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1.  Structural Modifications of (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione that Improve Selectivity for the Inhibition of Melanoma Cells Containing Active ERK Signaling 
Organic & biomolecular chemistry  2013;11(22):3706-3732.
Towards the development of potent and selective inhibitors of melanoma cells containing active ERK signaling, we herein report on the pharmacophore determination and optimization of the ERK docking domain inhibitor (Z)-3-(2-aminoethyl)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione.
doi:10.1039/c3ob40199e
PMCID: PMC3663054  PMID: 23624850
2.  Assessment of the Potential Diagnostic Value of Serum p53 Antibody for Cancer: A Meta-Analysis 
PLoS ONE  2014;9(6):e99255.
Background
Mutant p53 protein over-expression has been reported to induce serum antibodies against p53. We assessed the diagnostic precision of serum p53 (s-p53) antibodies for diagnosis of cancer patients and compared the positive rates of the s-p53 antibody in different types of cancers.
Methods
We systematically searched PubMed and Embase, through May 31, 2012. Studies were assessed for quality using QUADAS (quality assessment of studies of diagnostic accuracy). The positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures using diagnostic odds ratios (DORs) and Area under the curve(AUC). Meta regression and subgroup analyses were done, and heterogeneity and publication bias were assessed.
Results
Of 1089 studies initially identified, 100 eligible studies with 23 different types of tumor met the inclusion criteria for the meta-analysis (cases = 15953, controls = 8694). However, we could conduct independent meta analysis on only 13 of 36 types of tumors. Approximately 56% (56/100) of the included studies were of high quality (QUADAS score≥8). The summary estimates for quantitative analysis of serum p53 antibody in the diagnosis of cancers were: PLR 5.75 (95% CI: 4.60–7.19), NLR 0.81 (95%CI: 0.79–0.83) and DOR 7.56 (95% CI: 6.02–9.50). However, for the 13 types of cancers on which meta-analysis was conducted, the ranges for PLR (2.33–11.05), NLR (0.74–0.97), DOR (2.86–13.80), AUC(0.29–0.81), and positive rate (4.47%–28.36%) indicated significant heterogeneity. We found that breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer had relatively reasonable diagnostic accuracy. The remaining results of the five types of cancers suggested that s-p53 antibody had limited value.
Conclusions
The current evidence suggests that s-p53 antibody has potential diagnostic value for cancer, especially for breast, colorectal, esophageal, gastric, hepatic, lymphoma, lung and ovarian cancer. The results showed that s-p53 antibody had high correlation with cancers.
doi:10.1371/journal.pone.0099255
PMCID: PMC4049633  PMID: 24911057
3.  In situ Growth of NixCu1-x Alloy Nanocatalysts on Redox-reversible Rutile (Nb,Ti)O4 Towards High-Temperature Carbon Dioxide Electrolysis 
Scientific Reports  2014;4:5156.
In this paper, we report the in situ growth of NixCu1-x (x = 0, 0.25, 0.50, 0.75 and 1.0) alloy catalysts to anchor and decorate a redox-reversible Nb1.33Ti0.67O4 ceramic substrate with the aim of tailoring the electrocatalytic activity of the composite materials through direct exsolution of metal particles from the crystal lattice of a ceramic oxide in a reducing atmosphere at high temperatures. Combined analysis using XRD, SEM, EDS, TGA, TEM and XPS confirmed the completely reversible exsolution/dissolution of the NixCu1-x alloy particles during the redox cycling treatments. TEM results revealed that the alloy particles were exsolved to anchor onto the surface of highly electronically conducting Nb1.33Ti0.67O4 in the form of heterojunctions. The electrical properties of the nanosized NixCu1-x/Nb1.33Ti0.67O4 were systematically investigated and correlated to the electrochemical performance of the composite electrodes. A strong dependence of the improved electrode activity on the alloy compositions was observed in reducing atmospheres at high temperatures. Direct electrolysis of CO2 at the NixCu1-x/Nb1.33Ti0.67O4 composite cathodes was investigated in solid-oxide electrolysers. The CO2 splitting rates were observed to be positively correlated with the Ni composition; however, the Ni0.75Cu0.25 combined the advantages of metallic nickel and copper and therefore maximised the current efficiencies.
