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1.  Disturbed Small-World Networks and Neurocognitive Function in Frontal Lobe Low-Grade Glioma Patients 
PLoS ONE  2014;9(4):e94095.
Background
Brain tumor patients often associated with losses of the small-world configuration and neurocognitive functions before operations. However, few studies were performed on the impairments of frontal lobe low-grade gliomas (LGG) after tumor resection using small-world network features.
Methodology/Principal Findings
To detect differences in the whole brain topology among LGG patients before and after operation, a combined study of neurocognitive assessment and graph theoretical network analysis of fMRI data was performed. We collected resting-state fMRI data of 12 carefully selected frontal lobe LGG patients before and after operation. We calculated the topological properties of brain functional networks in the 12 LGG, and compared with 12 healthy controls (HCs). We also applied Montreal Cognitive Assessment (MoCA) in a subset of patients (n = 12, including before and after operation groups) and HCs (n = 12). The resulting functional connectivity matrices were constructed for all 12 patients, and binary network analysis was performed. In the range of , the functional networks in preoperative LGG and postoperative one both fitted the definition of small-worldness. We proposed as small-world network interval, and the results showed that the topological properties were found to be disrupted in the two LGG groups, meanwhile the global efficiency increased and the local efficiency decreased. in the two LGG groups both were longer than HCs. in the LGG groups were smaller than HCs. Compared with the Hcs, MoCA in the two LGG groups were lower than HCs with significant difference, and the disturbed networks in the LGG were negatively related to worse MoCA scores.
Conclusions
Disturbed small-worldness preperty in the two LGG groups was found and widely spread in the strength and spatial organization of brain networks, and the alterated small-world network may be responsible for cognitive dysfunction in frontal lobe LGG patients.
doi:10.1371/journal.pone.0094095
PMCID: PMC3979755  PMID: 24714669
2.  Identification of Duplication Downstream of BMP2 in a Chinese Family with Brachydactyly Type A2 (BDA2) 
PLoS ONE  2014;9(4):e94201.
Brachydactyly type A2 (BDA2, MIM 112600) is characterized by the deviation and shortening of the middle phalange of the index finger and the second toe. Using genome-wide linkage analysis in a Chinese BDA2 family, we mapped the maximum candidate interval of BDA2 to a ∼1.5 Mb region between D20S194 and D20S115 within chromosome 20p12.3 and found that the pairwise logarithm of the odds score was highest for marker D20S156 (Zmax = 6.09 at θ = 0). Based on functional and positional perspectives, the bone morphogenetic protein 2 (BMP2) gene was identified as the causal gene for BDA2 in this region, even though no point mutation was detected in BMP2. Through further investigation, we identified a 4,671 bp (Chr20: 6,809,218–6,813,888) genomic duplication downstream of BMP2. This duplication was located within the linked region, co-segregated with the BDA2 phenotype in this family, and was not found in the unaffected family members and the unrelated control individuals. Compared with the previously reported duplications, the duplication in this family has a different breakpoint flanked by the microhomologous sequence GATCA and a slightly different length. Some other microhomologous nucleotides were also found in the duplicated region. In summary, our findings support the conclusions that BMP2 is the causing gene for BDA2, that the genomic location corresponding to the duplication region is prone to structural changes associated with malformation of the digits, and that this tendency is probably caused by the abundance of microhomologous sequences in the region.
doi:10.1371/journal.pone.0094201
PMCID: PMC3978006  PMID: 24710560
3.  Dendritic Cells Decreased the Concomitant Expanded Tregs and Tregs Related IL-35 in Cytokine-Induced Killer Cells and Increased Their Cytotoxicity against Leukemia Cells 
PLoS ONE  2014;9(4):e93591.
Regulatory T cells (Tregs) are potent immunosuppressive cells and essential for inducing immune tolerance. Recent studies have reported that Tregs and Tregs related cytokines can inhibit the antitumor activity of cytokine-induced killer (CIK) cells, but dendritic cells co-cultured CIK (DC-CIK) cells can be used for induction of a specific immune response by blocking of Tregs and TGF-β, IL-10. As a novel identified cytokine, IL-35 is specially produced by Tregs and plays an essential role in immune regulation. However, it remains unknown whether IL-35 roles in tumor immunotherapy mediated by CIK and DC-CIK cells. In this study, we cultured CIK and DC-CIK cells from the same healthy adult samples, and investigated their phenotype, proliferation, cytotoxic activity against leukemia cell lines K562 and NB4 by FCM and CCK-8, measured IL-35, TGF-β and IL-10 protein by ELISA, detected Foxp3, IL-35 and IL-35 receptor mRNA by Real-time PCR, respectively. We found Tregs and IL-35 concomitantly expanded by a time-dependent way during the generation of CIK cells, but DC significantly down-regulated the expression of them and simultaneously up-regulated the proliferation ability as well as cytotoxic activity of CIK cells against leukemia cell lines. Therefore, our data suggested that DC decreased concomitant expanded Tregs and Tregs related IL-35 in CIK cells and might contribute to improve their cytotoxicity against leukemia cells in vitro.
