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1.  Synthesis of 14N and 15N-labeled trityl-nitroxide biradicals with strong spin-spin interaction and improved sensitivity to redox status and oxygen 
The Journal of organic chemistry  2010;75(22):7796-7802.
Simultaneous evaluation redox status and oxygenation in biological systems is of great importance for the understanding of biological functions. Electron paramagnetic resonance spectroscopy coupled with the use of the nitroxide radicals have been an indispensable technique for this application but are still limited by its low oxygen sensitivity, and low EPR resolution in part due to the moderately broad EPR triplet and spin quenching through bioreduction. In this study, we showed that these drawbacks can be overcome through the use of trityl-nitroxide biradicals allowing for the simultaneous measurement of redox status and oxygenation. A new trityl-nitroxide biradical TNN14 composed of a pyrrolidinyl-nitroxide and a trityl, and its isotopically labeled 15N analogue TNN15 were synthesized and characterized. Both biradicals exhibited much stronger spin-spin interaction with J > 400 G than the previous synthesized trityl-nitroxide biradicals TN1 (~160 G) and TN2 (~52 G) with longer linker chain length. The enhanced stability of TNN14 was evaluated using ascorbate as reductant and the effect of different types of cyclodextrins on its stability in the presence of ascorbate was also investigated. Both biradicals are sensitive to redox status, and their corresponding trityl-hydroxylamines resulting from the reduction of the biradicals by ascorbate share the same oxygen sensitivity. Of note is that the 15N-labeled TNN15-H with an EPR doublet exhibits improved EPR signal amplitude as compared to TNN14-H with an EPR triplet. In addition, cyclic voltammetric studies verify the characteristic electrochemical behaviors of the trityl-nitroxide biradicals.
PMCID: PMC4073600  PMID: 21028905
2.  Synthesis of trityl radical-conjugated disulfide biradicals for the measurement of thiol concentration 
The Journal of organic chemistry  2011;76(10):3853-3860.
Measurement of thiol concentrations is of great importance for characterizing their critical role in normal metabolism and disease. Low-frequency electron paramagnetic resonance (EPR) spectroscopy and imaging, coupled with the use of exogenous paramagnetic probes, have been indispensable techniques for the in vivo measurement of various physiological parameters owing to the specificity, noninvasiveness and good depth of magnetic field penetration in animal tissues. However, in vivo detection of thiol levels by EPR spectroscopy and imaging is limited due to the need for improved probes. We report the first synthesis of trityl radical-conjugated disulfide biradicals (TSSN and TSST) as paramagnetic thiol probes. The use of trityl radicals in the construction of these biradicals greatly facilitates thiol measurement by EPR spectroscopy since trityls have extraordinary stability in living tissues with single narrow EPR line that enables high sensitivity and resolution for in vivo EPR spectroscopy and imaging. Both biradicals exhibit broad characteristic EPR spectra at room temperature due to their intramolecular spin-spin interaction. Reaction of these biradicals with thiol compounds such as glutathione (GSH) and cysteine results in the formation of trityl monoradicals which exhibit high spectral sensitivity to oxygen. The moderately slow reaction between the biradicals and GSH (k2 ∼ 0.3 M-1s-1 for TSSN and 0.2 M-1s-1 for TSST) allows for in vivo measurement of GSH concentration without altering the redox environment in biological systems. The GSH concentration in rat liver was determined to be 3.49 ± 0.14 mM by TSSN and 3.67 ± 0.24 mM by TSST, consistent with the value (3.71 ± 0.09 mM) determined by the Ellman's reagent. Thus, these trityl-based thiol probes exhibit unique properties enabling measurement of thiols in biological systems and should be of great value for monitoring redox metabolism.
PMCID: PMC4073604  PMID: 21488696
3.  Dose Dependent Effects of Reactive Oxygen and Nitrogen Species on the Function of Neuronal Nitric Oxide Synthase 
Reactive nitrogen species (RNS) and oxygen species (ROS) have been reported to modulate the function of nitric oxide synthase (NOS); however, the precise dosedependent effects of specific RNS and ROS on NOS function are unknown. Questions remain unanswered regarding whether pathophysiological levels of RNS and ROS alter NOS function, and if this alteration is reversible. We measured the effects of peroxynitrite (ONOO-), superoxide (O2.-), hydroxyl radical (.OH), and H2O2 on nNOS activity. The results showed that NO production was inhibited in a dose-dependent manner by all four oxidants, but only O2.- and ONOO- were inhibitory at pathophysiological concentrations (≤ 50 μM). Subsequent addition of tetrahydrobiopterin (BH4) fully restored activity after O2.- exposure, while BH4 partially rescued the activity decrease induced by the other three oxidants. Furthermore, treatment with either ONOO- or O2.- stimulated nNOS uncoupling with decreased NO and enhanced O2.- generation. Thus, nNOS is reversibly uncoupled by O2.- (≤ 50 μM), but irreversibly uncoupled and inactivated by ONOO-. Additionally, we observed that the mechanism by which oxidative stress alters nNOS activity involves not only BH4 oxidation, but also nNOS monomerization as well as possible degradation of the heme.
