diabetes mellitus group (n=43) compared to those in the non-small-cell lung cancer group (n=62), the stage I–II lung cancer group (n=25) and the lung cancer without diabetes group (n=37), respectively (P<0.05). Thus, the present study suggests that the increased serum HbA1c, C-peptide and IGF-1 levels are significantly correlated with the development and progression of lung cancer.
doi:10.3892/mco.2014.289
PMCID: PMC4051575  PMID: 24940485
diabetes mellitus; lung cancer; hemoglobin A1c; C-peptide; insulin-like growth factor-1
20.  ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel 
Cancer Biology & Therapy  2013;14(5):450-457.
Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G0/G1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.
doi:10.4161/cbt.24423
PMCID: PMC3672189  PMID: 23917377
4-aminopiperidine; hERG; potassium channel; SH-SY5Y; neuroblastoma; cancer; cell cycle
21.  Computational Prediction of Protein Function Based on Weighted Mapping of Domains and GO Terms 
BioMed Research International  2014;2014:641469.
In this paper, we propose a novel method, SeekFun, to predict protein function based on weighted mapping of domains and GO terms. Firstly, a weighted mapping of domains and GO terms is constructed according to GO annotations and domain composition of the proteins. The association strength between domain and GO term is weighted by symmetrical conditional probability. Secondly, the mapping is extended along the true paths of the terms based on GO hierarchy. Finally, the terms associated with resident domains are transferred to host protein and real annotations of the host protein are determined by association strengths. Our careful comparisons demonstrate that SeekFun outperforms the concerned methods on most occasions. SeekFun provides a flexible and effective way for protein function prediction. It benefits from the well-constructed mapping of domains and GO terms, as well as the reasonable strategy for inferring annotations of protein from those of its domains.
doi:10.1155/2014/641469
PMCID: PMC4017789  PMID: 24868539
22.  Neuroprotective Effect of TAT-14-3-3ε Fusion Protein against Cerebral Ischemia/Reperfusion Injury in Rats 
PLoS ONE  2014;9(3):e93334.
Stroke is the major cause of death and disability worldwide, and the thrombolytic therapy currently available was unsatisfactory. 14-3-3ε is a well characterized member of 14-3-3 family, and has been reported to protect neurons against apoptosis in cerebral ischemia. However, it cannot transverse blood brain barrier (BBB) due to its large size. A protein transduction domain (PTD) of HIV TAT protein, is capable of delivering a large variety of proteins into the brain. In this study, we generated a fusion protein TAT-14-3-3ε, and evaluated its potential neuroprotective effect in rat focal ischemia/reperfusion (I/R) model. Western blot analysis validated the efficient transduction of TAT-14-3-3ε fusion protein into brain via a route of intravenous injection. TAT-14-3-3ε pre-treatment 2 h before ischemia significantly reduced cerebral infarction volume and improved neurologic score, while post-treatment 2 h after ischemia was less effective. Importantly, pre- or post-ischemic treatment with TAT-14-3-3ε significantly increased the number of surviving neurons as determined by Nissl staining, and attenuated I/R-induced neuronal apoptosis as showed by the decrease in apoptotic cell numbers and the inhibition of caspase-3 activity. Moreover, the introduction of 14-3-3ε into brain by TAT-mediated delivering reduced the formation of autophagosome, attenuated LC3B-II upregulation and reversed p62 downregulation induced by ischemic injury. Such inhibition of autophagy was reversed by treatment with an autophagy inducer rapamycin (RAP), which also attenuated the neuroprotective effect of TAT-14-3-3ε. Conversely, autophagy inhibitor 3-methyladenine (3-MA) inhibited I/R-induced the increase in autophagic activity, and attenuated I/R-induced brain infarct. These results suggest that TAT-14-3-3ε can be efficiently transduced into brain and exert significantly protective effect against brain ischemic injury through inhibiting neuronal apoptosis and autophagic activation.
