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1.  ABCG1 rs57137919G>A Polymorphism Is Functionally Associated with Varying Gene Expression and Apoptosis of Macrophages 
PLoS ONE  2014;9(6):e97044.
ATP-binding cassette transporter G1 (ABCG1) is a transmembrane cholesterol transporter involved in macrophage sterol homeostasis, reverse cholesterol transport (RCT), and atherosclerosis. The role of ABCG1 in atherosclerosis remains controversial, especially in animal models. Our previous study showed that single nucleotide polymorphism rs57137919 (-367G>A) in the ABCG1 promoter region was associated with reduced risk for atherosclerotic coronary artery disease (CAD). This study was designed to provide functional evidence for the role of rs57137919G>A in atherosclerosis in humans. We combined in vitro and ex vivo studies using cell lines and human monocyte-derived macrophages to investigate the functional consequences of the promoter polymorphism by observing the effects of the rs57137919A allele on promoter activity, transcription factor binding, gene expression, cholesterol efflux, and apoptosis levels. The results showed that the rs57137919A allele was significantly associated with decreased ABCG1 gene expression possibly due to the impaired ability of protein-DNA binding. ABCG1-mediated cholesterol efflux decreased by 23% with rs57137919 A/A versus the G/G genotype. Cholesterol-loaded macrophage apoptosis was induced 2-fold with the A/A genotype compared with the G/G genotype. Proapoptotic genes Bok and Bid mRNA levels were significantly increased in macrophages from the A/A genotype compared with those from the G/G genotype. These findings demonstrated that the ABCG1 promoter rs57137919G>A variant had an allele-specific effect on ABCG1 expression and was associated with an increased apoptosis in cholesterol-loaded macrophages, providing functional evidence to explain the reduced risk for atherosclerosis in subjects with the ABCG1 promoter rs57137919A allele as reported in our previous study.
doi:10.1371/journal.pone.0097044
PMCID: PMC4074052  PMID: 24972087
2.  Receptor Interactive Protein Kinase 3 Promotes Cisplatin-Triggered Necrosis in Apoptosis-Resistant Esophageal Squamous Cell Carcinoma Cells 
PLoS ONE  2014;9(6):e100127.
Cisplatin-based chemotherapy is currently the standard treatment for locally advanced esophageal cancer. Cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, but the mechanism by which programmed necrosis is induced remains unknown. In this study, we provide evidence that cisplatin induces necrotic cell death in apoptosis-resistant esophageal cancer cells. This cell death is dependent on RIPK3 and on necrosome formation via autocrine production of TNFα. More importantly, we demonstrate that RIPK3 is necessary for cisplatin-induced killing of esophageal cancer cells because inhibition of RIPK1 activity by necrostatin or knockdown of RIPK3 significantly attenuates necrosis and leads to cisplatin resistance. Moreover, microarray analysis confirmed an anti-apoptotic molecular expression pattern in esophageal cancer cells in response to cisplatin. Taken together, our data indicate that RIPK3 and autocrine production of TNFα contribute to cisplatin sensitivity by initiating necrosis when the apoptotic pathway is suppressed or absent in esophageal cancer cells. These data provide new insight into the molecular mechanisms underlying cisplatin-induced necrosis and suggest that RIPK3 is a potential marker for predicting cisplatin sensitivity in apoptosis-resistant and advanced esophageal cancer.
doi:10.1371/journal.pone.0100127
PMCID: PMC4069059  PMID: 24959694
3.  Clinical Characteristics of Heavy and Non-Heavy Smokers with Schizophrenia 
Schizophrenia research  2012;138(0):285-289.
Up to 50–90% of persons with schizophrenia smoke cigarettes. Limited data and theories suggest persons with schizophrenia may smoke for different reasons than persons without schizophrenia, making smoking cessation interventions particularly challenging in this population. Although health consequences of smoking are widely known, less information is available regarding characteristics of different amounts of smoking exposure in this population. This study was performed to investigate differences between heavy (≥1 pack per day) and non-heavy (<1 pack per day) smoking in patients with schizophrenia. Data from 745 patients, mean age 41.3 +/−12.6 years, were drawn from a population of smokers admitted to State of Maryland inpatient mental health facilities (1994–2000). Records were reviewed to obtain demographic information, diagnosis, medication, smoking and substance use. 43% of patients were characterized as heavy smokers. Heavy and non-heavy groups did not differ in age, GAF, weight, or BMI. No differences were found in race, gender or antipsychotic treatments. However, patients smoking ≥1 packs per day were more likely to use other substances such as alcohol (χ2=6.67, df=1, p=0.01), cocaine (χ2=6.66, df=1, p=0.01), and other substances (χ2=9.95, df=1, p=0.003) compared to non-heavy smokers. No differences in cannabis or heroin use were found by smoking category. Controlling for age, race, sex and BMI, heavy smokers had higher total cholesterol (190.7(51.6) mg/dl) compared to non-heavy smokers (178.2 (43.0) mg/dl, p=0.03), but no differences were found in glucose or blood pressure. Heavy smoking may be a particular health risk in schizophrenia and significant efforts for smoking cessation or reduction are needed.
doi:10.1016/j.schres.2012.03.024
PMCID: PMC4062915  PMID: 22578720
smoking; cigarettes; schizophrenia; heavy; tobacco
4.  Anatomical and functional outcomes after Densiron 68 heavy silicone oil tamponade for complicated retinal detachment in Chinese eyes 
AIM
To evaluate the safety and efficacy of Densiron 68 heavy silicone oil (HSO) tamponade for complicated retinal detachment (RD) in Chinese eyes.