PMCID: PMC4073612  PMID: 18201545
neuronal nitric oxide synthase; nitric oxide; superoxide; peroxynitrite; hydroxyl; hydrogen peroxide; dose-dependent; uncoupling; tetrahydrobiopterin; monomerization
4.  Reactive Oxygen and Nitrogen Species Regulate Inducible Nitric Oxide Synthase Function Shifting the Balance of Nitric Oxide and Superoxide Production 
Inducible NOS (iNOS) is induced in diseases associated with inflammation and oxidative stress, and questions remain regarding its regulation. We demonstrate that reactive oxygen / nitrogen species (ROS/RNS) dose-dependently regulate iNOS function. Tetrahydrobiopterin (BH4)-replete iNOS was exposed to increasing concentrations of ROS/RNS and activity was measured with and without subsequent BH4 addition. Peroxynitrite (ONOO−) produced the greatest change in NO generation rate, ~95% decrease, and BH4 only partially restored this loss of activity. Superoxide (O2.−) greatly decreased NO generation, however, BH4 addition restored this activity. Hydroxyl radical (.OH) mildly decreases NO generation in a BH4-dependent manner. iNOS was resistant to H2O2 with only slightly decreased NO generation with up to millimolar concentrations. In contrast to the inhibition of NO generation, ROS enhanced O2.− production from iNOS, while ONOO− had the opposite effect. Thus, ROS promote reversible iNOS uncoupling, while ONOO− induces irreversible enzyme inactivation and decreases both NO and O2.− production.
PMCID: PMC4073618  PMID: 19932078
inducible nitric oxide synthase; nitric oxide; superoxide; peroxynitrite; hydroxyl; hydrogen peroxide; dose-dependent; uncoupling; tetrahydrobiopterin; monomerization
5.  Enhancing the light absorbance of polymer solar cells by introducing pulsed laser-deposited CuIn0.8Ga0.2Se2 nanoparticles 
Nanoscale Research Letters  2014;9(1):308.
Evenly separated crystalline CuIn0.8Ga0.2Se2 (CIGS) nanoparticles are deposited on ITO-glass substrate by pulsed laser deposition. Such CIGS layers are introduced between conjugated polymer layers and ITO-glass substrates for enhancing light absorbance of polymer solar cells. The P3HT:PCBM absorbance between 300 and 650 nm is enhanced obviously due to the introduction of CIGS nanoparticles. The current density-voltage curves of a P3HT:PCBM/CIGS solar cell demonstrate that the short-circuit current density is improved from 0.77 to 1.20 mA/cm2. The photoluminescence spectra show that the excitons in the polymer are obviously quenched, suggesting that the charge transfer between the P3HT:PCBM and CIGS occurred. The results reveal that the CIGS nanoparticles may exhibit the localized surface plasmon resonance effect just as metallic nanostructures.
61.46. + w; 61.41.e; 81.15.Fg; 81.07.b
PMCID: PMC4067071  PMID: 24994961
CuIn0.8Ga0.2Se2 nanoparticles; P3HT:PCBM; Pulsed laser deposition; Absorption; Polymer solar cells; Photoluminescence
6.  Crystal structure of the ubiquitin-like domain of human TBK1 
Protein & cell  2012;3(5):383-391.
