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1.  An Efficient Strategy for Heterologous Expression and Purification of Active Peptide Hainantoxin-IV 
PLoS ONE  2015;10(2):e0117099.
Hainantoxin-IV (HNTX-IV) from the venom of the spider Selenocosmia hainana is a potent antagonist that specifically inhibits the tetrodotoxin-sensitive (TTX-S) sodium channels. The toxin peptide consists of 35 amino acids and adopts a typical inhibitory cystine knot (ICK) motif. To obtain adequate HNTX-IV peptides for further insight into the structure-activity relationships of the toxin, a novel strategy including cloning, expression and purification was developed in an E. coli expression system. For this purpose, a seamless restriction-free (RF) cloning method was employed for the construction of an expression vector to avoid introducing unwanted sequences into the target gene. Furthermore, the solubility of recombinant HNTX-IV could be promoted efficiently by the combination of a glutathione S-transferase (GST) tag and a small ubiquitin-related modifier (SUMO) tag. Finally, an affinity-chromatography-free purification strategy was developed by cut-off dialysis tubing combined with trichloroacetic acid (TCA) extraction. Further HPLC purification yielded recombinant, tag-free HNTX-IV with high yield and purity. The molecular weight of recombinant HNTX-IV (rHNTX-IV) is identical to its theoretical value according to Matrix-Assisted Laser Desorption / Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) analysis. The recombinant toxin has similar activity (IC50 value of 120 nM) on the tetrodotoxin-sensitive (TTX-S) sodium channels in adult rat dorsal root ganglion (DRG) neurons to native toxins. In the report, an efficient and cost-effective strategy for producing rHNTX-IV was developed, which paved the way for the further study of structure-activity relationships of rHNTX-IV and its pharmaceutical applications.
doi:10.1371/journal.pone.0117099
PMCID: PMC4315428  PMID: 25647561
2.  Cardiac fibroblasts mediate IL-17A–driven inflammatory dilated cardiomyopathy 
The Journal of Experimental Medicine  2014;211(7):1449-1464.
IL-17A stimulates cardiac fibroblasts to produce inflammatory mediators critical for the recruitment and differentiation of myeloid cells during inflammatory dilated cardiomyopathy.
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra−/− mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A–fibroblast–GM-CSF–MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
doi:10.1084/jem.20132126
PMCID: PMC4076595  PMID: 24935258
3.  Twenty-five-year changing pattern of gonococcal antimicrobial susceptibility in Shanghai: surveillance and its impact on treatment guidelines 
BMC Infectious Diseases  2014;14:731.
Background
Antimicrobial resistance of Neisseria gonorrhoeae is a serious health problem in China. Gonococcal antimicrobial susceptibility has been monitored in Shanghai since 1988. In this study, we examined the changing pattern of gonococcal antimicrobial susceptibility based on data from N. gonorrhoeae isolates collected over the past 25 years.
Methods
Approximately 100–200 isolates each year (1988–2013) were tested for their susceptibility to penicillin (PEN), tetracycline (TET), ciprofloxacin (CIP), ceftriaxone (CRO) and spectinomycin (SPT), using the agar dilution method. Plasmid-mediated N. gonorrhoeae antimicrobial resistance, comprising penicillinase-producing N. gonorrhoeae (presumed PPNG) and high-level tetracycline resistance N. gonorrhoeae (presumed TRNG), were also determined. Breakpoints for susceptibilities followed those described by the Clinical and Laboratory Standard Institute and the European Committee on Antimicrobial Susceptibility Testing.
Results
A high proportion of isolates were resistant to PEN, TET and CIP, ranging from less than 20% at the beginning of the survey, increasing in the late 1990s and reaching over 90% in recent years. The proportion of isolates exhibiting plasmid-mediated resistance exceeded 38% for presumed PPNG and 20% for presumed TRNG in recent years. The proportion of CRO nonsusceptible isolates (MIC ≥ 0.125 mg/L) ranged from 7% to 13% in most of the study years. Almost all isolates were susceptible to SPT. The SPT MIC90 was 16–32 mg/L for 2008–2013. The proportion of CRO nonsusceptible-associated multiple-drug-resistant (MDR) isolates was over 5% in most of the study years.
