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1.  Investigation of LRS dependence on the retention of HRS in CBRAM 
The insufficient retention prevents the resistive random access memory from intended application, such as code storage, FPGA, encryption, and others. The retention characteristics of high resistance state (HRS) switching from different low resistance state (LRS) were investigated in a 1-kb array with one transistor and one resistor configuration. The HRS degradation was found strongly dependent on the LRS: the lower the resistance of the LRS (RLRS) is, the worse HRS retention will be. According to the quantum point contact model, the HRS corresponds to a tiny tunnel gap or neck bridge with atomic size in the filament. The degradation of HRS is due to the filling or widening of the neck point by the diffusion of copper species from the residual filament. As the residual filament is stronger in case of the lower RLRS, the active area around the neck point for copper species diffusion is larger, resulting in higher diffusion probability and faster degradation of HRS during the temperature-accelerated retention measurement.
PMCID: PMC4385049  PMID: 25852358
Resistive random access memory (RRAM); High resistance state (HRS); Retention; Quantum point contact (QPC) model
2.  Impact of program/erase operation on the performances of oxide-based resistive switching memory 
Further performance improvement is necessary for resistive random access memory (RRAM) to realize its commercialization. In this work, a novel pulse operation method is proposed to improve the performance of RRAM based on Ti/HfO2/Pt structure. In the DC voltage sweep of the RRAM device, the SET transition is abrupt under positive bias. If current sweep with positive bias is utilized in SET process, the SET switching will become gradual, so SET is current controlled. In the negative voltage sweep for RESET process, the change of current with applied voltage is gradual, so RESET is voltage controlled. Current sweep SET and voltage sweep RESET shows better controllability on the parameter variation. Considering the SET/RESET characteristics in DC sweep, in the corresponding pulse operation, the width and height of the pulse series can be adjusted to control the SET and RESET process, respectively. Our new method is different from the traditional pulse operation in which both the width and height of program/erase pulse are simply kept constant which would lead to unnecessary damage to the device. In our new method, in each program or erase operation, a series of pulses with the width/height gradually increased are made use of to fully finish the SET/RESET switching but no excessive stress is generated at the same time, so width/height-controlled accurate SET/RESET can be achieved. Through the operation, the uniformity and endurance of the RRAM device has been significantly improved.
PMCID: PMC4385037  PMID: 25852336
Resistive random access memory (RRAM); Current sweep; Pulse operation; Uniformity; Endurance; Weibull distribution
3.  Statistical characteristics of reset switching in Cu/HfO2/Pt resistive switching memory 
A major challenge of resistive switching memory (resistive random access memory (RRAM)) for future application is how to reduce the fluctuation of the resistive switching parameters. In this letter, with a statistical methodology, we have systematically analyzed the reset statistics of the conductive bridge random access memory (CBRAM) with a Cu/HfO2/Pt structure which displays bipolar switching property. The experimental observations show that the distributions of the reset voltage (Vreset) and reset current (Ireset) are greatly influenced by the initial on-state resistance (Ron) which is closely related to the size of the conductive filament (CF) before the reset process. The reset voltage increases and the current decreases with the on-state resistance, respectively, according to the scatter plots of the experimental data. Using resistance screening method, the statistical data of the reset voltage and current are decomposed into several ranges and the distributions of them in each range are analyzed by the Weibull model. Both the Weibull slopes of the reset voltage and current are demonstrated to be independent of the on-state resistance which indicates that no CF dissolution occurs before the reset point. The scale factor of the reset voltage increases with on-state resistance while that of the reset current decreases with it. These behaviors are fully in consistency with the thermal dissolution model, which gives an insight on the physical mechanism of the reset switching. Our work has provided an inspiration on effectively reducing the variation of the switching parameters of RRAM devices.
PMCID: PMC4493841  PMID: 26089007
RRAM; Statistics; Conductive filament; Weibull model; Thermal dissolution
4.  Identification and Characterization of Long Non-Coding RNAs Related to Mouse Embryonic Brain Development from Available Transcriptomic Data 
PLoS ONE  2013;8(8):e71152.