doi:10.1038/srep05156
PMCID: PMC4042123  PMID: 24889679
4.  A sensitive and quantitative autolysosome probe for detecting autophagic activity in live and prestained fixed cells 
Autophagy  2013;9(6):894-904.
Autophagy is a complex, multi-step and biologically important pathway mediated by autophagosomes and autolysosomes. Accurately dissecting and detecting different stages of autophagy is important to elucidate its molecular mechanism and thereby facilitate the discovery of pharmaceutical molecules. We herein reported a small-molecule synthetic probe, Zn-G4, which is only fluorescent upon starvation- or chemical agent-induced autophagy within the autolysosome or possible the late endosome/lysosome networks. The probe can be detected by one-photon microscopy, which gives a high signal-to-noise ratio readout of autophagic activity. The pH gradient-independent fluorescence can be detected both in live and prestained fixed cells. Moreover, the fluorescent recording can be used to quantify autophagic activity at a single point without transfection or false positive signals due to protein aggregation. Furthermore, autophagy-induced fluorescence in autolysosomes can also be detected by two-photon microscopy, suggesting potential applications in deep tissue and in vivo. In conclusion, we have developed a sensitive and specific autolysosomal probe that can be used for monitoring autophagy during later stages along with quantitative assays together with widely used early markers or microtubule-associated protein 1 light chain 3 (LC3)-based probes.
doi:10.4161/auto.24241
PMCID: PMC3672298  PMID: 23575440
autophagy; autolysosome; ZnSalen; optical imaging; probe
5.  On-chip high-throughput manipulation of particles in a dielectrophoresis-active hydrophoretic focuser 
Scientific Reports  2014;4:5060.
This paper proposes a novel concept of dielectrophoresis (DEP)-active hydrophoretic focusing of micro-particles and murine erythroleukemia (MEL) cells. The DEP-active hydrophoretic platform consists of crescent shaped grooves and interdigitated electrodes that generate lateral pressure gradients. These embedded electrodes exert a negative DEP force onto the particles by pushing them into a narrow space in the channel where the particle to groove interaction is intensive and hydrophoretic ordering occurs. Particles passing through the microfluidic device are directed towards the sidewalls of the channel. The critical limitation of DEP operating at a low flow rate and the specific hydrophoretic device for focusing particles of given sizes were overcome with the proposed microfluidic device. The focusing pattern can be modulated by varying the voltage. High throughput was achieved (maximum flow rate ~150 μL min−1) with good focusing performance. The non-spherical MEL cells were utilised to verify the effectiveness of the DEP-active hydrophoretic device.
doi:10.1038/srep05060
PMCID: PMC4033927  PMID: 24862936
6.  IQGAP3 Promotes EGFR-ERK Signaling and the Growth and Metastasis of Lung Cancer Cells 
PLoS ONE  2014;9(5):e97578.
Proteins of the IQGAP family display complicated and often contradictory activities in tumorigenesis. IQGAP1 has well documented oncogenic potential and IQGAP2 has putative tumor-suppressive function. IQGAP3 is the latest addition to this family and its role in cancer development remains to be defined. Here we demonstrate IQGAP3 expression is markedly increased in lung cancer tissues at both mRNA and protein levels. Overexpression of IQGAP3 promoted tumor cell growth, and migration and invasion, whereas knockdown of IQGAP3 exhibited opposite effects. Moreover, suppression of IQGAP3 in a lung cancer cell line caused a reduction in the tumorigenicity of these cells in lung tissue after intravenous injection. Furthermore, we showed that IQGAP3 is able to interact with ERK1 and enhance its phosphorylation following treatment with EGF. These data suggest that IQGAP3 may contribute to the pathogenesis of lung cancer by modulating EGFR-ERK signaling.
doi:10.1371/journal.pone.0097578
PMCID: PMC4029748  PMID: 24849319
7.  Incorporating MRI structural information into bioluminescence tomography: system, heterogeneous reconstruction and in vivo quantification 
Biomedical Optics Express  2014;5(6):1861-1876.