Conclusions
N. gonorrhoeae isolates in Shanghai were resistant to PEN, TET and CIP. Furthermore, CRO nonsusceptible and MDR isolates were prevalent. N. gonorrhoeae isolates were also found to be susceptible to SPT. It is recommended that the CRO dose be increased from currently recommended 250 mg to 500 mg and that SPT be an alternative in treating urogenital gonorrhea. Our findings highlight the importance of both regional and national surveillance programs for the prompt modification of treatment guidelines, vital in responding to the changing pattern of gonococcal antimicrobial susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-014-0731-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-014-0731-9
PMCID: PMC4334756  PMID: 25547132
Neisseria gonorrhoeae; Antimicrobial susceptibility; Multiple drug resistance; Ceftriaxone; Spectinomycin
4.  Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN 
British Journal of Haematology  2013;164(1):811-821.
Summary
Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4CRBN. T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4CRBN substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4CRBN is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4CRBN with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4CRBN, leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.
doi:10.1111/bjh.12708
PMCID: PMC4232904  PMID: 24328678
lenalidomide; pomalidomide; Cereblon; Ikaros; Aiolos
5.  Epigenetics of hyper-responsiveness to allergen challenge following intrauterine growth retardation rat 
Respiratory Research  2014;15(1):137.
Background
Epidemiological studies have revealed that intrauterine growth retardation (IUGR) or low birth weight is linked to the later development of asthma. Epigenetic regulatory mechanisms play an important role in the fetal origins of adult disease. However, little is known regarding the correlation between epigenetic regulation and the development of asthma following IUGR.
Methods
An IUGR and ovalbumin (OVA)-sensitization/challenge rat model was used to study whether epigenetic mechanisms play a role in the development of asthma following IUGR.
Results
Maternal nutrient restriction increased histone acetylation levels of the endothelin-1 (ET-1) gene promoter in lung tissue of offspring, but did not cause significant alterations of DNA methylation. The effect was maintained until 10 weeks after birth. Furthermore, these epigenetic changes may have induced IUGR individuals to be highly sensitive to OVA challenge later in life, resulting in more significant changes related to asthma.
Conclusions
These findings suggest that epigenetic mechanisms might be closely associated with the development of asthma following IUGR, providing further insight for improved prevention of asthma induced by environmental factors.
doi:10.1186/s12931-014-0137-7
PMCID: PMC4233040  PMID: 25391516
Allergen; Asthma; Epigenetics; Endothelin-1; Intrauterine growth retardation
6.  Clinical evaluation of the Asian proximal femur intramedullary nail antirotation system (PFNA-II) for treatment of intertrochanteric fractures 
Background
The preferred treatment of intertrochanteric fractures in aged patients is controversial. The purpose of the present study was to evaluate the outcomes of the Asian proximal femur intramedullary nail antirotation system (PFNA-II) for stabilization of such fractures.
Methods
The PFNA-II was used to treat intertrochanteric fractures in 163 elderly patients from March 2010 to March 2013. The patients comprised 69 men and 94 women with a mean age of 74.7 ± 13.0 years. All fractures were classified by the Orthopaedic Trauma Association classification system; 53, 83, and 27 fractures were classified as 31A1, 31A2, and 31A3, respectively. We statistically evaluated the intraoperative blood loss, operation time, incision length, X-ray exposure time, and postoperative outcomes. Patients were followed up for a mean of 15.2 months (range, 10–24 months). Functional outcomes were assessed according to the Harris hip scoring system.
Results
Statistical analysis revealed an average operation time of 45.7 min (range, 35–110 min), average intraoperative blood loss of 115.2 mL (range, 65–430 mL), X-ray exposure time of 2.7 ± 1.4 s (range, 2–6 s), and total incision length of 6.5 ± 2.2 cm (range, 5.5–13.0 cm). Patients were followed up for a mean of 14.5 months (range, 10–24 months). The neck shaft angle was 134° ±15° (range, 115°–150°), and the fracture healing time was 14.0 ± 2.5 weeks (range, 11–19 weeks). The Harris hip score was 85.6 ± 17.5 points (range, 65–100 points) and included 41 excellent cases (25.15%), 92 good cases (56.44%), 26 moderate cases (15.95%), and 4 poor cases (2.45%) for a positive outcome rate of 81.60%. There were no varus hip deformities, screw cutouts, or femoral shaft fractures. Fourteen patients had thigh pain (9.82%), and five had inner thigh pain (3.07%); seven had more severe pain that was improved by physical therapy.