Long non-coding RNAs (lncRNAs) as a key group of non-coding RNAs have gained widely attention. Though lncRNAs have been functionally annotated and systematic explored in higher mammals, few are under systematical identification and annotation. Owing to the expression specificity, known lncRNAs expressed in embryonic brain tissues remain still limited. Considering a large number of lncRNAs are only transcribed in brain tissues, studies of lncRNAs in developmental brain are therefore of special interest. Here, publicly available RNA-sequencing (RNA-seq) data in embryonic brain are integrated to identify thousands of embryonic brain lncRNAs by a customized pipeline. A significant proportion of novel transcripts have not been annotated by available genomic resources. The putative embryonic brain lncRNAs are shorter in length, less spliced and show less conservation than known genes. The expression of putative lncRNAs is in one tenth on average of known coding genes, while comparable with known lncRNAs. From chromatin data, putative embryonic brain lncRNAs are associated with active chromatin marks, comparable with known lncRNAs. Embryonic brain expressed lncRNAs are also indicated to have expression though not evident in adult brain. Gene Ontology analysis of putative embryonic brain lncRNAs suggests that they are associated with brain development. The putative lncRNAs are shown to be related to possible cis-regulatory roles in imprinting even themselves are deemed to be imprinted lncRNAs. Re-analysis of one knockdown data suggests that four regulators are associated with lncRNAs. Taken together, the identification and systematic analysis of putative lncRNAs would provide novel insights into uncharacterized mouse non-coding regions and the relationships with mammalian embryonic brain development.
PMCID: PMC3743905  PMID: 23967161
5.  Lead Induces Apoptosis and Histone Hyperacetylation in Rat Cardiovascular Tissues 
PLoS ONE  2015;10(6):e0129091.
Acute and chronic lead (Pb) exposure might cause hypertension and cardiovascular diseases. The purpose of this study was to evaluate the effects of early acute exposure to Pb on the cellular morphology, apoptosis, and proliferation in rats and to elucidate the early mechanisms involved in the development of Pb-induced hypertension. Very young Sprague-Dawley rats were allowed to drink 1% Pb acetate for 12 and 40 days. Western blot analysis indicated that the expression of proliferating cell nuclear antigen (PCNA) decreased in the tissues of the abdominal and thoracic aortas and increased in the cardiac tissue after 12 and 40 days of Pb exposure, respectively. Bax was upregulated and Bcl-2 was downregulated in vascular and cardiac tissues after 40 days of Pb exposure. In addition, an increase in caspase-3 activity was observed after 40 days of exposure to Pb. In terms of morphology, we found that the internal elastic lamina (IEL) of aorta lost the original curve and the diameter of cardiac cell was enlarged after 40 days. Furthermore, the exposure led to a marked increase in acetylated histone H3 levels in the aortas and cardiac tissue after 12 and 40 days, than that in the control group. These findings indicate that Pb might increase the level of histone acetylation and induce apoptosis in vascular and cardiac tissues. However, the mechanism involved need to be further investigated.
PMCID: PMC4468051  PMID: 26075388
6.  Cerebral Activity Changes in Different Traditional Chinese Medicine Patterns of Psychogenic Erectile Dysfunction Patients 
Background. Pattern differentiation is the foundation of traditional Chinese medicine (TCM) treatment for erectile dysfunction (ED). This study aims to investigate the differences in cerebral activity in ED patients with different TCM patterns. Methods. 27 psychogenic ED patients and 27 healthy subjects (HS) were enrolled in this study. Each participant underwent an fMRI scan in resting state. The fractional amplitude of low-frequency fluctuation (fALFF) was used to detect the brain activity changes in ED patients with different patterns. Results. Compared to HS, ED patients showed an increased cerebral activity in bilateral cerebellum, insula, globus pallidus, parahippocampal gyrus, orbitofrontal cortex (OFC), and middle cingulate cortex (MCC). Compared to the patients with liver-qi stagnation and spleen deficiency pattern (LSSDP), the patients with kidney-yang deficiency pattern (KDP) showed an increased activity in bilateral brainstem, cerebellum, hippocampus, and the right insula, thalamus, MCC, and a decreased activity in bilateral putamen, medial frontal gyrus, temporal pole, and the right caudate nucleus, OFC, anterior cingulate cortex, and posterior cingulate cortex (P < 0.005). Conclusions. The ED patients with different TCM patterns showed different brain activities. The differences in cerebral activity between LSSDP and KDP were mainly in the emotion-related regions, including prefrontal cortex and cingulated cortex.
PMCID: PMC4477190  PMID: 26180534
7.  Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901 
OncoTargets and therapy  2015;8:1265-1270.
This study was designed to investigate the proliferation inhibition and apoptosis-promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo-chemotherapy group were drastically lower than the control group (P<0.05). For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05). 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37°C and 43°C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01). The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46°C (P>0.05), which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5-fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901.