Combining two or more imaging modalities to provide complementary information has become commonplace in clinical practice and in preclinical and basic biomedical research. By incorporating the structural information provided by computed tomography (CT) or magnetic resonance imaging (MRI), the ill poseness nature of bioluminescence tomography (BLT) can be reduced significantly, thus improve the accuracies of reconstruction and in vivo quantification. In this paper, we present a small animal imaging system combining multi-view and multi-spectral BLT with MRI. The independent MRI-compatible optical device is placed at the end of the clinical MRI scanner. The small animal is transferred between the light tight chamber of the optical device and the animal coil of MRI via a guide rail during the experiment. After the optical imaging and MRI scanning procedures are finished, the optical images are mapped onto the MRI surface by interactive registration between boundary of optical images and silhouette of MRI. Then, incorporating the MRI structural information, a heterogeneous reconstruction algorithm based on finite element method (FEM) with L 1 normalization is used to reconstruct the position, power and region of the light source. In order to validate the feasibility of the system, we conducted experiments of nude mice model implanted with artificial light source and quantitative analysis of tumor inoculation model with MDA-231-GFP-luc. Preliminary results suggest the feasibility and effectiveness of the prototype system.
doi:10.1364/BOE.5.001861
PMCID: PMC4052915  PMID: 24940545
(110.0110) Imaging systems; (170.3880) Medical and biological imaging; (110.6955) Tomographic imaging
8.  Generation of gene-modified mice via Cas9/RNA-mediated gene targeting 
Cell Research  2013;23(5):720-723.
doi:10.1038/cr.2013.46
PMCID: PMC3641603  PMID: 23545779
9.  Inhibition of Apurinic/apyrimidinic endonuclease I’s redox activity revisited 
Biochemistry  2013;52(17):2955-2966.
The essential base excision repair protein, apurinic/apyrimidinic endonuclease 1 (APE1), plays an important role in redox regulation in cells and is currently targeted for development of cancer therapeutics. One compound that binds APE1 directly is (E)-3-(2-(5,6-dimethoxy-3-methyl-1,4-benzoquinonyl))-2-nonyl propenoic acid (E3330). Here, we revisit the mechanism by which this negatively charged compound interacts with APE1 and inhibits its redox activity. At high concentrations (mM), E3330 interacts with two regions in the endonuclease active site of APE1, as mapped by hydrogen/deuterium exchange mass spectrometry. However, this interaction lowers the melting temperature of APE1 consistent with a loss of structure in APE1, as measured by both differential scanning fluorimetry and circular dichroism. These results are consistent with other findings that concentrations of E3330 greater than 100 μM are required to inhibit APE1’s endonuclease activity. To determine the role of E3330’s negatively charged carboxylate in redox inhibition, we converted the carboxylate to an amide by synthesizing (E)-2-((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylene)-N-methoxy-undecanamide (E3330-amide), a novel uncharged derivative. E3330-amide has no effect on the melting temperature of APE1, suggesting that it does not interact with the fully-folded protein. However, E3330-amide inhibits APE1’s redox activity in in vitro EMSA redox and cell-based transactivation assays producing lower IC50 values as compared to E3330, 8.5 μM vs. 20 μM and 7 μM vs. 55 μM, respectively. Thus, E3330’s negatively charged carboxylate is not required for redox inhibition. Collectively, our results provide additional support for a mechanism of redox inhibition involving interaction of E3330 or E3330-amide with partially unfolded APE1.
doi:10.1021/bi400179m
PMCID: PMC3706204  PMID: 23597102
10.  Combined probiotic bacteria promotes intestinal epithelial barrier function in interleukin-10-gene-deficient mice 
AIM: To investigate the protective effects of combinations of probiotic (Bifico) on interleukin (IL)-10-gene-deficient (IL-10 KO) mice and Caco-2 cell monolayers.