Conclusion
PFNA-II has the advantages of a simple operation, few complications, and clinical efficacy for the treatment of intertrochanteric fractures. However, evaluation of its long-term efficacy and risk of other complications requires a large-sample, multicenter observational study.
doi:10.1186/s13018-014-0112-5
PMCID: PMC4233078  PMID: 25391985
7.  Functional expression, characterization and application of the human S100A4 protein 
Molecular Medicine Reports  2014;11(1):175-181.
Preparations utilizing monoclonal antibodies against S100A4 provide useful tools for functional studies to investigate the clinical applications of the human S100A4 protein. In the present study, human S100A4 protein was expressed in Escherichia coli (E. coli) BL21 (DE3), successfully purified by diethylaminoethyl cellulose anion-exchange chromatography and identified by western blot analysis. Soluble S100A4 bioactivity was confirmed by Transwell migration and invasion assays in the human HeLa cell line. Monoclonal antibodies (mAbs) were generated utilizing the standard hybridoma method and were validated by enzyme-linked immunosorbent assay and western blot analysis. The antibody was then used to examine human gastric carcinoma specimens by immunohistochemistry. Recombinant S100A4 was functionally expressed in E. coli and promoted the migration and invasion of HeLa cells. Four hybridoma cell lines, which secreted mAbs specifically against human S100A4 protein, were obtained. One of the four mAbs, namely 2A12D10B2, recognized human S100A4 as indicated by immunohistochemical staining of human gastric carcinoma specimens and recombinant S100A4 was functionally expressed in E. coli. The mAbs of recombinant S100A4 were suitable for detecting S100A4 expression in human tissues and for investigating the subsequent clinical applications of the protein.
doi:10.3892/mmr.2014.2745
PMCID: PMC4237081  PMID: 25339497
human S100A4 protein; monoclonal antibody; preparation; application
8.  The resistive switching memory of CoFe2O4 thin film using nanoporous alumina template 
Nanoscale Research Letters  2014;9(1):584.
A novel conductive process for resistive random access memory cells is investigated based on nanoporous anodized aluminum oxide template. Bipolar resistive switching characteristic is clearly observed in CoFe2O4 thin film. Stable and repeatable resistive switching behavior is acquired at the same time. On the basis of conductive filament model, possible generation mechanisms for the resistive switching behaviors are discussed intensively. Besides, the magnetic properties of samples (before and after the annealing process) are characterized, and the distinct changes of magnetic anisotropy and coercive field are detected. The present results provide a new perspective to comprehend the underlying physical origin of the resistive switching effect.
PACS
68.37.-d; 73.40.Rw; 73.61.-r
doi:10.1186/1556-276X-9-584
PMCID: PMC4232846  PMID: 25404869
Nanowire; Thin film; Electrochemical deposition; Resistive random access memory
9.  Fatal eosinophilic myocarditis develops in the absence of IFNγ and IL17A 
CD4+ T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with helper T cell effector function as a necessary mediator of this pathophysiology. IFNγ-deficient mice developed severe autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, while IL17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFNγ−/−IL17A−/− mice to assess whether IL17 signaling was responsible for the severe EAM of IFNγ−/− mice. Surprisingly, IFNγ−/−IL17A−/− mice developed a rapidly fatal EAM. Eosinophils comprised a third of infiltrating leukocytes, qualifying this disease eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, and Th2 deviation among heart-infiltrating CD4+ cells. Ablation of eosinophil development improved survival of IFNγ−/−IL17A−/− mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFNγ and IL17A constitutes a novel model of eosinophilic heart disease in humans. This is also the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.
doi:10.4049/jimmunol.1301282
PMCID: PMC3927983  PMID: 24048893
myocarditis; autoimmune disease; cytokines; IFNγ; IL17A; eosinophils; Th2 cells
10.  BraLTP1, a Lipid Transfer Protein Gene Involved in Epicuticular Wax Deposition, Cell Proliferation and Flower Development in Brassica napus 
PLoS ONE  2014;9(10):e110272.