TANK-binding kinase 1 (TBK1) is an important enzyme in the regulation of cellular antiviral effects. TBK1 regulates the activity of the interferon regulatory factors IRF3 and IRF7, thereby playing a key role in type I interferon (IFN) signaling pathways. The structure of TBK1 consists of an N-terminal kinase domain, a middle ubiquitin-like domain (ULD), and a C-terminal elongated helical domain. It has been reported that the ULD of TBK1 regulates kinase activity, playing an important role in signaling and mediating interactions with other molecules in the IFN pathway. In this study, we present the crystal structure of the ULD of human TBK1 and identify several conserved residues by multiple sequence alignment. We found that a hydrophobic patch in TBK1, containing residues Leu316, Ile353, and Val382, corresponding to the “Ile44 hydrophobic patch” observed in ubiquitin, was conserved in TBK1, IκB kinase epsilon (IKKε/IKKi), IκB kinase alpha (IKKα), and IκB kinase beta (IKKβ). In comparison with the structure of the IKKβ ULD domain of Xenopus laevis, we speculate that the Ile44 hydrophobic patch of TBK1 is present in an intramolecular binding surface between ULD and the C-terminal elongated helices. The varying surface charge distributions in the ULD domains of IKK and IKK-related kinases may be relevant to their specificity for specific partners.
PMCID: PMC4057185  PMID: 22610919
TBK1; ubiquitin-like domain; crystal structure; hydrophobic patch
7.  Arthroscopic evaluation for omalgia patients undergoing the clavicular hook plate fixation of distal clavicle fractures 
The aim of this study is to investigate the anatomic changes in the shoulder joints responsible for omalgia after the clavicular hook plate fixation under arthroscope.
Arthroscopic examination was carried out for 12 omalgia patients who underwent clavicular hook plate fixation due to distal clavicle fractures. Functional outcome of shoulder was measured by the Japanese Orthopaedic Association (JOA) score before and after the withdrawal of the fixation plate.
The rotator cuff compression by the clavicular hook was arthroscopically observed in 11 of the 12 cases. The JOA scores of the shoulder were significantly improved at 1 month after the withdrawal of the fixation plate (pain, 28 ± 2.4 vs. 15 ± 5.2; function, 19.2 ± 1.0 vs. 11.7 ± 1.9; range of movements, 26.8 ± 2.6 vs. 14.8 ± 3.4) compared with before.
The impingement of the hook to the rotator cuff may be the main cause for the omalgia. The appropriate hook and plate that fit to the curve of the clavicle as well as the acromion are necessary to decrease the severity of omalgia.
PMCID: PMC4084496  PMID: 24917508
Clavicular hook plate; Distal clavicle fractures; Shoulder arthroscopy
8.  Usefulness of Ventricular Endocardial Electric Reconstruction from Body Surface Potential Maps to Noninvasively Localize Ventricular Ectopic Activity in Patients 
Physics in medicine and biology  2013;58(11):3897-3909.
As radio frequency (RF) catheter ablation becomes increasingly prevalent in the management of ventricular arrhythmia in patients, an accurate and rapid determination of the arrhythmogenic site is of important clinical interest. The aim of this study was to test the hypothesis that the inversely reconstructed ventricular endocardial current density distribution from body surface potential maps (BSPMs) can localize the regions critical for maintenance of a ventricular ectopic activity. Patients with isolated and monomorphic premature ventricular contractions (PVCs) were investigated by noninvasive BSPMs and subsequent invasive catheter mapping and ablation. Equivalent current density (CD) reconstruction (CDR) during symptomatic PVCs was obtained on the endocardial ventricular surface in 6 patients (4 men, 2 women, years 23–77), and the origin of the spontaneous ectopic activity was localized at the location of the maximum CD value. Compared with the last (successful) ablation site (LAS), the mean and standard deviation of localization error of the CDR approach were 13.8 mm and 1.3 mm, respectively. In comparison, the distance between the LASs and the estimated locations of an equivalent single moving dipole (SMD) in the heart was 25.5 ± 5.5 mm. The obtained CD distribution of activated sources extending from the catheter ablation site also showed a high consistency with the invasively recorded electroanatomical maps. The noninvasively reconstructed endocardial CD distribution is suitable to predict a region of interest containing or close to arrhythmia source, which may have the potential to guide RF catheter ablation.
PMCID: PMC3776132  PMID: 23681281
electrocardiographic inverse problem; current density reconstruction; radio frequency catheter ablation; premature ventricular contraction; body surface potential mapping
9.  A Novel Hemagglutinin with Antiproliferative Activity against Tumor Cells from the Hallucinogenic Mushroom Boletus speciosus 
BioMed Research International  2014;2014:340467.