METHODS: IL-10 KO mice were used to assess the benefits of Bifico in vivo. IL-10 KO and control mice received approximately 1.5 × 108 cfu/d of Bifico for 4 wk. Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber, while an ELISA was used to evaluate proinflammatory cytokines. The colon epithelial cell line, Caco-2, was used to test the benefit of Bifico in vitro. Enteroinvasive Escherichia coli (EIEC) and the probiotic mixture Bifico, or single probiotic strains, were applied to cultured Caco-2 monolayers. Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression.
RESULTS: Treatment of IL-10 KO mice with Bifico partially restored body weight, colon length, and epithelial barrier integrity to wild-type levels. In addition, IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-α and interferon-γ, and attenuated colonic disease. Moreover, treatment of Caco-2 monolayers with Bifico or single-strain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines.
CONCLUSION: Bifico reduced colon inflammation in IL-10 KO mice, and promoted and improved epithelial-barrier function, enhanced resistance to EIEC invasion, and decreased proinflammatory cytokine secretion.
doi:10.3748/wjg.v20.i16.4636
PMCID: PMC4000500  PMID: 24782616
Probiotic bacteria; Intestinal barrier function; Tight junction proteins; Interleukin-10 gene-deficient mice; Caco-2 monolayers
11.  Integrated IVUS-OCT Imaging for Atherosclerotic Plaque Characterization 
For the diagnosis of atherosclerosis, biomedical imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have been developed. The combined use of IVUS and OCT is hypothesized to remarkably increase diagnostic accuracy of vulnerable plaques. We have developed an integrated IVUS-OCT imaging apparatus, which includes the integrated catheter, motor drive unit, and imaging system. The dual-function imaging catheter has the same diameter of current clinical standard. The imaging system is capable for simultaneous IVUS and OCT imaging in real time. Ex vivo and in vivo experiments on rabbits with atherosclerosis were conducted to demonstrate the feasibility and superiority of the integrated intravascular imaging modality.
doi:10.1109/JSTQE.2013.2274724
PMCID: PMC3996710  PMID: 24771992
IVUS; OCT; intravascular; multimodal
12.  A self-made disposable iris retractor in small pupil phacoemulsification 
AIM
To explore a simple and low-cost self-made disposable flexible iris retractor and study its clinical efficacy and safety in small pupil phacoemulsification.
METHODS
Polyproplyene suture and scalp acupuncture were used to make iris retractor. A prospective study were carried on 50 patients (50 eyes) with a maximally dilated pupil size of 2.5-4.0 mm which underwent phacoemulsification using this self-made iris retractor. Another 50 cases of phacoemulsification with normal pupil size sever as control group. The mean operation time, ultrasound time and ultrasonic power, volume of irrigation fluid were documented intraoperatively. The visual acuity, pupil size and complication were observed on 1d, 1wk, 1mo and 1y after operation. Corneal endothelial cell was measured at 1mo postoperatively.
RESULT
Pupils could be expanded to approximately 4.5-5.5 mm with our self-made iris retractor in operation. No serious postoperative complication was found. Most (88%) of the pupils returned round or oval shape, light reflex restored to varying degrees at the first day after surgery. Best corrected visual acuity stabilized in 37 eyes (74%) at one day, in 43 eyes (86%) at one week, in 44 eyes (88%) at one month and 46 eyes (92%) at one year. Compared with the control, more time was needed to complete the operation in the small pupil group. There was no significant difference of the mean ultrasound time, ultrasonic power, volume of irrigation fluid required and corneal endothelial cell loss in 1mo follow up between the two groups.