doi:10.1371/journal.pone.0093334
PMCID: PMC3966873  PMID: 24671253
23.  Direct Conversion of Pretreated Straw Cellulose into Citric Acid by Co-cultures of Yarrowia lipolytica SWJ-1b and Immobilized Trichoderma reesei Mycelium 
The immobilized cellulase-producing mycelium of Trichoderma reesei was found to produce 2.9 U/ml of cellulase activity within 144 h while 2.1 U/ml of cellulase activity was produced within 120 h by the free mycelium of the same strain. When the immobilized mycelium of T. reesei was co-cultivated with the free cells of Yarrowia lipolytica SWJ-1b in flask, Y. lipolytica SWJ-1b could yield 10.7 g/l of citric acid and 3.9 g/l of isocitric acid from 40.0 g/l pretreated straw within 240 h. Under the similar conditions, Y. lipolytica SWJ-1b could yield 32.8 g/l of citric acid and 4.7 g/l of isocitric acid from 40.0 g/l pretreated straw supplemented with 20.0 g/l glucose within 288 h. When the co-cultures were grown in 10-l fermentor, Y. lipolytica SWJ-1b could yield 83.4 g/l of citric acid and 8.7 g/l of isocitric acid from 100.0 g/l of pretreated straw supplemented with 50.0 g/l glucose within 312 h.
doi:10.1007/s12010-014-0856-8
PMCID: PMC4007025  PMID: 24659047
Citric acid; Yarrowia lipolytica; Pretreated straw; Immobilization; SSF
24.  A Time Scheduling Model of Logistics Service Supply Chain Based on the Customer Order Decoupling Point: A Perspective from the Constant Service Operation Time 
The Scientific World Journal  2014;2014:756178.
In mass customization logistics service, reasonable scheduling of the logistics service supply chain (LSSC), especially time scheduling, is benefit to increase its competitiveness. Therefore, the effect of a customer order decoupling point (CODP) on the time scheduling performance should be considered. To minimize the total order operation cost of the LSSC, minimize the difference between the expected and actual time of completing the service orders, and maximize the satisfaction of functional logistics service providers, this study establishes an LSSC time scheduling model based on the CODP. Matlab 7.8 software is used in the numerical analysis for a specific example. Results show that the order completion time of the LSSC can be delayed or be ahead of schedule but cannot be infinitely advanced or infinitely delayed. Obtaining the optimal comprehensive performance can be effective if the expected order completion time is appropriately delayed. The increase in supply chain comprehensive performance caused by the increase in the relationship coefficient of logistics service integrator (LSI) is limited. The relative concern degree of LSI on cost and service delivery punctuality leads to not only changes in CODP but also to those in the scheduling performance of the LSSC.
doi:10.1155/2014/756178
PMCID: PMC3970053  PMID: 24715818
25.  SoyFN: a knowledge database of soybean functional networks 
Many databases for soybean genomic analysis have been built and made publicly available, but few of them contain knowledge specifically targeting the omics-level gene–gene, gene–microRNA (miRNA) and miRNA–miRNA interactions. Here, we present SoyFN, a knowledge database of soybean functional gene networks and miRNA functional networks. SoyFN provides user-friendly interfaces to retrieve, visualize, analyze and download the functional networks of soybean genes and miRNAs. In addition, it incorporates much information about KEGG pathways, gene ontology annotations and 3′-UTR sequences as well as many useful tools including SoySearch, ID mapping, Genome Browser, eFP Browser and promoter motif scan. SoyFN is a schema-free database that can be accessed as a Web service from any modern programming language using a simple Hypertext Transfer Protocol call. The Web site is implemented in Java, JavaScript, PHP, HTML and Apache, with all major browsers supported. We anticipate that this database will be useful for members of research communities both in soybean experimental science and bioinformatics.
Database URL: http://nclab.hit.edu.cn/SoyFN
doi:10.1093/database/bau019
PMCID: PMC3949006  PMID: 24618044

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