Little was known about bioactive compounds from the hallucinogenic mushroom Boletus speciosus. In the present study, a hemagglutinin (BSH, B. speciosus hemagglutinin) was isolated from its fruiting bodies and enzymatic properties were also tested. The chromatographic procedure utilized comprised anion exchange chromatography on Q-Sepharose, cation exchange chromatography on CM-Cellulose, cation exchange chromatography on SP-Sepharose, and gel filtration by FPLC on Superdex 75. The hemagglutinin was a homodimer which was estimated to be approximately 31 kDa in size. The activity of BSH was stable up to 60°C, while there was a precipitous drop in activity when the temperature was elevated to 70°C. BSH retained 25% hemagglutinating activity when exposed to 100 mM NaOH and 25 mM HCl. The activity was potently inhibited by 1.25 mM Hg2+ and slightly inhibited by Fe2+, Ca2+, and Pb2+. None of the sugars tested showed inhibition towards BSH. Its hemagglutinating activity towards human erythrocytes type A, type B, and type AB was higher than type O. The hemagglutinin showed antiproliferative activity towards hepatoma Hep G2 cells and mouse lymphocytic leukemia cells (L1210) in vitro, with IC50 of 4.7 μM and 7.0 μM, respectively. It also exhibited HIV-1 reverse transcriptase inhibitory activity with an IC50 of 7.1 μM.
PMCID: PMC4058106  PMID: 24977148
10.  Automatic Lung Tumor Segmentation on PET/CT Images Using Fuzzy Markov Random Field Model 
The combination of positron emission tomography (PET) and CT images provides complementary functional and anatomical information of human tissues and it has been used for better tumor volume definition of lung cancer. This paper proposed a robust method for automatic lung tumor segmentation on PET/CT images. The new method is based on fuzzy Markov random field (MRF) model. The combination of PET and CT image information is achieved by using a proper joint posterior probability distribution of observed features in the fuzzy MRF model which performs better than the commonly used Gaussian joint distribution. In this study, the PET and CT simulation images of 7 non-small cell lung cancer (NSCLC) patients were used to evaluate the proposed method. Tumor segmentations with the proposed method and manual method by an experienced radiation oncologist on the fused images were performed, respectively. Segmentation results obtained with the two methods were similar and Dice's similarity coefficient (DSC) was 0.85 ± 0.013. It has been shown that effective and automatic segmentations can be achieved with this method for lung tumors which locate near other organs with similar intensities in PET and CT images, such as when the tumors extend into chest wall or mediastinum.
PMCID: PMC4058834  PMID: 24987451
11.  A Special Phase Detector for Magnetic Inductive Measurement of Cerebral Hemorrhage 
PLoS ONE  2014;9(5):e97179.
Cerebral hemorrhage is an important clinical problem that is often monitored and studied with expensive techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). These devices are not readily available in economically underdeveloped regions of the world and in emergency departments and emergency zones. The magnetic inductive method is an emerging technology that may become a new tool to detect cerebral hemorrhage. In this study, a special phase detector (PD) was developed and used for cerebral hemorrhage detection with the magnetic inductive method. The performance indicated that the PD can achieve phase noise as low as 6 m° and a 4-hour phase drift as low as 30 m° at 21.4 MHz. The noise and drift decreased as the frequency decreased. The performance at 10.7 MHz was slightly better than that of other recently developed phase detection systems. To test the practicality of the system, the PD was used to detect the volume change in a self-made physical model of the brain. The measured phase shift was approximately proportional to the volume change of physiological saline inside the model. The change of the phase shift increased as the volume change and frequency increased. The results are in agreement with those from previous reports. To verify the feasibility of in vivo detection, an autologous blood injection model was established in rabbit brain. The results from the injection group showed a similar trend of increasing phase shift change with increasing injection volume. The average phase shift change induced by a 3-ml injection of blood was 0.502°±0.119°, which was much larger than that of the control group. The measurement system can distinguish a minimal cerebral hemorrhage volume of approximately 0.5 ml. All of the results demonstrated that the PD used with this method can detect cerebral hemorrhage.
PMCID: PMC4016262  PMID: 24816470
12.  A microRNA miR-34a Regulated Bimodal Switch targets Notch in Colon Cancer Stem Cells 
Cell stem cell  2013;12(5):602-615.
microRNAs regulate developmental cell fate decisions, tissue homeostasis and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell fate determinant in early stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR34a distributes at high levels in differentiating progeny, while low levels of miR34a demarcate self renewing CCSCs. Moreover, miR34a loss of function and gain of function alters the balance between self-renewal and differentiation both in vitro and in vivo. Mechanistically, miR34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal versus differentiation. In contrast, the canonical cell fate determinant Numb regulates Notch levels in a continuously graded manner. Taken together, our findings highlight a unique microRNA regulated mechanism that converts noisy input into a toggle switch for robust cell fate decisions in CCSCs.