CONCLUSION
Our self-made disposable flexible iris retractor could be easy obtained preoperatively or intraoperatively. It performed both safety and efficacy in our clinical trials. This simple self-made device has shown economic and practical values, especially in primary care hospital of the less developed districts.
doi:10.3980/j.issn.2222-3959.2014.02.17
PMCID: PMC4003084  PMID: 24790872
small pupil; iris retractor; phacoemulsification
14.  Radiation-induced malignant fibrous histiocytoma of the occipital: a case report 
Malignant fibrous histiocytoma (MFH) is a rare neoplasm exhibiting a propensity for aggressive clinical behavior. Effective treatment modality is surgical resection with wide margins, but its rate of recurrence and metastasis is still high. Early detection and complete excision of the tumor is necessary. A MFH of the occipital developed in a 51-year-old woman eight years after surgery and radiation for medulloblastoma of the cerebellar vermis. The secondary neoplasm arose at the site of tumor resection within the irradiated field, and was resected. The development of sarcomas is a recognized complication of radiation therapy. The final diagnosis after the operation was MFH. Radiation-induced sarcoma (RIS) is well known, but radiation-induced MFH is relatively rare in the head and neck region, especially in the occipital. The imaging findings are not diagnosis specific, but strict follow-up within the radiation field by computerized tomography (CT) and magnetic resonance imaging (MRI) and appreciation of the expected latency period may help in providing the diagnosis of RIS.
doi:10.1186/1477-7819-12-98
PMCID: PMC3999727  PMID: 24742094
Malignant fibrous histiocytoma; Radiation induced sarcoma; Occipital
15.  Parent-adolescent interaction and risk of adolescent internet addiction: a population-based study in Shanghai 
BMC Psychiatry  2014;14:112.
Background
Family-based intervention is essential for adolescents with behavioral problems. However, limited data are available on the relationship between family-based factors and adolescent internet addiction (AIA). We aimed to examine this relationship using a representative sample of Shanghai adolescents.
Methods
In October 2007, a total of 5122 adolescents were investigated from 16 high schools via stratified-random sampling in Shanghai. Self-reported and anonymous questionnaires were used to assess parent-adolescent interaction and family environments. AIA was assessed by DRM-52 Scale, developed from Young’s Internet-addiction Scale, using seven subscales to evaluate psychological symptoms of AIA.
Results
Adjusting for adolescents’ ages, genders, socio-economic status, school performances and levels of the consumption expenditure, strong parental disapproval of internet-use was associated with AIA (vs. parental approval, OR = 2.20, 95% CI: 1.24-3.91). Worse mother-adolescent relationships were more significantly associated with AIA (OR = 3.79, 95% CI: 2.22-6.48) than worse father-adolescent relationships (OR = 1.76, 95% CI: 1.10-2.80). Marital status of “married-but-separated” and family structure of “left-behind adolescents” were associated with symptoms of some subscales. When having high monthly allowance, resident students tended to develop AIA but commuter students did not. Family social-economic status was not associated with the development of AIA.
Conclusions
The quality of parent-adolescent relationship/communication was closely associated with the development of AIA, and maternal factors were more significantly associated with development of AIA than paternal factors. Family social-economic status moderated adolescent internet-use levels but not the development of AIA.
doi:10.1186/1471-244X-14-112
PMCID: PMC3999889  PMID: 24731648
Adolescents; Internet addiction; Mother-child relations; Father-child relations; China; Marital status; Family structure
16.  Automatic Localization of the Left Ventricle from Cardiac Cine Magnetic Resonance Imaging: A New Spectrum-Based Computer-Aided Tool 
PLoS ONE  2014;9(4):e92382.