METHODS
Twenty-one eyes of 21 patients with complicated RD were included in this retrospective study. All patients underwent pars plana vitrectomy with an internal tamponade using Densiron 68 HSO. Anatomical and functional results and complications were evaluated, including retinal status, visual acuity (VA), intraocular pressure (IOP), intraocular inflammation, lens opacity, and HSO emulsification.
RESULTS
All the patients were followed up for 3mo to 1y (5.8±1.16mo). Retinal reattachment was achieved in 19 of 21 patients (90.5%). VA improved in 18 of 21 patients (85.7%), from 1.93 logMAR (±0.48) to 1.52 logMAR (±0.45) (P=0.001). Postoperative complications included early dispersion of HSO in 7 eyes (38.8%), cataract in 10 of 18 phakic eyes (55.5%), moderate postoperative inflammation reaction in 10 eyes (47.6%), and elevated IOP in 5 eyes (23.8%), all of which were controlled by medication or by surgery.
CONCLUSION
High anatomical and functional success rates can be achieved with primary vitrectomy for complicated RD by using Densiron 68 HSO; however, it should not be ignored that Densiron 68 HSO can cause some complications in the eye.
doi:10.3980/j.issn.2222-3959.2014.03.15
PMCID: PMC4067661  PMID: 24967193
complicated retinal detachment; heavy silicone oil; intraocular tamponade; vitreoretinal surgery
5.  Prevalence and clinical characteristics of lower limb atherosclerotic lesions in newly diagnosed patients with ketosis-onset diabetes: a cross-sectional study 
Background
The clinical features of atherosclerotic lesions in ketosis-onset diabetes are largely absent. We aimed to compare the characteristics of lower limb atherosclerotic lesions among type 1, ketosis-onset and non-ketotic type 2 diabetes.
Methods
A cross-sectional study was performed in newly diagnosed Chinese patients with diabetes, including 53 type 1 diabetics with positive islet-associated autoantibodies, 208 ketosis-onset diabetics without islet-associated autoantibodies, and 215 non-ketotic type 2 diabetics. Sixty-two subjects without diabetes were used as control. Femoral intima-media thickness (FIMT), lower limb atherosclerotic plaque and stenosis were evaluated and compared among the four groups based on ultrasonography. The risk factors associated with lower limb atherosclerotic plaque were evaluated via binary logistic regression in patients with diabetes.
Results
After adjusting for age and sex, the prevalence of lower limb plaque in the patients with ketosis-onset diabetes (47.6%) was significantly higher than in the control subjects (25.8%, p = 0.013), and showed a higher trend compared with the patients with type 1 diabetes (39.6%, p = 0.072), but no difference was observed in comparison to the patients with non-ketotic type 2 diabetes (62.3%, p = 0.859). The mean FIMT in the ketosis-onset diabetics (0.73 ± 0.17 mm) was markedly greater than that in the control subjects (0.69 ± 0.13 mm, p = 0.045) after controlling for age and sex, but no significant differences were found between the ketosis-onset diabetics and the type 1 diabetics (0.71 ± 0.16 mm, p = 0.373), and the non-ketotic type 2 diabetics (0.80 ± 0.22 mm, p = 0.280), respectively. Age and FIMT were independent risk factors for the presence of lower limb plaque in both the ketosis-onset and non-ketotic type 2 diabetic patients, while sex and age in the type 1 diabetic patients.
Conclusions
The prevalence and risk of lower limb atherosclerotic plaque in the ketosis-onset diabetes were remarkably higher than in the control subjects without diabetes. The features and risk factors of lower limb atherosclerotic lesions in the ketosis-onset diabetes resembled those in the non-ketotic type 2 diabetes, but different from those in the type 1 diabetes. Our findings provide further evidences to support the classification of ketosis-onset diabetes as a subtype of type 2 diabetes rather than idiopathic type 1 diabetes.
doi:10.1186/1758-5996-6-71
PMCID: PMC4054910  PMID: 24926320
Type 1 diabetes; Ketosis-onset diabetes; Type 2 diabetes; Lower limb arteries; Atherosclerosis
6.  Clinic-Genomic Association Mining for Colorectal Cancer Using Publicly Available Datasets 
BioMed Research International  2014;2014:170289.
In recent years, a growing number of researchers began to focus on how to establish associations between clinical and genomic data. However, up to now, there is lack of research mining clinic-genomic associations by comprehensively analysing available gene expression data for a single disease. Colorectal cancer is one of the malignant tumours. A number of genetic syndromes have been proven to be associated with colorectal cancer. This paper presents our research on mining clinic-genomic associations for colorectal cancer under biomedical big data environment. The proposed method is engineered with multiple technologies, including extracting clinical concepts using the unified medical language system (UMLS), extracting genes through the literature mining, and mining clinic-genomic associations through statistical analysis. We applied this method to datasets extracted from both gene expression omnibus (GEO) and genetic association database (GAD). A total of 23517 clinic-genomic associations between 139 clinical concepts and 7914 genes were obtained, of which 3474 associations between 31 clinical concepts and 1689 genes were identified as highly reliable ones. Evaluation and interpretation were performed using UMLS, KEGG, and Gephi, and potential new discoveries were explored. The proposed method is effective in mining valuable knowledge from available biomedical big data and achieves a good performance in bridging clinical data with genomic data for colorectal cancer.
doi:10.1155/2014/170289
PMCID: PMC4060771  PMID: 24987669
7.  Mycorrhizas alter nitrogen acquisition by the terrestrial orchid Cymbidium goeringii 
Annals of Botany  2013;111(6):1181-1187.