doi:10.1371/journal.pone.0093591
PMCID: PMC3976313  PMID: 24705499
4.  Antiviral RNA Silencing Initiated in the Absence of RDE-4, a Double-Stranded RNA Binding Protein, in Caenorhabditis elegans 
Journal of Virology  2013;87(19):10721-10729.
Small interfering RNAs (siRNAs) processed from double-stranded RNA (dsRNA) of virus origins mediate potent antiviral defense through a process referred to as RNA interference (RNAi) or RNA silencing in diverse organisms. In the simple invertebrate Caenorhabditis elegans, the RNAi process is initiated by a single Dicer, which partners with the dsRNA binding protein RDE-4 to process dsRNA into viral siRNAs (viRNAs). Notably, in C. elegans this RNA-directed viral immunity (RDVI) also requires a number of worm-specific genes for its full antiviral potential. One such gene is rsd-2 (RNAi spreading defective 2), which was implicated in RDVI in our previous studies. In the current study, we first established an antiviral role by showing that rsd-2 null mutants permitted higher levels of viral RNA accumulation, and that this enhanced viral susceptibility was reversed by ectopic expression of RSD-2. We then examined the relationship of rsd-2 with other known components of RNAi pathways and established that rsd-2 functions in a novel pathway that is independent of rde-4 but likely requires the RNA-dependent RNA polymerase RRF-1, suggesting a critical role for RSD-2 in secondary viRNA biogenesis, likely through coordinated action with RRF-1. Together, these results suggest that RDVI in the single-Dicer organism C. elegans depends on the collective actions of both RDE-4-dependent and RDE-4-independent mechanisms to produce RNAi-inducing viRNAs. Our study reveals, for the first time, a novel siRNA-producing mechanism in C. elegans that bypasses the need for a dsRNA-binding protein.
doi:10.1128/JVI.01305-13
PMCID: PMC3807410  PMID: 23885080
5.  Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF 
Recombinant human erythropoietin (rhEPO) induces neurogenesis and angiogenesis. Using a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of adult mouse, we investigated the hypothesis that neural progenitor cells treated with rhEPO promote angiogenesis. Treatment of neural progenitor cells with rhEPO significantly increased their expression and secretion of vascular endothelial growth factor (VEGF) and activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2). Selective inhibition of the Akt and ERK1/2 signaling pathways significantly attenuated the rhEPO-induced VEGF expression in neural progenitor cells. The supernatant harvested from neural progenitor cells treated with rhEPO significantly increased the capillary-like tube formation of MBECs. SU1498, a specific VEGF type-2 receptor (VEGFR2) antagonist, abolished the supernatant-enhanced angiogenesis. In addition, coculture of MBECs with neural progenitor cells treated with rhEPO substantially increased VEGFR2 mRNA and protein levels in MBECs. These in vitro results suggest that EPO enhances VEGF secretion in neural progenitor cells through activation of the PI3K/Akt and ERK1/2 signaling pathways and that neural progenitor cells treated with rhEPO upregulate VEGFR2 expression in cerebral endothelial cells, which along with VEGF secreted by neural progenitor cells promotes angiogenesis.
doi:10.1038/jcbfm.2008.32
PMCID: PMC3971950  PMID: 18414495
angiogenesis; mouse brain endothelial cell; neural progenitor cell; rhEPO
6.  Theoretical modeling of relative humidity on contact electrification of sand particles 
Scientific Reports  2014;4:4399.
Contact electrification of identical insulating particles has crucial significance for industrial and environmental science, especially in wind-blown granular systems. At the same time, the experimental phenomena of charge transfer first increased and then decreased with the increase of relative humidity has attracted the interest of many researchers. Humidity can affect the charge transfer has been early observed in the experiment, but the reason always puzzles researchers. In this study, based on trapped high-energy electron transfer mechanism, we introduce the effect of the water film in the charge transfer model and consider the actual situations of the sand particles in the collision process. Furthermore, charge transfer between sand particles in a single collision under different humidity conditions is investigated. The predicted results agree well with the law obtained in existing experiments qualitatively and thereby a possible explanation why humidity can affect the charge transfer is given.
doi:10.1038/srep04399
PMCID: PMC3957149  PMID: 24637964
7.  Seven Day Insertion Rest in Whole Body Vibration Improves Multi-Level Bone Quality in Tail Suspension Rats 
PLoS ONE  2014;9(3):e92312.