PMCID: PMC3646336  PMID: 23642368
13.  Characterization of Multidrug-Resistant Salmonella enterica Serovars Indiana and Enteritidis from Chickens in Eastern China 
PLoS ONE  2014;9(5):e96050.
A total of 310 Salmonella isolates were isolated from 6 broiler farms in Eastern China, serotyped according to the Kauffmann-White classification. All isolates were examined for susceptibility to 17 commonly used antimicrobial agents, representative isolates were examined for resistance genes and class I integrons using PCR technology. Clonality was determined by pulsed-field gel electrophoresis (PFGE). There were two serotypes detected in the 310 Salmonella strains, which included 133 Salmonella enterica serovar Indiana isolates and 177 Salmonella enterica serovar Enteritidis isolates. Antimicrobial sensitivity results showed that the isolates were generally resistant to sulfamethoxazole, ampicillin, tetracycline, doxycycline and trimethoprim, and 95% of the isolates sensitive to amikacin and polymyxin. Among all Salmonella enterica serovar Indiana isolates, 108 (81.2%) possessed the blaTEM, floR, tetA, strA and aac (6')-Ib-cr resistance genes. The detected carriage rate of class 1 integrons was 66.5% (206/310), with 6 strains carrying gene integron cassette dfr17-aadA5. The increasing frequency of multidrug resistance rate in Salmonella was associated with increasing prevalence of int1 genes (rs = 0.938, P = 0.00039). The int1, blaTEM, floR, tetA, strA and aac (6')-Ib-cr positive Salmonella enterica serovar Indiana isolates showed five major patterns as determined by PFGE. Most isolates exhibited the common PFGE patterns found from the chicken farms, suggesting that many multidrug-resistant isolates of Salmonella enterica serovar Indiana prevailed in these sources. Some isolates with similar antimicrobial resistance patterns represented a variety of Salmonella enterica serovar Indiana genotypes, and were derived from a different clone.
PMCID: PMC4008530  PMID: 24788434
14.  A Multipoint Correction Method for Environmental Temperature Changes in Airborne Double-Antenna Microwave Radiometers 
Sensors (Basel, Switzerland)  2014;14(5):7820-7830.
This manuscript describes a new type Ka-band airborne double-antenna microwave radiometer (ADAMR) designed for detecting atmospheric supercooled water content (SCWC). The source of the measurement error is investigated by analyzing the model of the system gain factor and the principle of the auto-gain compensative technique utilized in the radiometer. Then, a multipoint temperature correction method based on the two-point calibration method for this radiometer is proposed. The multipoint temperature correction method can eliminate the effect of changes in environmental temperature by establishing the relationship between the measurement error and the physical temperatures of the temperature-sensitive units. In order to demonstrate the feasibility of the correction method, the long-term outdoor temperature experiment is carried out. The multipoint temperature correction equations are obtained by using the least square regression method. The comparison results show that the measuring accuracy of the radiometer can be increased more effectively by using the multipoint temperature correction method.
PMCID: PMC4063080  PMID: 24787639
microwave radiometer; temperature correction method; auto-gain compensation; airborne; double-antenna
15.  Historical Perspective of Traditional Indigenous Medical Practices: The Current Renaissance and Conservation of Herbal Resources 
In recent years, increasing numbers of people have been choosing herbal medicines or products to improve their health conditions, either alone or in combination with others. Herbs are staging a comeback and herbal “renaissance” occurs all over the world. According to the World Health Organization, 75% of the world's populations are using herbs for basic healthcare needs. Since the dawn of mankind, in fact, the use of herbs/plants has offered an effective medicine for the treatment of illnesses. Moreover, many conventional/pharmaceutical drugs are derived directly from both nature and traditional remedies distributed around the world. Up to now, the practice of herbal medicine entails the use of more than 53,000 species, and a number of these are facing the threat of extinction due to overexploitation. This paper aims to provide a review of the history and status quo of Chinese, Indian, and Arabic herbal medicines in terms of their significant contribution to the health promotion in present-day over-populated and aging societies. Attention will be focused on the depletion of plant resources on earth in meeting the increasing demand for herbs.
PMCID: PMC4020364  PMID: 24872833
16.  An improved peptide-spectral matching algorithm through distributed search over multiple cores and multiple CPUs 
Proteome Science  2014;12:18.