Background and Aims
Orchid mycorrhizas exhibit a unique type of mycorrhizal symbiosis that occurs between fungi and plants of the family Orchidaceae. In general, the roots of orchids are typically coarse compared with those of other plant species, leading to a considerably low surface area to volume ratio. As a result, orchids are often ill-adapted for direct nutrient acquisition from the soil and so mycorrhizal assocaitions are important. However, the role of the fungal partners in the acquisition of inorganic and organic N by terrestrial orchids has yet to be clarified.
Methods
Inorganic and amino acid N uptake by non-mycorrhizal and mycorrhizal Cymbidium goeringii seedlings, which were grown in pots in a greenhouse, was investigated using a 15N-labelling technique in which the tracer was injected at two different soil depths, 2·5 cm or 7·5 cm. Mycorrhizal C. goeringii seedlings were obtained by inoculation with three different mycorrhizal strains isolated from the roots of wild terrestrial orchids (two C. goeringii and one C. sinense).
Key Results
Non-mycorrhizal C. goeringii primarily took up NO3− from tracers injected at 2·5-cm soil depth, whereas C. goeringii inoculated with all three mycorrhiza primarily took up NH4+ injected at the same depth. Inoculation of the mycorrhizal strain MLX102 (isolated from adult C. sinense) on C. goeringii roots only significantly increased the below-ground biomass of the C. goeringii; however, it enhanced 15NH4+ uptake by C. goeringii at 2·5-cm soil depth. Compared to the uptake of tracers injected at 2·5-cm soil depth, the MLX102 fungal strain strongly enhanced glycine-N uptake by C. goeringii from tracers injected at 7·5-cm soil depth. Cymbidium goeringii inoculated with CLB113 and MLX102 fungal strains demonstrated a similar N uptake pattern to tracers injected at 2·5-cm soil depth.
Conclusions
These findings demonstrate that mycorrhizal fungi are able to switch the primary N source uptake of a terrestrial orchid, in this case C. goeringii, from NO3− to NH4+. The reasons for variation in N uptake in the different soil layers may be due to possible differentiation in the mycorrhizal hyphae of the C. goeringii fungal partner.
doi:10.1093/aob/mct062
PMCID: PMC3662508  PMID: 23532045
Mycorrhizal fungi; amino acid uptake; Cymbidium species; nutrient acquisition; 15N labelling
8.  Identification of biomarkers for hepatocellular carcinoma by semiquantitative immunocytochemistry 
AIM: To investigate the expression of key biomarkers in hepatoma cell lines, tumor cells from patients’ blood samples, and tumor tissues.
METHODS: We performed the biomarker tests in two steps. First, cells plated on coverslips were used to assess biomarkers, and fluorescence intensities were calculated using the NIH Image J software. The measured values were analyzed using the SPSS 19.0 software to make comparisons among eight cell lines. Second, eighty-four individual samples were used to assess the biomarkers’ expression. Negative enrichment of the blood samples was performed, and karyocytes were isolated and dropped onto pre-treated glass slides for further analysis by immunofluorescence staining. Fluorescence intensities were compared among hepatocellular carcinoma (HCC) patients, chronic HBV-infected patients, and healthy controls following methods similar to those used for cell lines. The relationships between the expression of biomarkers and clinical pathological parameters were analyzed by Spearman rank correlation tests. In addition, we studied the distinct biomarkers’ expression with three-dimensional laser confocal microscopy reconstructions, and Kaplan-Meier survival analysis was performed to understand the clinical significance of these biomarkers.
RESULTS: Microscopic examination and fluorescence intensity calculations indicated that cytokeratin 8/18/19 (CK) expression was significantly higher in six of the seven HCC cell lines examined than in the control cells, and the expression levels of asialoglycoprotein receptor (ASGPR) and glypican-3 (GPC3) were higher in all seven HCC cell lines than in the control. Cells obtained from HCC patients’ blood samples also displayed significantly higher expression levels of ASGPR, GPC3, and CK than cells from chronic HBV-infected patients or healthy controls; these proteins may be valuable surface biomarkers for identifying HCC circulating tumor cells isolated and enriched from the blood samples. The stem cell-like and epithelial-mesenchymal transition-related biomarkers could be detected on the karyocyte slides. ASGPR and GPC3 were expressed at high levels, and thus three-dimensional reconstructions were used to observe their expression in detail. This analysis indicated that GPC3 was localized in the cytoplasm and membrane, but that ASGPR had a polar localization. Survival analyses showed that expression of GPC3 and ASGPR is associated with a patient’s overall survival (OS).
CONCLUSION: ASGPR, GPC3, and CK may be valuable HCC biomarkers for CTC detection; the expression of ASGPR and GPC3 might be helpful for understanding patients’ OS.