Plant non-specific lipid transfer proteins (nsLTPs) constitute large multigene families that possess complex physiological functions, many of which remain unclear. This study isolated and characterized the function of a lipid transfer protein gene, BraLTP1 from Brassica rapa, in the important oilseed crops Brassica napus. BraLTP1 encodes a predicted secretory protein, in the little known VI Class of nsLTP families. Overexpression of BnaLTP1 in B. napus caused abnormal green coloration and reduced wax deposition on leaves and detailed wax analysis revealed 17–80% reduction in various major wax components, which resulted in significant water-loss relative to wild type. BnaLTP1 overexpressing leaves exhibited morphological disfiguration and abaxially curled leaf edges, and leaf cross-sections revealed cell overproliferation that was correlated to increased cytokinin levels (tZ, tZR, iP, and iPR) in leaves and high expression of the cytokinin biosynthsis gene IPT3. BnaLTP1-overexpressing plants also displayed morphological disfiguration of flowers, with early-onset and elongated carpel development and outwardly curled stamen. This was consistent with altered expression of a a number of ABC model genes related to flower development. Together, these results suggest that BraLTP1 is a new nsLTP gene involved in wax production or deposition, with additional direct or indirect effects on cell division and flower development.
doi:10.1371/journal.pone.0110272
PMCID: PMC4196963  PMID: 25314222
11.  Panax ginseng therapy for chronic obstructive pulmonary disease: a clinical trial protocol and pilot study 
Chinese Medicine  2014;9:20.
Background
Panax ginseng (Ren shen) has been used to treat chronic obstructive pulmonary disease (COPD). This article aims to present a study protocol and pilot trial comparing P. ginseng with placebo for treating moderate to very severe COPD.
Methods
COPD was diagnosed spirometrically, with participants having a forced expiratory volume in one second (FEV1) of between 20% and 79% and FEV1 to forced vital capacity (FVC) ratio of less than 70%. Outcome measures included exacerbation rate, St. Georges Respiratory Questionnaire, COPD Assessment Test and Short-form Health Survey (SF-36). Other outcome measures included the six-minute walk test, FEV1, FVC, relief medication use, use of COPD-specific medical resources, and adverse events. The study is a randomized, double-blind, placebo controlled clinical trial. The method of this pilot trial was based on a planned full-scale trial except that participants were enrolled for ten weeks compared to 52 weeks. In the pilot trial, 14 participants (57–73 years old) with moderate to very severe COPD were recruited from a community health program at a public Chinese medicine hospital in Guangdong Province, China. After a 2-week run-in period, 10 participants were eligible for the study and were randomly assigned to either P. ginseng group (n = 5) (200 mg twice daily for four weeks) or placebo group (n = 5), and then followed-up for an additional 4 weeks for a total of 10 weeks.
Results
Nine participants completed the trial and one dropped out. The exacerbation rate could not be evaluated because there were no exacerbations. One participant in P. ginseng group reported events of sore throat, cough and fever. Trial investigators did not consider these events as COPD exacerbations or adverse events.
Conclusions
Participant recruitment, study design, data collection and outcome measurement have been tested in a pilot trial. A full-scale trial is warranted.
doi:10.1186/1749-8546-9-20
PMCID: PMC4144315  PMID: 25161696
12.  Association between Serum Uric Acid Level and Metabolic Syndrome and Its Sex Difference in a Chinese Community Elderly Population 
Objective. This study aimed to evaluate the association between serum uric acid (SUA) levels within a normal to high range and the risk of metabolic syndrome (MetS) among community elderly and explore the sex difference. Design and Methods. A cross-sectional study was conducted in a representative urban area of Beijing between 2009 and 2010. A two-stage stratified clustering sampling method was used and 2102 elderly participants were included. Results. The prevalence of hyperuricemia and MetS was 16.7% and 59.1%, respectively. There was a strong association between hyperuricemia and four components of MetS in women and three components in men. Multiple logistic regression analysis showed ORs of hyperuricemia for MetS were 1.67 (95% CI: 1.11–2.50) in men and 2.73 (95% CI: 1.81–4.11) in women. Even in the normal range, the ORs for MetS increased gradually according to SUA levels. MetS component number also showed an increasing trend across SUA quartile in both sexes (P for trend < 0.01). Conclusion. This study suggests that higher SUA levels, even in the normal range, are positively associated with MetS among Chinese community elderly, and the association is stronger in women than men. Physicians should recognize MetS as a frequent comorbidity of hyperuricemia and take early action to prevent subsequent disease burden.
doi:10.1155/2014/754678
PMCID: PMC4129973  PMID: 25136366
13.  Integrated Navigation Fusion Strategy of INS/UWB for Indoor Carrier Attitude Angle and Position Synchronous Tracking 
The Scientific World Journal  2014;2014:215303.