Objective
This study aimed to investigate the effects of low-magnitude, high-frequency vibration with rest days on bone quality at multiple levels.
Methods
Forty-nine three-month-old male Wistar rats were randomly divided into seven groups, namely, vibrational loading for X day followed by X day rest (VLXR, X = 1, 3, 5, 7), vibrational loading every day (VLNR), tail suspension (SPD), and baseline control (BCL). One week after tail suspension, rats were loaded by vibrational loading (35 Hz, 0.25 g, 15 min/day) except SPD and BCL. Fluorescence markers were used in all rats. Eight weeks later, femora were harvested to investigate macromechanical properties, and micro-computed tomography scanning and fluorescence test were used to evaluate microarchitecture and bone growth rate. Atomic force microscopy analyses and nanoindentation test were used to analyze the nanostructure and mechanical properties of bone material, respectively. Inductively coupled plasma optical emission spectroscopy was used for quantitative chemical analyses.
Results
Microarchitecture, mineral apposition rate and bone formation rate and macromechanical properties were improved in VL7R. Grain size and roughness were significantly different among all groups. No statistical difference was found for the mechanical properties of the bone material, and the chemical composition of all groups was almost similar.
Conclusions
Low-magnitude, high-frequency vibration with rest days altered bone microarchitecture and macro-biomechanical properties, and VL7R was more efficacious in improving bone loss caused by mechanical disuse, which provided theoretical basis and explored the mechanisms of vibration for improving bone quality in clinics.
doi:10.1371/journal.pone.0092312
PMCID: PMC3956900  PMID: 24637608
8.  Complete matrix properties of [001]c and [011]c poled 0.33Pb(In1/2Nb1/2)O3-0.38Pb(Mg1/3Nb2/3)O3-0.29PbTiO3 single crystals 
The elastic, piezoelectric, and dielectric properties of [001]c and [011]c poled 0.33Pb(In1/2Nb1/2)O3-0.38Pb(Mg1/3Nb2/3)O3-0.29PbTiO3 single crystals have been fully characterized at room temperature, and the temperature and frequency dependence of the dielectric susceptibility ε33 were also measured. The depoling temperature of this crystal is more than 20 °C higher than that of the corresponding binary 0.71Pb(Mg1/3Nb2/3)O3-0.29PbTiO3 system. From the measured P-E hysteresis loops, the coercive fields along [001]c and [011]c directions have been determined to be 6.0 kV/cm and 6.6 kV/cm, respectively, which indicate that these domain engineered ternary relaxor-based ferroelectric single crystals are excellent candidates for high-power applications.
doi:10.1016/j.jallcom.2012.11.111
PMCID: PMC3559011  PMID: 23378702
Ferroelectric; PIN-PMN-PT; material constants; piezoelectric
9.  Polarized Raman study on phase transitions in 0.24Pb(In1/2Nb1/2)O3–0.43Pb(Mg1/3Nb2/3)O3–0.33PbTiO3 single crystal 
Polarized Raman spectroscopy was performed to investigate the local lattice structure and phase transitions of unpoled 0.24Pb(In1/2Nb1/2)O3–0.43Pb(Mg1/3Nb2/3)O3–0.33PbTiO3 (0.24PIN–0.43PMN–0.33PT) single crystal in the temperature range from 30 °C to 260 °C. MA- and MC-type monoclinic phases were detected by micro-Raman spectra measured in different micro areas. Temperature dependence of Raman intensities, frequency shifts, mode merge and intensity ratios in the VV and VH geometries were investigated. Our results indicated that the monoclinic–tetragonal (M–T) phase transition of the ternary relaxorbased ferroelectric single crystal 0.24PIN–0.43PMN–0.33PT occurs at 85 °C, which is verified by the mode merging from 520 cm−1 and 580 cm−1 to 500 cm−1, and the tetragonal–cubic (T–C) phase transition happens at 200 °C based on the vanishing mode at 780 cm−1 measured in the VH polarization.
doi:10.1016/j.jallcom.2012.10.029
PMCID: PMC3947392  PMID: 24619338
PIN–PMN–PT; Micro-Raman; Phase transitions
10.  Synthesis and Evaluation of a Backbone Biodegradable Multiblock HPMA Copolymer Nanocarrier for the Systemic Delivery of Paclitaxel 
The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer- PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents.
doi:10.1016/j.jconrel.2012.12.009
PMCID: PMC3565036  PMID: 23262201
N-(2-hydroxypropyl)methacrylamide (HPMA); biodegradable multiblock copolymer; paclitaxel; ovarian cancer
11.  Comparison of risk of radiogenic second cancer following photon and proton craniospinal irradiation for a pediatric medulloblastoma patient 
Physics in medicine and biology  2013;58(4):807-823.