Traditionally, cardiac image analysis is done manually. Automatic image processing can help with the repetitive tasks, and also deal with huge amounts of data, a task which would be humanly tedious. This study aims to develop a spectrum-based computer-aided tool to locate the left ventricle using images obtained via cardiac magnetic resonance imaging. Discrete Fourier Transform was conducted pixelwise on the image sequence. Harmonic images of all frequencies were analyzed visually and quantitatively to determine different patterns of the left and right ventricles on spectrum. The first and fifth harmonic images were selected to perform an anisotropic weighted circle Hough detection. This tool was then tested in ten volunteers. Our tool was able to locate the left ventricle in all cases and had a significantly higher cropping ratio of 0.165 than did earlier studies. In conclusion, a new spectrum-based computer aided tool has been proposed and developed for automatic left ventricle localization. The development of this technique, which will enable the automatic location and further segmentation of the left ventricle, will have a significant impact in research and in diagnostic settings. We envisage that this automated method could be used by radiographers and cardiologists to diagnose and assess ventricular function in patients with diverse heart diseases.
doi:10.1371/journal.pone.0092382
PMCID: PMC3982962  PMID: 24722328
17.  Triazole derivatives with improved in vitro antifungal activity over azole drugs 
A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F) can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π–π face-to-edge interactions.
doi:10.2147/DDDT.S58680
PMCID: PMC3986111  PMID: 24748772
synthesis; CYP51; molecular docking; azole agents
18.  Site-specific quantitative analysis of cardiac mitochondrial protein phosphorylation 
Journal of proteomics  2012;81:15-23.
We report the development of a multiple-reaction monitoring (MRM) strategy specifically tailored to the detection and quantification of mitochondrial protein phosphorylation. We recently derived 68 MRM transitions specific to protein modifications in the respiratory chain, voltage-dependent anion channel, and adenine nucleotide translocase. Here, we have now expanded the total number of MRM transitions to 176 to cover proteins from the tricarboxylic acid cycle, pyruvate dehydrogenase complex, and branched-chain alpha-keto acid dehydrogenase complex. We utilized the transition set to analyze endogenous protein phosphorylation in human heart, mouse heart, and mouse liver. The data demonstrate the potential utility of the MRM workflow for studying the functional details of mitochondrial phosphorylation signaling.
doi:10.1016/j.jprot.2012.09.015
PMCID: PMC3593810  PMID: 23022582
Multiple-reaction monitoring; mitochondria; phosphorylation; cardioprotection; quantification; cardiac biology
19.  Hemostatic and neuroprotective effects of human recombinant activated factor VII therapy after traumatic brain injury in pigs 
Experimental neurology  2008;210(2):645-655.
Human recombinant activated factor-VII (rFVIIa) has been used successfully in the treatment of spontaneous intracerebral hemorrhage. In addition, there is increasing interest in its use to treat uncontrolled bleeding of other origins, including trauma. The aim of this study was to evaluate the safety and potential effectiveness of rFVIIa to mitigate bleeding using a clinically relevant model of traumatic brain injury (TBI) in the pig. A double injury model was chosen consisting of (1) an expanding cerebral contusion induced by the application of negative pressure to the exposed cortical surface and (2) a rapid rotational acceleration of the head to induce diffuse axonal injury (DAI). Injuries were performed on 10 anesthetized pigs. Five minutes after injury, 720 μg/kg rFVIIa (n = 5) or vehicle control (n = 5) was administered intravenously. Magnetic resonance imaging (MRI) studies were performed within 30 min and at 3 days post-TBI to determine the temporal expansion of the cerebral contusion. Euthanasia and histopathologic analysis were performed at day 3. This included observations for hippocampal neuronal degeneration, axonal pathology and microclot formation. The expansion of contusion volume over the 3 days post-injury period was reduced significantly in animals treated with rFVIIa compared to vehicle controls. Surprisingly, immunohistochemical analysis demonstrated that the number of dead/dying hippocampal neurons and axonal pathology was reduced substantially by rFVIIa treatment compared to vehicle. In addition, there was no difference in the extent of microthrombi between groups. rFVIIa treatment after TBI in the pig reduced expansion of hemorrhagic cerebral contusion volume without exacerbating the severity of microclot formation. Finally, rFVIIa treatment provided a surprising neuroprotective effect by reducing hippocampal neuron degeneration as well as the extent of DAI.