doi:10.3748/wjg.v20.i19.5826
PMCID: PMC4024792  PMID: 24914343
Hepatocellular carcinoma; Biomarker; Immunocytochemistry; Semiquantitative analysis; Three-dimensional reconstruction
9.  General Acteoside of Rehmanniae Leaves in the Treatment of Primary Chronic Glomerulonephritis: A Randomized Controlled Trial 
The objective of the study was to investigate the effectiveness and efficacy of the randomized, parallel, and controlled trial of Traditional Chinese Medicine, general acteoside of Rehmanniae leaves, compared with piperazine ferulate in the treatment of primary chronic glomerulonephritis. Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis. A total of 400 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (general acteoside of Rehmanniae leaves, two 200mg tablets, bid) or the control group (piperazine ferulate, four 50-mg tablets, bid ). The primary outcome was 24-h urinary protein. Secondary outcome measures included estimated glomerular filtration rate (eGFR), erythrocyturia, and electrolytes. After 8 weeks of treatment, the treatment group and the control group showed a mean reduction in 24-h proteinuria of 34.81% and 37.66%. The 95% CI of difference of the mean reduction in 24-h proteinuria between the two groups was [−11.50%, 5.80%]. No significant differences were found between the two groups in the erythrocyturia reduction. Neither group showed obvious changes between baseline and 8 weeks in eGFR or electrolytes. Adverse events occurred at a similarly low rate in the treatment group (1.5%) and control group (2.5%, P = 0.7238). Both general acteoside of Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis.
PMCID: PMC3794400  PMID: 24146510
Chronic glomerulonephritis; General acteoside of Rehmanniae leaves; Piperazine ferulate; Randomized controlled trials
10.  Positional Assembly of Enzymes on Bacterial Outer Membrane Vesicles for Cascade Reactions 
PLoS ONE  2014;9(5):e97103.
The systematic organization of enzymes is a key feature for the efficient operation of cascade reactions in nature. Here, we demonstrate a facile method to create nanoscale enzyme cascades by using engineered bacterial outer membrane vesicles (OMVs) that are spheroid nanoparticles (roughly 50 nm in diameter) produced by Gram-negative bacteria during all phases of growth. By taking advantage of the fact that OMVs naturally contain proteins found in the outer cell membrane, we displayed a trivalent protein scaffold containing three divergent cohesin domains for the position-specific presentation of a three-enzyme cascade on OMVs through a truncated ice nucleation protein anchoring motif (INP). The positional assembly of three enzymes for cellulose hydrolysis was demonstrated. The enzyme-decorated OMVs provided synergistic cellulose hydrolysis resulting in 23-fold enhancement in glucose production than free enzymes.
doi:10.1371/journal.pone.0097103
PMCID: PMC4018249  PMID: 24820175
11.  Broad-Spectrum Transgenic Resistance against Distinct Tospovirus Species at the Genus Level 
PLoS ONE  2014;9(5):e96073.
Thrips-borne tospoviruses cause severe damage to crops worldwide. In this investigation, tobacco lines transgenic for individual WLm constructs containing the conserved motifs of the L RNA-encoded RNA-dependent RNA polymerase (L) gene of Watermelon silver mottle virus (WSMoV) were generated by Agrobacterium-mediated transformation. The WLm constructs included: (i) translatable WLm in a sense orientation; (ii) untranslatable WLmt with two stop codons; (iii) untranslatable WLmts with stop codons and a frame-shift; (iv) untranslatable antisense WLmA; and (v) WLmhp with an untranslatable inverted repeat of WLm containing the tospoviral S RNA 3′-terminal consensus sequence (5′-ATTGCTCT-3′) and an NcoI site as a linker to generate a double-stranded hairpin transcript. A total of 46.7–70.0% transgenic tobacco lines derived from individual constructs showed resistance to the homologous WSMoV; 35.7–100% plants of these different WSMoV-resistant lines exhibited broad-spectrum resistance against four other serologically unrelated tospoviruses Tomato spotted wilt virus, Groundnut yellow spot virus, Impatiens necrotic spot virus and Groundnut chlorotic fan-spot virus. The selected transgenic tobacco lines also exhibited broad-spectrum resistance against five additional tospoviruses from WSMoV and Iris yellow spot virus clades, but not against RNA viruses from other genera. Northern analyses indicated that the broad-spectrum resistance is mediated by RNA silencing. To validate the L conserved region resistance in vegetable crops, the constructs were also used to generate transgenic tomato lines, which also showed effective resistance against WSMoV and other tospoviruses. Thus, our approach of using the conserved motifs of tospoviral L gene as a transgene generates broad-spectrum resistance against tospoviruses at the genus level.
doi:10.1371/journal.pone.0096073
PMCID: PMC4014477  PMID: 24811071
12.  Clinical and computed tomography features of adult abdominopelvic desmoplastic small round cell tumor 
To investigate the clinical and computed tomography (CT) features of desmoplastic small round cell tumor (DSRCT), we retrospectively analyzed the clinical presentations, treatment and outcome, as well as CT manifestations of four cases of DSRCT confirmed by surgery and pathology. The CT manifestations of DSRCT were as follows: (1) multiple soft-tissue masses or diffuse peritoneal thickening in the abdomen and pelvis, with the dominant mass usually located in the pelvic cavity; (2) masses without an apparent organ-based primary site; (3) mild to moderate homogeneous or heterogeneous enhancement in solid area on enhanced CT; and (4) secondary manifestations, such as ascites, hepatic metastases, lymphadenopathy, hydronephrosis and hydroureter. The prognosis and overall survival rates were generally poor. Commonly used treatment strategies including aggressive tumor resection, polychemotherapy, and radiotherapy, showed various therapeutic effects. CT of DSRCT shows characteristic features that are helpful in diagnosis. Early discovery and complete resection, coupled with postoperative adjuvant chemotherapy, are important for prognosis of DSRCT. Whole abdominopelvic rather than locoregional radiotherapy is more effective for unresectable DSRCT.
doi:10.3748/wjg.v20.i17.5157
PMCID: PMC4009557  PMID: 24803835
Desmoplastic small round cell tumor; Peritoneum; Pathology; Computed tomography; Clinical features
13.  MicroPure Imaging for the Evaluation of Microcalcifications in Gouty Arthritis Involving the First Metatarsophalangeal Joint: A Preliminary Study 
PLoS ONE  2014;9(5):e95743.