Pediatric patients who received radiation therapy are at risk of developing side effects like radiogenic second cancer. We compared proton and photon therapies in terms of the predicted risk of second cancers for a 4-year-old medulloblastoma patient receiving craniospinal irradiation (CSI). Two CSI treatment plans with 23.4 Gy or Gy (RBE) prescribed dose were computed: a three-field 6-MV photon therapy plan and a four-field proton therapy plan. The primary doses for both plans were determined using a commercial treatment planning system. Stray radiation doses for proton therapy were determined from Monte Carlo simulations, and stray radiation doses for photon therapy were determined from measured data. Dose-risk models based on the Biological Effects of Ionization Radiation VII report were used to estimate risk of second cancer in eight tissues/organs. Baseline predictions of the relative risk for each organ were always less for proton CSI than for photon CSI at all attained ages. The total lifetime attributable risks of the incidence of second cancer considered after proton CSI and photon CSI were 7.7% and 92%, respectively, and the ratio of lifetime risk was 0.083. Uncertainty analysis revealed that the qualitative findings of this study were insensitive to any plausible changes of dose-risk models and mean radiation weighting factor for neutrons. Proton therapy confers lower predicted risk of second cancer than photon therapy for the pediatric medulloblastoma patient.
doi:10.1088/0031-9155/58/4/807
PMCID: PMC3615542  PMID: 23322160
Proton therapy; second cancer; medulloblastoma; craniospinal irradiation; comparative treatment planning
12.  Posterior short segment pedicle screw fixation and TLIF for the treatment of unstable thoracolumbar/lumbar fracture 
Background
Currently, Posterior Short Segment Pedicle Screw Fixation is a popular procedure for treating unstable thoracolumbar/lumbar burst fracture. But progressive kyphosis and a high rate of hardware failure because of lack of the anterior column support remains a concern. The efficacy of different methods remains debatable and each technique has its advantages and disadvantages.
Methods
A consecutive series of 20 patients with isolated thoracolumbar/lumbar burst fractures were treated by posterior short segment pedicle screw fixation and transforaminal thoracolumbar/lumbar interbody fusion (TLIF) between January 2005 and December 2007. All patients were followed up for a minimum of 2 years. Demographic data, neurologic status, anterior vertebral body heights, segmental Cobb angle and treatment-related complications were evaluated.
Results
The mean operative time was 167 minutes (range, 150–220). Blood loss was 450 ~ 1200 ml, an average of 820 ml. All patients recovered with solid fusion of the intervertebral bone graft, without main complications like misplacement of the pedicle screw, nerve or vessel lesion or hard ware failure. The post-operative radiographs demonstrated a good fracture reduction and it was well maintained until the bone graft fusion. Neurological recovery of one to three Frankel grade was seen in 14 patients with partial neurological deficit, three grades of improvement was seen in one patient, two grades of improvement was observed in 6 patients and one grade of improvement was found in 6 patients. All the 6 patients with no paraplegia on admission remained neurological intact, and in one patient with Frankel D on admission no improvement was observed.
Conclusion
Posterior short-segment pedicle fixation in conjunction with TLIF seems to be a feasible option in the management of selected thoracolumbar/lumbar burst fractures, thereby addressing all the three columns through a single approach with less trauma and good results.