doi:10.1016/j.expneurol.2007.12.019
PMCID: PMC3979422  PMID: 18291370
Traumatic brain injury; TBI; rFVIIa; Cerebral contusion; Recombinant Activated Factor VII; Hemostasis; Diffuse axonal injury; Neuroprotection
20.  The Potential Dual Effects of Anesthetic Isoflurane on Aβ-Induced Apoptosis 
Current Alzheimer research  2011;8(7):741-752.
β-amyloid protein (Aβ)-induced neurotoxicity is the main component of Alzheimer’s disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Aβ-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naïve mice, and naïve mice were treated with Aβ and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Aβ-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Aβ-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Aβ-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Aβ-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Aβ-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.
PMCID: PMC3973025  PMID: 21244349
Anesthesia; Alzheimer’s disease; isoflurane; apoptosis; β-Amyloid protein; dual effects; cytosolic calcium
21.  Establishing a novel knock-in mouse line for studying neuronal cytoplasmic dynein under normal and pathologic conditions 
Cytoskeleton (Hoboken, N.J.)  2013;70(4):215-227.
Cytoplasmic dynein plays important roles in mitosis and the intracellular transport of organelles, proteins, and mRNAs. Dynein function is particularly critical for survival of neurons, as mutations in dynein are linked to neurodegenerative diseases. Dynein function is also implicated in neuronal regeneration, driving the active transport of signaling molecules following injury of peripheral neurons. To enhance our understanding of dynein function and regulation in neurons, we established a novel knock-in mouse line in which the neuron-specific cytoplasmic dynein 1 intermediate chain 1 (IC-1) is tagged with both GFP and a 3xFLAG tag at its C-terminus. The fusion gene is under the control of IC-1’s endogenous promoter and is integrated at the endogenous locus of the IC-1-encoding gene Dync1i1. The IC-1-GFP-3xFLAG fusion protein is incorporated into the endogenous dynein complex, and movements of GFP-labeled dynein expressed at endogenous levels can be observed in cultured neurons for the first time. The knock-in mouse line also allows isolation and analysis of dynein-bound proteins specifically from neurons. Using this mouse line we have found proteins, including 14-3-3 zeta, which physically interact with dynein upon injury of the brain cortex. Thus, we have created a useful tool for studying dynein function in the central nervous system under normal and pathologic conditions.
doi:10.1002/cm.21102
PMCID: PMC3670090  PMID: 23475693
22.  Ethnic disparities in the prevalence of the metabolic syndrome in American adults: data from the Examination of National Health and Nutrition Examination Survey 1999–2010 
Data from the National Health and Nutrition Examination Survey were stratified by weight, gender, and ethnicity for six survey years from 1999 to 2010 for variables that satisfy the criteria for metabolic syndrome (MS). Results showed that 34% of the US adult population had MS. No significant gender disparities in MS prevalence were found. Black men had a significantly lower prevalence of MS than Black women and White men from 1999 to 2008 (P < 0.05). Women had a 60% higher abdominal adiposity than men in the US population (P = 0.00048; pregnant females were excluded). Although there seem to be ethnic differences in the prevalence of MS, the expression of MS is not a sufficient risk to culminate in cardiovascular disease; rather, nutritional, genetic, and environmental factors are necessary to finalize its expression into overt disease.