Objective
To assess the value of MicroPure, a new ultrasound image processing technique, in identifying microcalcifications (formed by monosodium urate crystals) in the first metatarsophalangeal joints attacked by gout compared to gray-scale ultrasound images.
Materials and Methods
Thirty-six patients who fulfilled the study inclusion criteria underwent gray-scale ultrasound and MicroPure examinations of the first metatarsophalangeal joints attacked by gout. Static images of the target areas were acquired using gray-scale ultrasound and MicroPure. Two independent and blinded investigators analyzed the images to determine the number of microcalcifications and to score for image quality and artifacts.
Results
The two investigators observed significantly more microcalcifications with MicroPure compared to gray-scale ultrasound (ρ<0.001). The level of agreement between the investigators consistently increased from gray-scale ultrasound to MicroPure imaging (gray-scale interclass correlation coefficient of 0.69 vs. MicroPure interclass correlation coefficient of 0.81). One investigator preferred the MicroPure image quality over gray-scale ultrasound (ρ<0.001), but the other investigator disagreed (ρ<0.001). Both investigators observed fewer artifacts with MicroPure than with gray-scale ultrasound (ρ<0.009).
Conclusion
MicroPure imaging identified significantly more microcalcifications than gray-scale ultrasound.
doi:10.1371/journal.pone.0095743
PMCID: PMC4008372  PMID: 24788200
14.  Wayside Bearing Fault Diagnosis Based on a Data-Driven Doppler Effect Eliminator and Transient Model Analysis 
Sensors (Basel, Switzerland)  2014;14(5):8096-8125.
A fault diagnosis strategy based on the wayside acoustic monitoring technique is investigated for locomotive bearing fault diagnosis. Inspired by the transient modeling analysis method based on correlation filtering analysis, a so-called Parametric-Mother-Doppler-Wavelet (PMDW) is constructed with six parameters, including a center characteristic frequency and five kinematic model parameters. A Doppler effect eliminator containing a PMDW generator, a correlation filtering analysis module, and a signal resampler is invented to eliminate the Doppler effect embedded in the acoustic signal of the recorded bearing. Through the Doppler effect eliminator, the five kinematic model parameters can be identified based on the signal itself. Then, the signal resampler is applied to eliminate the Doppler effect using the identified parameters. With the ability to detect early bearing faults, the transient model analysis method is employed to detect localized bearing faults after the embedded Doppler effect is eliminated. The effectiveness of the proposed fault diagnosis strategy is verified via simulation studies and applications to diagnose locomotive roller bearing defects.
doi:10.3390/s140508096
PMCID: PMC4062996  PMID: 24803197
fault diagnosis; locomotive bearing; wayside monitoring; Doppler effect; transient model
15.  Anthraquinone Derivatives as Potent Inhibitors of c-Met Kinase and the Extracellular Signaling Pathway 
ACS Medicinal Chemistry Letters  2013;4(4):408-413.
The aberrant function of c-Met kinase signaling pathway is ubiquitously involved in a broad spectrum of human cancers; thus, a strong rationale exists for targeting the kinase pathway in cancer therapy. Via integration of computational and experimental studies, anthraquinone derivatives were identified for the first time as potent c-Met kinase inhibitors in this research. The aberrant activation of the c-Met kinase pathway results from (TPR)-Met, MET gene mutation, or amplification and a hepatocyte growth factor (HGF)/scatter factor-dependent autocrine or paracrine mechanism. However, anthraquinone derivatives exclusively suppressed c-Met phosphorylation stimulated by HGF in A549 cells, indicating that the compounds possess the ability to block the extracellular HGF-dependent pathway. A surface plasmon resonance assay revealed that the most potent compound, 2a, shows a high binding affinity for HGF with an equilibrium dissociation constant of 1.95 μM. The dual roles of compound 2a demonstrate the potency of anthraquinone derivatives and provide a new design solution for the c-Met kinase signaling pathway.
doi:10.1021/ml4000047
PMCID: PMC4027229  PMID: 24900685
Anthraquinone derivatives; c-Met kinase inhibitors; binding affinity with HGF
16.  Cuticular differences associated with aridity acclimation in African malaria vectors carrying alternative arrangements of inversion 2La 
Parasites & Vectors  2014;7:176.
Background
Principal malaria vectors in Africa, An. gambiae and An. coluzzii, share an inversion polymorphism on the left arm of chromosome 2 (2La/2L+a) that is distributed non-randomly in the environment. Genomic sequencing studies support the role of strong natural selection in maintaining steep clines in 2La inversion frequency along environmental gradients of aridity, and physiological studies have directly implicated 2La in heat and desiccation tolerance, but the precise genetic basis and the underlying behavioral and physiological mechanisms remain unknown. As the insect cuticle is the primary barrier to water loss, differences in cuticle thickness and/or epicuticular waterproofing associated with alternative 2La arrangements might help explain differences in desiccation resistance.
Methods
To test that hypothesis, two subcolonies of both An. gambiae and An. coluzzii were established that were fixed for alternative 2La arrangements (2La or 2L+a) on an otherwise homosequential and shared genetic background. Adult mosquitoes reared under controlled environmental conditions (benign or arid) for eight days post-eclosion were collected and analyzed. Measurements of cuticle thickness were made based on scanning electron microscopy, and cuticular hydrocarbon (CHC) composition was evaluated by gas chromatography–mass spectrometry.