In some GPS failure conditions, positioning for mobile target is difficult. This paper proposed a new method based on INS/UWB for attitude angle and position synchronous tracking of indoor carrier. Firstly, error model of INS/UWB integrated system is built, including error equation of INS and UWB. And combined filtering model of INS/UWB is researched. Simulation results show that the two subsystems are complementary. Secondly, integrated navigation data fusion strategy of INS/UWB based on Kalman filtering theory is proposed. Simulation results show that FAKF method is better than the conventional Kalman filtering. Finally, an indoor experiment platform is established to verify the integrated navigation theory of INS/UWB, which is geared to the needs of coal mine working environment. Static and dynamic positioning results show that the INS/UWB integrated navigation system is stable and real-time, positioning precision meets the requirements of working condition and is better than any independent subsystem.
doi:10.1155/2014/215303
PMCID: PMC4121039  PMID: 25121111
14.  Hydrogen sulfide reduces kidney injury due to urinary-derived sepsis by inhibiting NF-κB expression, decreasing TNF-α levels and increasing IL-10 levels 
The present study aimed to investigate the effect of hydrogen sulfide (H2S) on kidney injury induced by urinary-derived sepsis. Rabbits were randomly divided into control, sham, sepsis, NaHS 2.8 μmol/kg and NaHS 8.4 μmol/kg groups, with six rabbits in each group. Upper urinary tract obstruction and acute infection was induced to establish the sepsis model. Blood was collected to carry out a white blood cell (WBC) count, and creatinine (Cr) and blood urea nitrogen (BUN) analysis. Morphological changes were observed by hematoxylin and eosin (H&E) staining and transmission electron microscopy. Immunohistochemical staining was used to detect the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-10 and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). Cystathionine-γ-lyase (CSE) activity was measured by the spectrophotometric methylene blue method and the blood H2S concentration was measured by deproteinization. WBC, Cr and BUN levels were significantly elevated in the sepsis group compared with those in the control group (P<0.05). Following treatment with NaHS, the WBC, Cr and BUN levels were significantly decreased in the NaHS groups compared with those in the sepsis group (P<0.05). The pathological features of kidney injury were also alleviated by NaHS. In the sepsis group, the levels of TNF-α, IL-10 and NF-κB were significantly increased compared with those in the control group (P<0.05). In the NaHS groups, the TNF-α and NF-κB levels were significantly reduced whereas the IL-10 level was significantly increased compared with the respective levels in the sepsis group (P<0.05). The H2S concentration was significantly decreased in the sepsis group and this reduction was attenuated in the NaHS groups (P<0.05). Furthermore, the NaHS 8.4 μmol/kg dose revealed a more potent effect than the NaHS 2.8 μmol/kg dose. Thus, exogenous H2S reduced kidney injury from urinary-derived sepsis by decreasing the levels of NF-κB and TNF-α, and increasing the level of IL-10.
doi:10.3892/etm.2014.1781
PMCID: PMC4079422  PMID: 25009602
hydrogen sulfide; kidney injury; urinary-derived sepsis; NF-κB; TNF-α; IL-10
15.  Screening for Voltage-Gated Sodium Channel Interacting Peptides 
Scientific Reports  2014;4:4569.
The voltage-gated sodium channel (VGSC) interacting peptide is of special interest for both basic research and pharmaceutical purposes. In this study, we established a yeast-two-hybrid based strategy to detect the interaction(s) between neurotoxic peptide and the extracellular region of VGSC. Using a previously reported neurotoxin JZTX-III as a model molecule, we demonstrated that the interactions between JZTX-III and the extracellular regions of its target hNav1.5 are detectable and the detected interactions are directly related to its activity. We further applied this strategy to the screening of VGSC interacting peptides. Using the extracellular region of hNav1.5 as the bait, we identified a novel sodium channel inhibitor SSCM-1 from a random peptide library. This peptide selectively inhibits hNav1.5 currents in the whole-cell patch clamp assays. This strategy might be used for the large scale screening for target-specific interacting peptides of VGSCs or other ion channels.
doi:10.1038/srep04569
PMCID: PMC3972499  PMID: 24691553
16.  The spatiospectral characterization of brain networks: fusing concurrent EEG spectra and fMRI maps 
NeuroImage  2012;69:101-111.