PMCID: PMC3954654  PMID: 24688184
23.  A cohort analysis of the cardiovascular risk factors in the employees of a pediatric hospital from 2009 to 2012 
A retrospective longitudinal cohort regression analysis was completed in 853 of the 3435 employees of Cook Children's Hospital who participated all 4 years (2009 to 2012) in an employer wellness program. The presence of the metabolic syndrome (MS) was used as an outcome measure for the success of the wellness program. Data were stratified by weight, gender, and ethnicity. The odds ratios and regression analysis showed a significant decline in MS over the 4 years of the study (P = 0.008), as well as a significant association between MS and obesity and overweight status (P < 0.0001), male gender (P = 0.0018), and all ethnic categories (P < 0.05) except African American ethnicity and the multiple ethnicity category. Age was strongly associated with risk for MS. Overall, the study showed that the wellness program significantly decreased the incidence of MS (P < 0.05).
PMCID: PMC3954655  PMID: 24688185
24.  Inertial particle separation by differential equilibrium positions in a symmetrical serpentine micro-channel 
Scientific Reports  2014;4:4527.
This paper presents an inertial microfluidic device with a simple serpentine micro-channel to continuously separate particles with high performance. Separation of micro/nano-particles has a variety of potential applications in biomedicine and industry. Among the existing separation technologies, a label-free technique without the use of antibody affinity, filter or centrifugation is highly desired to ensure minimal damage and alteration to the cells. Inertial microfluidics utilising hydrodynamic forces to separate particles is one of the most suitable label-free technologies with a high throughput. Our separation concept relies on size-based differential equilibrium positions of the particles perpendicular to the flow. Highly efficient separation is demonstrated with particles of different sizes. The results indicate that the proposed device has an integrative advantage to the existing microfluidic separation techniques, taking accounts of purity, efficiency, parallelizability, footprint, throughput and resolution. Our device is expected to be a good alternative to conventional separation methods for sample preparation and clinical diagnosis.
doi:10.1038/srep04527
PMCID: PMC3970124  PMID: 24681628
25.  QTLs for Seed Vigor-Related Traits Identified in Maize Seeds Germinated under Artificial Aging Conditions 
PLoS ONE  2014;9(3):e92535.
High seed vigor is important for agricultural production due to the associated potential for increased growth and productivity. However, a better understanding of the underlying molecular mechanisms is required because the genetic basis for seed vigor remains unknown. We used single-nucleotide polymorphism (SNP) markers to map quantitative trait loci (QTLs) for four seed vigor traits in two connected recombinant inbred line (RIL) maize populations under four treatment conditions during seed germination. Sixty-five QTLs distributed between the two populations were identified and a meta-analysis was used to integrate genetic maps. Sixty-one initially identified QTLs were integrated into 18 meta-QTLs (mQTLs). Initial QTLs with contribution to phenotypic variation values of R2>10% were integrated into mQTLs. Twenty-three candidate genes for association with seed vigor traits coincided with 13 mQTLs. The candidate genes had functions in the glycolytic pathway and in protein metabolism. QTLs with major effects (R2>10%) were identified under at least one treatment condition for mQTL2, mQTL3-2, and mQTL3-4. Candidate genes included a calcium-dependent protein kinase gene (302810918) involved in signal transduction that mapped in the mQTL3-2 interval associated with germination energy (GE) and germination percentage (GP), and an hsp20/alpha crystallin family protein gene (At5g51440) that mapped in the mQTL3-4 interval associated with GE and GP. Two initial QTLs with a major effect under at least two treatment conditions were identified for mQTL5-2. A cucumisin-like Ser protease gene (At5g67360) mapped in the mQTL5-2 interval associated with GP. The chromosome regions for mQTL2, mQTL3-2, mQTL3-4, and mQTL5-2 may be hot spots for QTLs related to seed vigor traits. The mQTLs and candidate genes identified in this study provide valuable information for the identification of additional quantitative trait genes.
doi:10.1371/journal.pone.0092535
PMCID: PMC3961396  PMID: 24651614

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