doi:10.1186/1471-2474-15-40
PMCID: PMC3930337  PMID: 24517217
Short segment fixation; Thoracic vertebrae; Lumbar vertebrae; Unstable burst fractures; Pedicle screw; TLIF
13.  Huperzine A in the Treatment of Alzheimer's Disease and Vascular Dementia: A Meta-Analysis 
The objective of our study was to perform an updated meta-analysis of placebo-controlled RCTs of Huperzine A (Hup A) on patients with Alzheimer's disease (AD) and vascular dementia (VD), in order to provide the basis and reference for clinical rational drug use. The primary outcome measures assessed were minimental state examination (MMSE) and activities of daily living scale (ADL). Eight AD trials with 733 participants and two VD trials with 92 participants that met our inclusion criteria were identified. The results showed that Hup A could significantly improve the MMSE and ADL score of AD and VD patients, and longer durations would result in better efficacy for the patients with AD. It seemed that there was significant improvement of cognitive function measured by memory quotient (MQ) in patients with AD. Most adverse effects in AD were generally of mild to moderate severity and transient. Compared to the patients with AD, Hup A may offer fewer side effects for participants with VD in this study. Therefore, Hup A is a well-tolerated drug that could significantly improve cognitive performance in patients with AD or VD, but we need to use it with caution in the clinical treatment.
doi:10.1155/2014/363985
PMCID: PMC3930088  PMID: 24639880
14.  Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model 
Pain  2012;154(2):294-305.
It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund’s adjuvant (CFA, 0.08 ml, 40 μg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (−48 h) and 2 and 24 h after CFA to assess hyperalgesia. IL-17 antibody (0.2–2 μg/rat) was given intrathecally (i.t.) 24 h before CFA to block the action of basal IL-17 and 2 h prior to each of two PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10–400 ng/rat) was administered to naive rats to determine its effects on PWL and phosphorylated-NR1 (p-NR1). P-NR1 modulates N-methyl-D-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for western blot of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time PCR of IL-17RA. The data shows that 1) IL-17 is up-regulated in activated and non-activated astrocytes, 2) IL-17RA is localized in NR1-immunoreactive neurons and up-regulated, and 3) IL-17 antibody at 2 μg/rat significantly increased PWL (P<0.05) and decreased p-NR1 and IL-17RA compared to control in CFA- and IL-17-injected rats. The results suggest that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate pain.
doi:10.1016/j.pain.2012.10.022
PMCID: PMC3563420  PMID: 23246025
Interleukin-17; spinal cord; glial cells; hyperalgesia; inflammation; pain
15.  Metabotropic Glutamate Receptor 3 Is Associated with Heroin Dependence but Not Depression or Schizophrenia in a Chinese Population 
PLoS ONE  2014;9(1):e87247.
Metabotropic glutamate receptor subtype 3 (mGluR3, encoded by GRM3) plays important roles in the pathophysiology of schizophrenia, depression, and drug dependence. GRM3 polymorphisms were reported to be associated with prefrontal activity, cognitive shifting, and memory capability in healthy subjects, as well as susceptibility to schizophrenia and depression. The goal of this study was to replicate the association of GRM3 with schizophrenia and depression and to explore GRM3’s potential association with heroin dependence (HD) in a Chinese population. Seventeen SNPs throughout the GRM3 gene were genotyped using MALDI-TOF within the MassARRAY system, and the allele and genotype distributions were compared between 619 healthy controls and 433 patients with schizophrenia, 409 patients with major depression, and 584 unrelated addicts. We found that GRM3 polymorphisms modulate the susceptibility to HD but do not significantly influence the risk for schizophrenia or depression. An increased risk of HD was significantly associated with the minor alleles of two GRM3 SNPs, including the T allele of rs274618 (Odds ratio (OR) = 1.631, 95% confidence interval (95%CI): 1.317–2.005), the T allele of rs274622 (OR = 1.652, 95% CI: 1.336–2.036), compared with the major alleles. The addicts carrying the minor allele of rs274618 or rs274622 had a shortened duration for transition from first use to dependence (DTFUD) in comparison to homozygote for major allele (P<0.0001 for each SNP using log rank test). Additionally, a 6-SNP haplotype within 5′ region of the GRM3 including the minor alleles of the two aforementioned SNPs was significantly associated with an increased risk of HD (P = 0.00001, OR = 1.668, 95% CI: 1.335–2.084). Our data indicated that GRM3 polymorphisms do not contribute to genetic susceptibility to schizophrenia and depression, but they confer an increased risk of HD in a Chinese population.
doi:10.1371/journal.pone.0087247
PMCID: PMC3909071  PMID: 24498053
16.  Hydrogen induced redox mechanism in amorphous carbon resistive random access memory 
We investigated the bipolar resistive switching characteristics of the resistive random access memory (RRAM) device with amorphous carbon layer. Applying a forming voltage, the amorphous carbon layer was carbonized to form a conjugation double bond conductive filament. We proposed a hydrogen redox model to clarify the resistive switch mechanism of high/low resistance states (HRS/LRS) in carbon RRAM. The electrical conduction mechanism of LRS is attributed to conductive sp2 carbon filament with conjugation double bonds by dehydrogenation, while the electrical conduction of HRS resulted from the formation of insulating sp3-type carbon filament through hydrogenation process.
doi:10.1186/1556-276X-9-52
PMCID: PMC3922695  PMID: 24475979
Carbon; Hydrogen redox; Conjugation double bond; RRAM
17.  The Evolutionary Divergence of psbA Gene in Synechococcus and Their Myoviruses in the East China Sea 
PLoS ONE  2014;9(1):e86644.