A real-time peptide-spectrum matching (RT-PSM) algorithm is a database search method to interpret tandem mass spectra (MS/MS) with strict time constraints. Restricted by the hardware and architecture of individual workstation, previous RT-PSM algorithms either are not fast enough to satisfy all real-time system requirements or need to sacrifice the level of inference accuracy to provide the required processing speed.
We develop two parallelized algorithms for MS/MS data analysis: a multi-core RT-PSM (MC RT-PSM) algorithm which works on individual workstations and a distributed computing RT-PSM (DC RT-PSM) algorithm which works on a computer cluster. Two data sets are employed to evaulate the performance of our proposed algorithms. The simulation results show that our proposed algorithms can reach approximately 216.9-fold speedup on a sub-task process (similarity scoring module) and 84.78-fold speedup on the overall process compared with a single-thread process of the RT-PSM algorithm when 240 logical cores are employed.
The improved RT-PSM algorithms can achieve the processing speed requirement without sacrificing the level of inference accuracy. With some configuration adjustments, the proposed algorithm can support many peptide identification programs, such as X!Tandem, CUDA version RT-PSM, etc.
PMCID: PMC4021225  PMID: 24721686
17.  Anp32e, a higher eukaryotic histone chaperone directs preferential recognition for H2A.Z 
Cell Research  2014;24(4):389-399.
H2A.Z is a highly conserved histone variant in all species. The chromatin deposition of H2A.Z is specifically catalyzed by the yeast chromatin remodeling complex SWR1 and its mammalian counterpart SRCAP. However, the mechanism by which H2A.Z is preferentially recognized by non-histone proteins remains elusive. Here we identified Anp32e, a novel higher eukaryote-specific histone chaperone for H2A.Z. Anp32e preferentially associates with H2A.Z-H2B dimers rather than H2A-H2B dimers in vitro and in vivo and dissociates non-nucleosomal aggregates formed by DNA and H2A-H2B. We determined the crystal structure of the Anp32e chaperone domain (186-232) in complex with the H2A.Z-H2B dimer. In this structure, the region containing Anp32e residues 214-224, which is absent in other Anp32 family proteins, specifically interacts with the extended H2A.Z αC helix, which exhibits an unexpected conformational change. Genome-wide profiling of Anp32e revealed a remarkable co-occupancy between Anp32e and H2A.Z. Cells overexpressing Anp32e displayed a strong global H2A.Z loss at the +1 nucleosomes, whereas cells depleted of Anp32e displayed a moderate global H2A.Z increase at the +1 nucleosomes. This suggests that Anp32e may help to resolve the non-nucleosomal H2A.Z aggregates and also facilitate the removal of H2A.Z at the +1 nucleosomes, and the latter may help RNA polymerase II to pass the first nucleosomal barrier.
PMCID: PMC3975505  PMID: 24613878
H2A.Z; Anp32e; nucleosome; crystal structure; histone chaperone
18.  Correlation of CTGF gene promoter methylation with CTGF expression in type 2 diabetes mellitus with or without nephropathy 
Molecular Medicine Reports  2014;9(6):2138-2144.
Increasing evidence shows that DNA methylation is involved in the development and progression of diabetes mellitus (DM) and its complications. Previous studies conducted by our group have indicated that high glucose levels may induce the demethylation process of the connective tissue growth factor (CTGF) gene promoter and increase the expression of CTGF in human glomerular mesangial cells. Based on these findings, the aim of the present study was to investigate the methylation level of genomic DNA and the CTGF promoter in patients with type 2 DM and to analyze its possible correlation with CTGF expression. Methylation levels of the whole genomic DNA were detected by high-performance liquid chromatography in a non-diabetes control (NDM) group (n=29), a diabetes without nephropathy (NDN) group (n=37) and a diabetes with nephropathy (DN) group (n=38). CTGF promoter methylation levels were detected by methylation-specific polymerase chain reaction and bisulfite sequencing. The levels of serum CTGF were assessed using the enzyme-linked immunosorbent assay. The methylation levels of the whole genomic DNA were not significantly different among the three groups. However, the CTGF methylation levels in the two diabetes groups were significantly lower than those in the NDM group (P<0.05), with the lowest methylation level in the DN group (P<0.05). The CTGF protein levels in the DN group were significantly higher than those in the NDM and NDN groups (P<0.05). Levels of CTGF were negatively correlated with the estimated glomerular filtration rate (eGFR) and the methylation level of the promoter, while they were positively correlated with age, urinary albumin-to-creatinine ratio (UACR), blood urea nitrogen, creatinine, fasting blood sugar and postprandial blood glucose. Multiple stepwise regression analysis showed that CTGF expression was associated with the UACR, CTGF methylation level and eGFR. DNA methylation is a regulatory mechanism of CTGF expression, which is decreased in patients with DM, particularly in those with DN, and may contribute to the pathogenesis of nephropathy.