Results
After removing the allometric effects of body weight, differences in mean cuticle thickness were found between alternative 2La karyotypes, but not between alternative environments. Moreover, the thicker cuticle of the An. coluzzii 2La karyotype was contrary to the known higher rate of water loss of this karyotype relative to 2L+a. On the other hand, quantitative differences in individual CHCs and overall CHC profiles between alternative karyotypes and environmental conditions were consistent with expectation based on previous physiological studies.
Conclusions
Our results suggest that alternative arrangements of the 2La inversion are associated with differences in cuticle thickness and CHC composition, but that only CHC composition appears to be relevant for desiccation resistance. Differences in the CHC composition were consistent with previous findings of a lower rate of water loss for the 2L+a karyotype at eight days post-eclosion, suggesting that CHC composition is an important strategy for maintaining water balance in this genetic background, but not for 2La. Despite a higher rate of water loss at eight days, higher body water content of the 2La karyotype confers a level of desiccation resistance equivalent to that of the 2L+a karyotype.
doi:10.1186/1756-3305-7-176
PMCID: PMC3991895  PMID: 24721548
An. gambiae; An. coluzzii; Cuticular hydrocarbons; Chromosomal inversion; Cuticle; Desiccation resistance; GC-MS; M and S molecular forms
17.  ALOX5 Is Associated with Tuberculosis in a Subset of the Pediatric Population of North China 
Background: Genetic factors are involved in the etiology of Mycobacterium tuberculosis infection. Recently, ALOX5 has been identified as a candidate gene for tuberculosis (TB) susceptibility. We investigated whether an association between ALOX5 and TB exists in a Chinese pediatric population from northern China. Methods: We conducted a case–control study comprising 488 individuals aged 2 months to 17 years by genotyping 18 tag-single-nucleotide polymorphisms (SNPs) from the ALOX5 gene. The tag-SNPs were selected from the international HapMap project. An Illumina BeadXpress Scanner was utilized for genotyping, supported by the high-density BeadArray technology in combination with an allele-specific extension, adapter ligation, and amplification assay. Statistical analyses were performed to determine correlations between genetic variation and disease. Results: Our study is the first to show that ALOX5 is associated with susceptibility to pediatric TB in a subset of children in northern China. The rs2115819 T allele of ALOX5 presents a risk factor for childhood TB disease.
doi:10.1089/gtmb.2012.0426
PMCID: PMC3609609  PMID: 23448388
18.  Overexpression of Testes-Specific Protease 50 (TSP50) Predicts Poor Prognosis in Patients with Gastric Cancer 
Purpose. To investigate the expression of TSP50 protein in human gastric cancers and its correlation with clinical/prognostic significance. Methods. Immunohistochemistry (IHC) analysis of TSP50 was performed on a tissue microarray (TMA) containing 334 primary gastric cancers. Western blot was carried out to confirm the expression of TSP50 in gastric cancers. Results. IHC analysis revealed high expression of TSP50 in 57.2% human gastric cancer samples (191 out of 334). However, it was poorly expressed in all of the 20 adjacent nontumor tissues. This was confirmed by western blot, which showed significantly higher levels of TSP50 expression in gastric cancer tissues than adjacent nontumor tissues. A significant association was found between high levels of TSP50 and clinicopathological characteristics including junior age at surgery (P = 0.001), later TNM stage (P = 0.000), and present lymph node metastases (P = 0.003). The survival of gastric cancer patients with high expression of TSP50 was significantly shorter than that of the patients with low levels of TSP50 (P = 0.021). Multivariate Cox regression analysis indicated that TSP50 overexpression was an independent prognostic factor for gastric cancer patients (P = 0.017). Conclusions. Our data demonstrate that elevated TSP50 protein expression could be a potential predictor of poor prognosis in gastric cancer patients.
doi:10.1155/2014/498246
PMCID: PMC3985325  PMID: 24799889
19.  Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage 
Molecular Brain  2014;7:20.
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is conventionally considered a critical enzyme that involves in glycolysis for energy production. Recent previous studies have suggested that GAPDH is important in glutamate-induced neuronal excitotoxicity, while accumulated evidence also demonstrated that GAPDH nuclear translocation plays a critical role in cell death. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we showed that GAPDH translocates to the nucleus in a Siah1-dependent manner upon glutamate stimulation. The nuclear GAPDH forms a protein complex with p53 and enhances p53 expression and phosphorylation. Disruption of the GAPDH-p53 interaction with an interfering peptide blocks glutamate-induced cell death and GAPDH-mediated up-regulation of p53 expression and phosphorylation. Furthermore, administration of the interfering peptide in vivo protects against ischemia-induced cell death in rats subjected to tMCAo. Our data suggest that the nuclear p53-GAPDH complex is important in regulating glutamate-mediated neuronal death and could serve as a potential therapeutic target for ischemic stroke treatment.
doi:10.1186/1756-6606-7-20
PMCID: PMC3986870  PMID: 24670206
20.  Structural and biochemical insights into the V/I505T mutation found in the EIAV gp45 vaccine strain 
Retrovirology  2014;11:26.