Marine Synechococcus is a principal component of the picophytoplankton and makes an important contribution to primary productivity in the ocean. Synechophages, infecting Synechococcus, are believed to have significant influences on the distribution and abundance of their hosts. Extensive previous ecological studies on cyanobacteria and viruses have been carried out in the East China Sea (ECS). Here we investigate the diversity and divergence of Synechococcus and their myoviruses (Synechomyoviruses) based on their shared photosynthesis psbA gene. Synechococcus is dominated by subclades 5.1A I, 5.1A II and 5.1A IV in the ECS, and clades I and II are the dominant groups in the Synechomyoviruses. As two phylogenetically independent clades, there is much higher diversity of the Synechomyoviruses than Synechococcus. Obvious partitioning characteristics of GC and GC3 (the GC content at the third codon position) contents are obtained among different picophytoplankton populations and their phages. The GC3 content causes the psbA gene in Synechococcus to have a higher GC content, while the opposite is true in the Synechomyoviruses. Analyzing more than one-time difference of the codon usage frequency of psbA sequences, the third position nucleotides of preferred codons for Synechococcus are all G and C, while most Synechomyoviral sequences (72.7%) have A and T at the third position of their preferred codons. This work shed light on the ecology and evolution of phage-host interactions in the environment.
doi:10.1371/journal.pone.0086644
PMCID: PMC3900582  PMID: 24466184
18.  Four Different Methods Comparison for Extraction of Astaxanthin from Green Alga Haematococcus pluvialis 
The Scientific World Journal  2014;2014:694305.
Haematococcus pluvialis is one of the potent organisms for production of astaxanthin. Up to now, no efficient method has been achieved due to its thick cell wall hindering solvent extraction of astaxanthin. In this study, four different methods, hydrochloric acid pretreatment followed by acetone extraction (HCl-ACE), hexane/isopropanol (6 : 4, v/v) mixture solvents extraction (HEX-IPA), methanol extraction followed by acetone extraction (MET-ACE, 2-step extraction), and soy-oil extraction, were intensively evaluated for extraction of astaxanthin from H. pluvialis. Results showed that HCl-ACE method could obtain the highest oil yield (33.3 ± 1.1%) and astaxanthin content (19.8 ± 1.1%). Quantitative NMR analysis provided the fatty acid chain profiles of total lipid extracts. In all cases, oleyl chains were predominant, and high amounts of polyunsaturated fatty acid chains were observed and the major fatty acid components were oleic acid (13–35%), linoleic acid (37–43%), linolenic acid (20–31%), and total saturated acid (17–28%). DPPH radical scavenging activity of extract obtained by HCl-ACE was 73.2 ± 1.0%, which is the highest amongst the four methods. The reducing power of extract obtained by four extraction methods was also examined. It was concluded that the proposed extraction method of HCl-ACE in this work allowed efficient astaxanthin extractability with high antioxidant properties.
doi:10.1155/2014/694305
PMCID: PMC3916103  PMID: 24574909
19.  MicroRNA-26a negatively regulates toll-like receptor 3 expression of rat macrophages and ameliorates pristane induced arthritis in rats 
Introduction
Abnormal toll-like receptor (TLR)3 signaling plays an indispensable role in pathogenesis of both experimental and human rheumatoid arthritis, and microRNAs (miRNAs) might orchestrate this signaling pathway. This study was performed to determine the relationship between miR-26a and TLR3 in rat macrophages and to observe effects of miR-26a mimic on pristane induced arthritis (PIA) in rats.
Methods
Dual luciferase reporter assay was used to validate the direct interaction between miR-26a (a candidate miRNA to target tlr3 mRNA) and tlr3 3′UTR. MiR-26a regulation on TLR3 gene expression was determined using RT-qPCR and Western blotting after miR-26a mimics and inhibitors were transfected into rat macrophage line NR8383 cells. Poly I:C (TLR3 ligand) was used to trigger TLR3 activation, and mRNA expression of its downstream cytokines interferon (ifn)-β and tumor necrosis factor (tnf)-α was accordingly detected to determine the regulation of TLR3 signaling. Expressions of TLR3 and miR-26a were detected during rat bone marrow derived macrophage (BMDM) induction, in pristane stimulated NR8383 cells and spleens from methotrexate (MTX) treated PIA rats. A miR-26a mimic was administrated intraperitoneally to PIA rats, and arthritis severity was evaluated by macroscopic or microscopic observations.