Different imaging modalities capture different aspects of brain activity. Functional Magnetic Resonance Imaging (fMRI) reveals intrinsic networks whose BOLD signals have periods from 100s (0.01 Hz) to about 10s (0.1 Hz). Electroencephalographic (EEG) recordings, in contrast, commonly reflect cortical electrical fluctuations with periods up to 20 ms (50 Hz) or above. We examined the correspondence between intrinsic fMRI and EEG network activity at rest in order to characterize brain networks both spatially (with fMRI) and spectrally (with EEG). Brain networks were separately identified within the concurrently recorded fMRI and EEG at the aggregate group level with group independent component analysis and the association between spatial fMRI and frequency by spatial EEG sources was examined by deconvolving their component time courses. The two modalities are considered linked if the estimated impulse response function (IRF) is significantly non-zero at biologically plausible delays. We found that negative associations were primarily present within two of five alpha components, which highlights the importance of considering multiple alpha sources in EEG-fMRI. Positive associations were primarily present within the lower (e.g. delta and theta) and higher (e.g. upper beta and lower gamma) spectral regions, sometimes within the same fMRI components. Collectively, the results demonstrate a promising approach to characterize brain networks spatially and spectrally, and reveal that positive and negative associations appear within partially distinct regions of the EEG spectrum.
doi:10.1016/j.neuroimage.2012.12.024
PMCID: PMC3568990  PMID: 23266744
EEG-fMRI; ICA; intrinsic connectivity networks; deconvolution
17.  Respiratory complications associated with ketamine anesthesia for ophthalmic procedures following intraocular pressure measurement in children 
Background:
We compared respiratory complications (RCs) in children who received intramuscular (IM) versus intravenous (IV) or no ketamine for intraocular pressure (IOP) measurement to test our observation that IM ketamine is associated with higher incidence of RCs.
Materials and Methods:
We analyzed 149 eye examinations under anesthesia with ketamine in 27 patients and 263 non-ketamine examinations under anesthesia in 81 patients using a mixed effects logistic regression model.
Results:
IM ketamine was strongly associated with increased odds of RCs compared to no ketamine (odds ratio (OR): 20.23, P < 0.0001) and to IV ketamine (OR: 6.78, P = 0.02), as were higher American Society of Anesthesiologists (ASA) classification (OR: 2.60, P = 0.04), and the use of volatile agents (OR: 3.32, P = 0.02).
Conclusion:
Further studies should be conducted to confirm our observation of increased RCs with IM ketamine.
doi:10.4103/0970-9185.130047
PMCID: PMC4009650  PMID: 24803768
Adverse events; child; infant; intravenous agents; ophthalmology
18.  Identification and Characterization of a Suite of Tumor Targeting Peptides for Non-Small Cell Lung Cancer 
Scientific Reports  2014;4:4480.
Tumor targeting ligands are emerging components in cancer therapies. Widespread use of targeted therapies and molecular imaging is dependent on increasing the number of high affinity, tumor-specific ligands. Towards this goal, we biopanned three phage-displayed peptide libraries on a series of well-defined human non-small cell lung cancer (NSCLC) cell lines, isolating 11 novel peptides. The peptides show distinct binding profiles across 40 NSCLC cell lines and do not bind normal bronchial epithelial cell lines. Binding of specific peptides correlates with onco-genotypes and activation of particular pathways, such as EGFR signaling, suggesting the peptides may serve as surrogate markers. Multimerization of the peptides results in cell binding affinities between 0.0071–40 nM. The peptides home to tumors in vivo and bind to patient tumor samples. This is the first comprehensive biopanning for isolation of high affinity peptidic ligands for a single cancer type and expands the diversity of NSCLC targeting ligands.
doi:10.1038/srep04480
PMCID: PMC3967199  PMID: 24670678
19.  Involvement of Oxidative Stress and Inflammation in Liver Injury Caused by Perfluorooctanoic Acid Exposure in Mice 
BioMed Research International  2014;2014:409837.
Perfluorooctanoic acid (PFOA) is widely present in the environment and has been reported to induce hepatic toxicity in animals and humans. In this study, mice were orally administered different concentrations of PFOA (2.5, 5, or 10 mg/kg/day). Histological examination showed that the exposure to PFOA for 14 consecutive days led to serious hepatocellular injury and obvious inflammatory cell infiltration. In addition, malondialdehyde formation and hydrogen peroxide generation, indicators of oxidative stress, were significantly induced by PFOA treatment in the liver of mice. Furthermore, hepatic levels of interleukin-6, cyclooxygenase-2, and C-reactive protein, markers of inflammatory response, were markedly increased by exposure to PFOA in mice. These results demonstrated that PFOA-induced hepatic toxicity may be involved in oxidative stress and inflammatory response in mice.
doi:10.1155/2014/409837
PMCID: PMC3958804  PMID: 24724082
20.  Functionally active rat S100A4 from a polymerase chain reaction-synthesized gene expressed in soluble form in Escherichia coli 
Oncology Letters  2014;7(4):1179-1184.