Background
The equine infectious anemia virus (EIAV) is a lentivirus of the Retrovirus family, which causes persistent infection in horses often characterized by recurrent episodes of high fever. It has a similar morphology and life cycle to the human immunodeficiency virus (HIV). Its transmembrane glycoprotein, gp45 (analogous to gp41 in HIV), mediates membrane fusion during the infection. However, the post-fusion conformation of EIAV gp45 has not yet been determined. EIAV is the first member of the lentiviruses for which an effective vaccine has been successfully developed. The attenuated vaccine strain, FDDV, has been produced from a pathogenic strain by a series of passages in donkey dermal cells. We have previously reported that a V/I505T mutation in gp45, in combination with other mutations in gp90, may potentially contribute to the success of the vaccine strain. To this end, we now report on our structural and biochemical studies of the gp45 protein from both wide type and vaccine strain, providing a valuable structural model for the advancement of the EIAV vaccine.
Results
We resolved crystal structures of the ecto-domain of gp45 from both the wild-type EIAV and the vaccine strain FDDV. We found that the V/I505T mutation in gp45 was located in a highly conserved d position within the heptad repeat, which protruded into a 3-fold symmetry axis within the six-helix bundle. Our crystal structure analyses revealed a shift of a hydrophobic to hydrophilic interaction due to this specific mutation, and further biochemical and virological studies confirmed that the mutation reduced the overall stability of the six-helix bundle in post-fusion conformation. Moreover, we found that altering the temperatures drastically affected the viral infectivity.
Conclusions
Our high-resolution crystal structures of gp45 exhibited high conservation between the gp45/gp41 structures of lentiviruses. In addition, a hydrophobic to hydrophilic interaction change in the EIAV vaccine strain was found to modulate the stability and thermal-sensitivity of the overall gp45 structure. Our observations suggest that lowering the stability of the six-helix bundle (post-fusion), which may stabilizes the pre-fusion conformation, might be one of the reasons of acquired dominance for FDDV in viral attenuation.
doi:10.1186/1742-4690-11-26
PMCID: PMC3997929  PMID: 24656154
EIAV; gp45; Crystal structure; Stability; Vaccine strain; Heptad repeat; Pre-fusion conformation; Replication
21.  Reduction of left ventricular longitudinal global and segmental systolic functions in patients with hypertrophic cardiomyopathy: Study of two-dimensional tissue motion annular displacement 
The early detection of abnormal left ventricular systolic functions in patients with hypertrophic cardiomyopathy (HCM) remains a challenge. The aim of this study was to identify a novel method for the assessment of left ventricular systolic function in patients with HCM. A total of 65 patients with HCM were included in this study. The patients were divided into obstructive HCM (HOCM; 16 cases) and non-obstructive HCM (NOHCM; 49 cases) groups. The healthy control group comprised 48 participants. Two-dimensional (2D) speckle-tracking technology was used to measure the left ventricular global and segmental longitudinal strains and mitral annular displacement (MADs). Compared with healthy control group, the six segmental strains and the global strain of the left ventricle (LSglobal) increased while six segmental MADs and MADglobal of the mitral annulus decreased in the HOCM and NOHCM groups (P<0.05). In addition, the six segmental MADs of the mitral annulus were significantly negatively correlated with the six segmental strains of the left ventricle (r=−0.744 to −0.647, P<0.001). MADglobal was significantly negatively correlated with LSglobal (r=−0.857, P<0.001). The tissue motion annular displacement (TMAD) at the midpoint was significantly negatively correlated with LSglobal (r=−0.871, P<0.001). The 2D TMAD technique of measuring MAD was feasible and practically approachable for rapidly evaluating the left ventricular longitudinal global and segmental systolic functions of patients with HCM.
doi:10.3892/etm.2014.1617
PMCID: PMC4043569  PMID: 24926326
echocardiography; hypertrophic cardiomyopathy; left ventricular function; two-dimensional strain; tissue motion annular displacement
22.  FTSJ2, a Heat Shock-Inducible Mitochondrial Protein, Suppresses Cell Invasion and Migration 
PLoS ONE  2014;9(3):e90818.
Ribosomal RNA large subunit methyltransferase J (RrmJ), an Escherichia coli heat shock protein, is responsible for 2′-O-ribose methylation in 23S rRNA. In mammals, three close homologs of RrmJ have been identified and have been designated as FTSJ1, FTSJ2 and FTSJ3; however, little is known about these genes. In this study, we characterized the mammalian FTSJ2, which was the most related protein to RrmJ in a phylogenetic analysis that had similar amino acid sequence features and tertiary protein structures of RrmJ. FTSJ2 was first identified in this study as a nucleus encoded mitochondrial protein that preserves the heat shock protein character in mammals in which the mRNA expressions was increased in porcine lung tissues and A549 cells after heat shock treatment. In addition, a recent study in non-small cell lung cancer (NSCLC) suggested that the FTSJ2 gene is located in a novel oncogenic locus. However, our results demonstrate that the expression of FTSJ2 mRNA was decreased in the more invasive subline (CL1-5) of the lung adenocarcinoma cells (CL1) compared with the less invasive subline (CL1-0), and overexpression of FTSJ2 resulted in the inhibition of cell invasion and migration in the rhabdomyosarcoma cell (TE671). In conclusion, our findings indicate that mammalian FTSJ2 is a mitochondrial ortholog of E. coli RrmJ and conserves the heat shock protein properties. Moreover, FTSJ2 possesses suppressive effects on the invasion and migration of cancer cells.
doi:10.1371/journal.pone.0090818
PMCID: PMC3942483  PMID: 24595062
23.  Inhibition of Baicalin on Metabolism of Phenacetin, a Probe of CYP1A2, in Human Liver Microsomes and in Rats 
PLoS ONE  2014;9(2):e89752.