PMCID: PMC4055476  PMID: 24676352
connective tissue growth factor; DNA methylation; diabetic nephropathy
19.  Efficacy Evaluation of Fungus Syncephalastrum racemosum and Nematicide Avermectin against the Root-Knot Nematode Meloidogyne incognita on Cucumber 
PLoS ONE  2014;9(2):e89717.
The root-knot nematode (RKN) is one of the most damaging agricultural pests.Effective biological control is need for controlling this destructive pathogen in organic farming system. During October 2010 to 2011, the nematicidal effects of the Syncephalastrum racemosum fungus and the nematicide, avermectin, alone or combined were tested against the RKN (Meloidogyne incognita) on cucumber under pot and field condition in China. Under pot conditions, the application of S. racemosum alone or combined with avermectin significantly increased the plant vigor index by 31.4% and 10.9%, respectively compared to the M. incognita-inoculated control. However, treatment with avermectin alone did not significantly affect the plant vigor index. All treatments reduced the number of root galls and juvenile nematodes compared to the untreated control. Under greenhouse conditions, all treatments reduced the disease severity and enhanced fruit yield compared to the untreated control. Fewer nematodes infecting plant roots were observed after treatment with avermectin alone, S. racemosum alone or their combination compared to the M. incognita-inoculated control. Among all the treatments, application of avermectin or S. racemosum combined with avermectin was more effective than the S. racemosum treatment. Our results showed that application of S. racemosum combined with avermectin not only reduced the nematode number and plant disease severity but also enhanced plant vigor and yield. The results indicated that the combination of S. racemosum with avermectin could be an effective biological component in integrated management of RKN on cucumber.
PMCID: PMC3933638  PMID: 24586982
20.  Sulforaphane Attenuation of Type 2 Diabetes-Induced Aortic Damage Was Associated with the Upregulation of Nrf2 Expression and Function 
Type 2 diabetes mellitus (T2DM) significantly increases risk for vascular complications. Diabetes-induced aorta pathological changes are predominantly attributed to oxidative stress. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses to oxidative stress. Sulforaphane protects against oxidative damage by increasing Nrf2 expression and its downstream target genes. Here we explored the protective effect of sulforaphane on T2DM-induced aortic pathogenic changes in C57BL/6J mice which were fed with high-fat diet for 3 months, followed by a treatment with streptozotocin at 100 mg/kg body weight. Diabetic and nondiabetic mice were randomly divided into groups with and without 4-month sulforaphane treatment. Aorta of T2DM mice exhibited significant increases in the wall thickness and structural derangement, along with significant increases in fibrosis (connective tissue growth factor and transforming growth factor), inflammation (tumor necrosis factor-α and vascular cell adhesion molecule 1), oxidative/nitrative stress (3-nitrotyrosine and 4-hydroxy-2-nonenal), apoptosis, and cell proliferation. However, these pathological changes were significantly attenuated by sulforaphane treatment that was associated with a significant upregulation of Nrf2 expression and function. These results suggest that sulforaphane is able to upregulate aortic Nrf2 expression and function and to protect the aorta from T2DM-induced pathological changes.
PMCID: PMC3953421  PMID: 24707343
21.  Effects of experimental conditions on the morphologies, structures and growth modes of pulsed laser-deposited CdS nanoneedles 
CdS nanoneedles with different morphologies, structures, and growth modes have been grown on Ni-coated Si(100) surface under different experimental conditions by pulsed laser deposition method. The effects of catalyst layer, substrate temperature, and laser pulse energy on the growth of the CdS nanoneedles were studied in detail. It was confirmed that the formation of the molten catalyst spheres is the key to the nucleation of the CdS nanoneedles by observing the morphologies of the Ni catalyst thin films annealed at different substrate temperatures. Both the substrate temperature and laser pulse energy strongly affected the growth modes of the CdS nanoneedles. The secondary growth of the smaller nanoneedles on the top of the main nanoneedles was found at appropriate conditions. A group of more completed pictures of the growth modes of the CdS nanoneedles were presented.