S100A4 protein is associated with Ca2+-dependent regulation of intracellular activities and is significant in the invasion, growth and metastasis of cancer. In order to express rat S100A4 functionally and identify its biological activity following purification, an S100A4 gene fragment was optimized and fully synthesized via overlapping polymerase chain reaction. The gene was inserted into the prokaryotic expression vector, pBV220, with phage λ PRPL promoters following confirmation by DNA sequencing. The pBV220-S100A4 plasmid was constructed and transformed into Escherichia coli DH5α. Following temperature induction, rat S100A4 was overexpressed and the protein was observed to be located in the supernatant of the lysates, which was ~30–40% of the total protein within the host. The protein was isolated and purified by metal-chelate affinity chromatography. High purity protein (>98% purity) was obtained and in vitro western blot analysis identified that the recombinant S100A4 was able to bind to the antibody against wild-type S100A4. The bioactivity of the recombinant protein was detected via Transwell migration and invasion assays. The polyclonal antibody of rat S100A4 protein was prepared for rabbit immunization and exhibited similar efficacies when compared with commercial S100A4. Therefore, rat S100A4 was functionally expressed in E. coli; thus, the production of active recombinant S100A4 protein in E. coli may further aid with the investigation and application of S100A4.
doi:10.3892/ol.2014.1870
PMCID: PMC3961442  PMID: 24944689
rat S100A4; functional expression; gene recombination
21.  Thoracotomy in refractory gestational trophoblastic neoplasia with lung metastasis after normalization of serum beta human chorionic gonadotropin (β-hCG) with salvage chemotherapy 
OncoTargets and therapy  2014;7:171-176.
Objective
To assess the need for pulmonary surgery in the treatment of refractory gestational trophoblastic neoplasia with lung metastasis after normalization of serum beta human chorionic gonadotropin (β-hCG) level with salvage chemotherapy.
Materials and methods
A review of medical records of patients with refractory gestational trophoblastic neoplasia who underwent pulmonary surgery and received combined chemotherapy between January 1995 and December 2008 at the Peking Union Medical College Hospital was retrospectively performed. The positive pathologic findings in surgical specimens were defined as trophoblastic cells documented in the specimen. Pathologic findings were reported.
Results
There were 21 patients with preoperative normal β-hCG. Of 21 patients, six (28.6%) had positive pathologic findings. The positive pathologic findings remained at 27.3% in 11 patients who had received no less than two cycles of consolidation chemotherapy before pulmonary surgery. Univariate analysis found that no variables in patient characteristics were associated with pathologic findings. At the median follow-up of 78 months (9–186 months), 85.7% (18 of 21) patients were alive, and no statistical difference was observed in the disease-free survival between the patients with positive and negative pathologic findings. The 5-year overall survival was 72.2%.
Conclusion
Pulmonary surgery is valuable in the treatment of refractory patients with lung metastasis after normalization of serum β-hCG level following salvage chemotherapy, irrespective of viable trophoblasts in surgical specimens. Further study will be necessary to clarify the importance of this observation.
doi:10.2147/OTT.S56361
PMCID: PMC3913543  PMID: 24511240
gestational trophoblastic neoplasia; refractory; pulmonary surgery
22.  Integrated Positioning for Coal Mining Machinery in Enclosed Underground Mine Based on SINS/WSN 
The Scientific World Journal  2014;2014:460415.
To realize dynamic positioning of the shearer, a new method based on SINS/WSN is studied in this paper. Firstly, the shearer movement model is built and running regularity of the shearer in coal mining face has been mastered. Secondly, as external calibration of SINS using GPS is infeasible in enclosed underground mine, WSN positioning strategy is proposed to eliminate accumulative error produced by SINS; then the corresponding coupling model is established. Finally, positioning performance is analyzed by simulation and experiment. Results show that attitude angle and position of the shearer can be real-timely tracked by integrated positioning strategy based on SINS/WSN, and positioning precision meet the demand of actual working condition.