Baicalin has been used as mainly bioactive constituent of about 100 kinds of traditional Chinese medicines in Chinese pharmacopoeia. The effect of baicalin on cytochrome P450 should be paid more attention because baicalin was used widely. The aim of this study was to investigate whether baicalin could inhibit CYP1A2 in pooled human liver microsomes (HLMs) and in rats in vivo and the gene polymorphisms could affect inter-individual variation in IC50 in 28 human livers. Phenacetin was used as probe of CYP1A2. Kinetic parameter of CYP1A2 and IC50 of baicalin on CYP1A2 to each sample were measured and the common CYP1A2 polymorphisms (−3860G>A and −163C>A) were genotyped. The results showed that baicalin exhibited a mixed-type inhibition in pooled HLMs, with a Ki value of 25.4 µM. There was substantial variation in Km, Vmax, CLint of CYP1A2 and IC50 of baicalin on CYP1A2 (3∼10-fold). The range was from 26.6 to 114.8 µM for Km, from 333 to 1330 pmol·min−1·mg−1protein for Vmax and from 3.8 to 45.3 µL·min−1·mg−1 protein for CLint in HLMs (n = 28). The Mean (range) value of IC50 in 28 HLMs was 36.3 (18.9 to 56.1) µM. The genotypes of −3860G>A and −163C>A had no significant effect on the inhibition of baicalin on CYP1A2. The animal experiment results showed that baicalin (450 mg/kg, i.v.) significantly decreased the Cmax and CL of phenacetin, and increased C60 min, t1/2, Vd and AUC (P<0.05). There were significant correlations between percentage of control in C60 min, t1/2, CL, AUC of phenacetin and Cmax of baicalin in 11 rats (P<0.05). Protein binding experiments in vitro showed that baicalin (0–2000 mg/L) increased the unbound phenacetin from 14.5% to 28.3%. In conclusion, baicalin can inhibit the activity of CYP1A2 in HLMs and exhibit large inter-individual variation that has no relationship with gene polymorphism. Baicalin can change the pharmacokinetics of phenacetin in rats.
doi:10.1371/journal.pone.0089752
PMCID: PMC3935934  PMID: 24587011
24.  Behavioural divergence of sympatric Anopheles funestus populations in Burkina Faso 
Malaria Journal  2014;13:65.
Background
In Burkina Faso, two chromosomal forms of the malaria vector Anopheles funestus, Folonzo and Kiribina, are distinguished by contrasting frequencies of shared polymorphic chromosomal inversions. Sympatric and synchronous populations of Folonzo and Kiribina mate assortatively, as indicated by a significant deficit of heterokaryotypes, and genetic associations among inversions on independently segregating chromosome arms. The present study aimed to assess, by intensive longitudinal sampling, whether sympatric Folonzo and Kiribina populations are characterized by behavioural differences in key malaria vectorial parameters.
Methods
The study was conducted in two adjacent villages near Ouagadougou, in the dry savanna of central Burkina Faso. Mosquito adult resting behaviour of both forms was compared based on parallel indoor/outdoor collections across six breeding seasons; 8,235 fully karyotyped samples of half-gravid females were analysed in total. Additionally, indoor/outdoor human biting behaviour, host selection, and Plasmodium falciparum sporozoite rate was assessed and compared between chromosomal forms.
Results
The Kiribina form was numerically predominant in the area. However, the Folonzo form was significantly over-represented in indoor resting collections and showed stronger post-prandial endophily, while Kiribina predominated outdoors. Neither form was statistically distinguishable in human biting behaviour, and both were more likely to seek human blood meals indoors than outside. The human blood index and sporozoite rate were comparably high in both chromosomal forms in indoor collections (>89% and >8%, respectively).
Conclusions
Both Kiribina and Folonzo chromosomal forms are formidable malaria vectors in Burkina Faso. However, the significantly greater tendency for the Kiribina form to rest outdoors despite its pronounced anthropophily suggests that uniform exposure of the overall An. funestus population to indoor-based vector control tools cannot be expected; Kiribina is more likely to evade indoor interventions and escape unharmed outdoors, reducing the efficacy of malaria control. Accordingly, more efficient methods to detect Kiribina and Folonzo, and a more complete understanding of their distribution and behaviour in Africa are advocated.
doi:10.1186/1475-2875-13-65
PMCID: PMC3937823  PMID: 24559382
Anopheles funestus; Anthropophily; Behavioural divergence; Chromosomal forms; Exophily; Folonzo; Kiribina; Malaria vector; West Africa
25.  Pulmonary vascular malformation complicating cryptococcal pneumonia in an immunocompetent patient 
An immunocompetent 50-year-old male presented with slight cough and occasional lung congestion. The radiologic findings included diffuse, bilateral reticular and one nodular opacity at the upper lobe of right lung without clear margin. A wedge resection of the lesion showed disordered distribution of the medium-sized vessels and arterioles, several arterioles densely gathered including a few occlusive arterioles, or medium veins dilated with irregular and elongated cavity, indicating the existence of vascular malformation. Interestingly, near to the malformed vessels, a large area of necrosis with granulomatous inflammation was found. Of note, numerous intracytoplasmic organisms with a nucleus, a wall and a thick capsule, were free in the alveoli or located within the macrophages and polykaryocytes, suggesting cryptococci infection. This is to our best knowledge the first case showing concurrent vascular malformation and local pulmonary cryptococcosis, and vascular malformation was likely an important pathological predisposing factor for local pulmonary cryptococcosis infection.
PMCID: PMC3971334  PMID: 24696743
Pulmonary cryptococci; vascular malformation

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