PMCID: PMC3941934  PMID: 24559455
CdS nanoneedles; Substrate temperature; Laser pulse energy; Growth mode; 61.46.-w; 61.46.Km; 68.37.Lp
22.  Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases 
Cardiovascular disease (CVD) remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs) and deacetylases (HDACs) are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.
PMCID: PMC3945289  PMID: 24693336
23.  TCRγδ+CD4−CD8− T Cells Suppress the CD8+ T-Cell Response to Hepatitis B Virus Peptides, and Are Associated with Viral Control in Chronic Hepatitis B 
PLoS ONE  2014;9(2):e88475.
The immune mechanisms underlying failure to achieve hepatitis B e antigen (HBeAg) seroconversion associated with viral control in chronic hepatitis B (CHB) remain unclear. Here we investigated the role of CD4−CD8− T (double-negative T; DNT) cells including TCRαβ+ DNT (αβ DNT) and TCRγδ+ DNT (γδ DNT) cells. Frequencies of circulating DNT cell subsets were measured by flow cytometry in a retrospective cohort of 51 telbivudine-treated HBeAg-positive CHB patients, 25 immune tolerant carriers (IT), 33 inactive carriers (IC), and 37 healthy controls (HC). We found that γδ DNT cell frequencies did not significantly change during treatment, being lower at baseline (P = 0.019) in patients with HBeAg seroconversion after 52 weeks of antiviral therapy (n = 20) than in those without (n = 31), and higher in the total CHB and IT than IC and HC groups (P<0.001). αβ DNT cell frequencies were similar for all groups. In vitro, γδ DNT cells suppressed HBV core peptide-stimulated interferon-γ and tumor necrosis factor-α production in TCRαβ+CD8+ T cells, which may require cell–cell contact, and could be partially reversed by anti-NKG2A. These findings suggest that γδ DNT cells limit CD8+ T cell response to HBV, and may impede HBeAg seroconversion in CHB.
PMCID: PMC3925121  PMID: 24551107
24.  Adrenal cortical neoplasms: a study of clinicopathological features related to epidermal growth factor receptor gene status 
Diagnostic Pathology  2014;9:19.
Adrenocortical carcinoma (ACC) is a rare but highly malignant neoplasm with limited treatment options.
In this study, the clinicopathological features of 22 ACCs and 22 adrenocortical adenomas (ACA) were analyzed, and the EGFR protein expression, EGFR gene mutation status and EGFR gene copy number alteration of all tumors were examined using immunohistochemistry, fluorescence in situ hybridization (FISH), and the Scorpion Amplification Refractory Mutation System (ARMS), respectively.
EGFR protein expression was detected in 63.6% of the ACC samples, and EGFR FISH was positive in 50% of the ACC samples (all were high polysomy on chromosome 7). In contrast, 27.3% of the ACA samples demonstrated EGFR expression, and none of the ACA samples tested positive by FISH. There were significant differences between the ACC and ACA in terms of protein expression (P = 0.035) and gene copy number alterations (P < 0.001).
EGFR protein expression and high polysomy on chromosome 7 are frequent abnormalities in ACC than in ACA.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3976095  PMID: 24457059
Adrenal cortical neoplasm; Epidermal growth factor receptor; Fluorescence in situ hybridization; Mutation
25.  A Comprehensive Estimation of the Economic Effects of Meteorological Services Based on the Input-Output Method 
The Scientific World Journal  2014;2014:904693.
Concentrating on consuming coefficient, partition coefficient, and Leontief inverse matrix, relevant concepts and algorithms are developed for estimating the impact of meteorological services including the associated (indirect, complete) economic effect. Subsequently, quantitative estimations are particularly obtained for the meteorological services in Jiangxi province by utilizing the input-output method. It is found that the economic effects are noticeably rescued by the preventive strategies developed from both the meteorological information and internal relevance (interdependency) in the industrial economic system. Another finding is that the ratio range of input in the complete economic effect on meteorological services is about 1 : 108.27–1 : 183.06, remarkably different from a previous estimation based on the Delphi method (1 : 30–1 : 51). Particularly, economic effects of meteorological services are higher for nontraditional users of manufacturing, wholesale and retail trades, services sector, tourism and culture, and art and lower for traditional users of agriculture, forestry, livestock, fishery, and construction industries.
PMCID: PMC3918718  PMID: 24578666

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