Results
Direct target relationship between miR-26a and tlr3 mRNA in rats was confirmed. Modifications of miR-26a function by transfection of miR-26a mimics and inhibitors exhibited corresponding repression and augmentation of TLR3 and its signaling downstream cytokine expressions in NR8383 cells. The alteration of miR-26a expression was negatively related with TLR3 expression during BMDM induction, in pristane-primed NR8383 cells and PIA rat spleens. Moreover, both abnormal expressions were rescued in MTX treated arthritis rat spleens. The miR-26a mimic treatment displayed the depression of TLR3 expression and ameliorated the disease severity in the rats with pristane induced arthritis.
Conclusions
MiR-26a negatively regulates TLR3 signaling via targeting of TLR3 itself in rat macrophages, and this finding provides a novel insight into abnormal TLR3 overexpression during experimental arthritis.
doi:10.1186/ar4435
PMCID: PMC3978458  PMID: 24423102
20.  The Associations of Uric Acid, Cardiovascular and All-Cause Mortality in Peritoneal Dialysis Patients 
PLoS ONE  2014;9(1):e82342.
Aims
To investigate whether uric acid (UA) is an independent predictor of cardiovascular (CV) and all-cause mortality in peritoneal dialysis (PD) patients after controlling for recognized CV risk factors.
Methods
A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic and laboratory data were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of CV and all-cause mortality with adjustments for recognized traditional and uremia-related CV factors.
Results
There were no significant differences in baseline characteristics between patients with (n = 2193) and without (n = 71) UA measured. Each 1 mg/dL of increase in UA was associated with higher all-cause mortality with 1.05(1.00∼1.10) of HR and higher CV mortality with 1.12 (1.05∼1.20) of HR after adjusting for age, gender and center size. The highest gender-specific tertile of UA predicted higher all-cause mortality with 1.23(1.00∼1.52) of HR and higher CV mortality with 1.69 (1.21∼2.38) of HR after adjusting for age, gender and center size. The predictive value of UA was stronger in patients younger than 65 years without CV disease or diabetes at baseline. The prognostic value of UA as both continuous and categorical variable weakened or disappeared after further adjusted for uremia-related and traditional CV risk factors.
Conclusions
The prognostic value of UA in CV and all-cause mortality was weak in PD patients generally, which was confounded by uremia-related and traditional CV risk factors.
doi:10.1371/journal.pone.0082342
PMCID: PMC3885378  PMID: 24416142
21.  Bufalin Induces the Interplay between Apoptosis and Autophagy in Glioma Cells through Endoplasmic Reticulum Stress 
Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Bufalin is the major component of Chan-Su (a traditional Chinese medicine) extracts from the venom of Bufo gargarizan. In this study, we evaluated the growth inhibitory effect of bufalin on glioma cells and explored the underlying molecular mechanisms. Our results showed that bufalin inhibited the growth of glioma cells significantly. Mechanistic studies demonstrated that bufalin induced apoptosis through mitochondrial apoptotic pathway. In addition, bufalin was also found to induce ER stress-mediated apoptosis, which was supported by the up- regulation of ER stress markers, CHOP and GRP78, and augmented phosphorylation of PERK and eIF2α as well as cleavage of caspase-4. Downregulation of CHOP using siCHOP RNA attenuated bufalin-induced apoptosis, further confirming the role of ER stress response in mediating bufalin-induced apoptosis. Evidence of bufalin-induced autophagy included formation of the acidic vesicular organelles, increase of autophagolysosomes and LC3-II accumulation. Further experiments showed that the mechanism of bufalin-induced autophagy associated with ATP deleption involved an increase in the active form of AMPK, decreased phosphorylation levels of mTOR and its downstream targets 4EBP1 and p70S6K1. Furthermore, TUDC and silencing of eIF2α or CHOP partially blocked bufalin-induced accumulation of LC3-II, which indicated that ER stress preceded bufalin-induced autophagy and PERK/eIF2α/CHOP signaling pathway played a major part in the process. Blockage of autophagy increased expression of ER stress associated proteins and the ratio of apoptosis, indicating that autophagy played a cytoprotective role in bufalin induced ER stress and cell death. In conclusion, bufalin inhibits glioma cell growth and induces interplay between apoptosis and autophagy through endoplasmic reticulum stress. It will provide molecular bases for developing bufalin into a drug candidate for the treatment of maglinant glioma.
doi:10.7150/ijbs.8056
PMCID: PMC3927133  PMID: 24550689
ER stress; autophagy; apoptosis; bufalin; glioma cancer.