doi:10.1155/2014/460415
PMCID: PMC3918390  PMID: 24574891
23.  Effects of the antihypertensive drug benidipine on osteoblast function in vitro 
The dihydropyridine-type calcium channel blocker, benidipine (BD) has been widely used in hypertension therapy. Previous studies have demonstrated that BD has a positive effect on bone metabolism. Inspired by this promoting phenomenon, the present study investigated the effects of BD on osteoblasts in vitro. Experiments were designed and performed, including an MTT assay, reverse transcription-polymerase chain reaction, western blot analysis, alkaline phosphatase activity measurements and alizarin red S staining. The results demonstrated that BD promoted osteoblast proliferation and osteogenic differentiation at concentrations from 1×10−6 to 1×10−9 M by upregulating Runx2, BMP2 and OCN gene expression levels. Overall, BD at appropriate concentrations has been demonstrated to have positive effects on osteoblast function in addition to its conventional clinical usage.
doi:10.3892/etm.2014.1475
PMCID: PMC3919856  PMID: 24520261
benidipine; calcium channel blockers; osteoporosis; hypertension
24.  A New Strategy for Enhancing the Oral Bioavailability of Drugs with Poor Water-Solubility and Low Liposolubility Based on Phospholipid Complex and Supersaturated SEDDS 
PLoS ONE  2013;8(12):e84530.
A novel supersaturated self-emulsifying drug delivery system (Super-SEDDS) loaded with scutellarin-phospholipid complex (SPC) was developed. The system aimed to address the limitations presented by conventional SEDDS as delivery carriers for drugs with poor water-solubility, low liposolubility and high dose. As an intermediate, SPC was first prepared based on the response surface design. The presence of amorphous scutellarin was demonstrated through differential scanning calorimetry (DSC) and X-ray diffraction (XRD), while enhanced liposolubility was confirmed through comparison with scutellarin powder via an octanol/water distribution test. On the basis of the solubility study and ternary phase diagram, Super-SEDDS containing SPC of up to 200% equilibrium solubility (Seq) was designed, which composed of ethyl oleate, Cremophor RH40 and Transcutol HP with a ratio of 60∶25∶15 (w/w%). The subsequent in vitro lipolysis study and ex vivo intestinal absorption test indicated that Super-SEDDS enhanced the cumulative dissolution from 70% to 100% and improved the intestinal absorption from 0.04 to 0.12 µg/cm2 compared with scutellarin powder. Furthermore, an in vivo study demonstrated that Super-SEDDS achieved the AUC0-t of scutellarin up to approximate 1.7-fold as scutellarin powder. It was also proved superior to SPC and the conventional SEDDS. Super-SEDDS showed great potential for expanding the usage of SEDDS and could act as an alternative to conventional SEDDS.
doi:10.1371/journal.pone.0084530
PMCID: PMC3877285  PMID: 24391965
25.  Serum peptidome patterns of hepatocellular carcinoma based on magnetic bead separation and mass spectrometry analysis 
Diagnostic Pathology  2013;8:130.
Background
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world,and the identification of biomarkers for the early detection is a relevant target. The purpose of the study is to discover specific low molecular weight (LMW) serum peptidome biomarkers and establish a diagnostic pattern for HCC.
Methods
We undertook this pilot study using a combined application of magnetic beads with Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique and ClinPro Tools v2.2 to detect 32 patients with HCC, 16 patients with chronic hepatitis (CH), 16 patients with liver cirrhosis (LC) and 16 healthy volunteers.
Results
The results showed 49, 33 and 37 differential peptide peaks respectively appeared in HCC, LC and CH groups. A Supervised Neural Network (SNN) algorithm was used to set up the classification model. Eleven of the identified peaks at m/z 5247.62, 7637.05, 1450.87, 4054.21, 1073.37, 3883.64, 5064.37, 4644.96, 5805.51, 1866.47 and 6579.6 were used to construct the peptides patterns. According to the model, we could clearly distinguish between HCC patients and healthy controls as well as between LC or CH patients and healthy controls.
Conclusions
The study demonstrated that a combined application of magnetic beads with MALDI-TOF MB technique was suitable for identification of potential serum biomarkers for HCC and it is a promising way to establish a diagnostic pattern.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1503629821958720.
doi:10.1186/1746-1596-8-130
PMCID: PMC3751178  PMID: 23915185
Hepatocellular carcinoma; Chronic hepatitis; Liver cirrhosis; Magnetic beads; Matri-assisted laser desorption/ionization time-of-flight mass spectrometry; Serum biomarkers

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