22.  Chondroprotective Activity of Murraya exotica through Inhibiting β-Catenin Signaling Pathway 
Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects of Murraya exotica (L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containing M. exotica (50 mg/kg, 100 mg/kg, and 200 mg/kg), M. exotica showed the activity of decreasing the contents of TNF-α and IL-1β in SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal that M. exotica can downregulate mRNA and protein expressions of β-catenin and COX-2 and reporter activity significantly. Conclusively, M. exotica exhibits antiapoptotic chondroprotective activity probably through inhibiting β-catenin signaling.
doi:10.1155/2013/752150
PMCID: PMC3880701  PMID: 24454514
23.  Highly sensitive hot electron bolometer based on disordered graphene 
Scientific Reports  2013;3:3533.
A bolometer is a device that makes an electrical resistive response to the electromagnetic radiation resulted from a raise of temperature due to heating. The combination of the extremely weak electron-phonon interactions along with its small electron heat capacity makes graphene an ideal material for applications in ultra-fast and sensitive hot electron bolometer. However, a major issue is that the resistance of pristine graphene weakly depends on the electronic temperature. We propose using disordered graphene to obtain a strongly temperature dependent resistance. The measured electrical responsivity of the disordered graphene bolometer reaches 6 × 106 V/W at 1.5 K, corresponding to an optical responsivity of 1.6 × 105 V/W. The deduced electrical noise equivalent power is 1.2 , corresponding to the optical noise equivalent power of 44 . The minimal device structure and no requirement for high mobility graphene make a step forward towards the applications of graphene hot electron bolometers.
doi:10.1038/srep03533
PMCID: PMC3866633  PMID: 24346418
24.  Space electric field concentrated effect for Zr:SiO2 RRAM devices using porous SiO2 buffer layer 
Nanoscale Research Letters  2013;8(1):523.
To improve the operation current lowing of the Zr:SiO2 RRAM devices, a space electric field concentrated effect established by the porous SiO2 buffer layer was investigated and found in this study. The resistive switching properties of the low-resistance state (LRS) and high-resistance state (HRS) in resistive random access memory (RRAM) devices for the single-layer Zr:SiO2 and bilayer Zr:SiO2/porous SiO2 thin films were analyzed and discussed. In addition, the original space charge limited current (SCLC) conduction mechanism in LRS and HRS of the RRAM devices using bilayer Zr:SiO2/porous SiO2 thin films was found. Finally, a space electric field concentrated effect in the bilayer Zr:SiO2/porous SiO2 RRAM devices was also explained and verified by the COMSOL Multiphysics simulation model.
doi:10.1186/1556-276X-8-523
PMCID: PMC3881491  PMID: 24330524
RRAM; Porous SiO2; Space charge limited current; Zr
25.  Impact of margin size on the predicted risk of radiogenic second cancers following proton arc therapy and volumetric modulated arc therapy for prostate cancer 
Physics in medicine and biology  2012;57(23):N469-N479.
We previously determined that the predicted risk of radiogenic second cancer in the bladder and rectum after proton arc therapy (PAT) was less than or equal to that after volumetric modulated arc therapy (VMAT) with photons, but we did not consider the impact of margin size on that risk. The current study was thus conducted to evaluate margin size’s effect on the predicted risks of second cancer for the two modalities and the relative risk between them. Seven treatment plans with margins ranging from 0 mm in all directions to 6 mm posteriorly and 8 mm in all other directions were considered for both modalities. We performed risk analyses using three risk models with varying amounts of cell sterilization and calculated ratios of risk for the corresponding PAT and VMAT plans. We found that the change in risk with margin size depended on the risk model but that the relative risk remained nearly constant with margin size, regardless of the amount of cell sterilization modeled. We conclude that while margin size influences the predicted risk of a second cancer for a given modality, it appears to affect both modalities in roughly equal proportions so that the relative risk between PAT and VMAT is approximately equivalent.
doi:10.1088/0031-9155/57/23/N469
PMCID: PMC3701958  PMID: 23154795
second cancer; second malignant neoplasm; volumetric modulated arc therapy; VMAT; proton arc therapy; proton therapy; prostate cancer; margin size

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