PMCID: PMC4455869  PMID: 26064061
gastric cancer; thermotherapy; 5-fluorouracil; Bcl-2; HSP70; thermotolerance
8.  Protective Effects of Hydrogen-Rich Saline on Rats with Smoke Inhalation Injury 
Objective. To explore the protective effects of hydrogen-rich saline on rats with smoke inhalation injury. Methods. 36 healthy male Sprague-Dawley rats were randomly divided into 3 groups (n = 12 per group): sham group (S), inhalation injury plus normal saline treatment group (I+NS), and inhalation injury plus hydrogen-rich saline treatment group (I+HS). 30 min after injury, normal saline and hydrogen-rich saline were injected intraperitoneally (5 mL/kg) in I+NS group and I+HS group, respectively. All rats were euthanized and blood and organ specimens were collected for determination 24 h after inhalation injury. Results. Tumor necrosis factor-alpha (TNF-α) levels, malondialdehyde (MDA) concentrations, nuclear factor kappa B (NF-κB) p65 expression, and apoptosis index (AI) in I+HS group were significantly decreased (P < 0.05), while superoxide dismutase (SOD) activities were increased compared with those in I+NS group; and a marked improvement in alveolar structure was also found after hydrogen-rich saline treatment. Conclusions. Hydrogen-rich saline treatment exerts protective effects in acute lung injury induced by inhalation injury, at least in part through the activation of anti-inflammatory and antioxidant pathways and inhibition of apoptosis.
PMCID: PMC4454757  PMID: 26090070
9.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
10.  Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice 
This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215–4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75–300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field.
Graphical Abstract
PMCID: PMC4327999  PMID: 25500813
Eupatorium adenophorum; Sesquiterpenes; Histopathology; Environmental toxicity; Biopesticide
11.  The Evolutionary History and Spatiotemporal Dynamics of the Fever, Thrombocytopenia and Leukocytopenia Syndrome Virus (FTLSV) in China 
In 2007, a novel bunyavirus was found in Henan Province, China and named fever, thrombocytopenia and leukocytopenia syndrome virus (FTLSV); since then, FTLSV has been found in ticks and animals in many Chinese provinces. Human-to-human transmission has been documented, indicating that FTLSV should be considered a potential public health threat. Determining the historical spread of FTLSV could help curtail its spread and prevent future movement of this virus.
Method/Principal Findings
To examine the pattern of FTLSV evolution and the origin of outbreak strains, as well to examine the rate of evolution, the genome of 12 FTLSV strains were sequenced and a phylogenetic and Bayesian phylogeographic analysis of all available FTLSV sequences in China were performed. Analysis based on the FTLSV L segment suggests that the virus likely originated somewhere in Huaiyangshan circa 1790 (95% highest probability density interval: 1756–1817) and began spreading around 1806 (95% highest probability density interval: 1773–1834). Analysis also indicates that when FTLSV arrived in Jiangsu province from Huaiyangshan, Jiangsu Province became another source for the spread of the disease. Bayesian factor test analysis identified three major transmission routes: Huaiyangshan to Jiangsu, Jiangsu to Liaoning, and Jiangsu to Shandong. The speed of FTLSV movement has increased in recent decades, likely facilitated by modern human activity and ecosystem changes. In addition, evidence of RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force in the evolution of this virus.
Results presented in the manuscript suggest that the Huaiyangshan area is likely be the origin of FTLSV in China and identified probable viral migration routes. These results provide new insights into the origin and spread of FTLSV in China, and provide a foundation for future virological surveillance and control.
Author Summary
FTLSV is novel bunyavirus belonging to genus Phlebovirus and was first found in Huaiyangshan area. The epidemiology and pathogenesis of FTLSV remain poorly understood. This lack of information underscores the importance of analyzing the movement and genetic history of FTLSV in China. Recent advances in Bayesian coalescent phylogenetic analyses have resulted in more sophisticated methods being available for determining the relative age of emerging pathogens. In this study, a phylogenetic and Bayesian phylogeographic analysis was performed for FTLSV whole genomic sequences isolated from China. Results identified the Huaiyangshan area as the most probable origin of FTLSV and suggested migrating routes of the virus. These results offer the first description of the movement and history of FTLSV in China. RNA segment reassortment was found in FTLSV; purifying selection appears to have been the dominant force driving the evolution of this virus. The results of this study could be used to facilitate the development of new strategies for controlling FTLSV.
PMCID: PMC4199521  PMID: 25329580
12.  Self-control study of combination treatment of 308 nm excimer laser and calcipotriene ointment on stable psoriasis vulgaris 
Objective: This study aims to compare the differences of clinical efficacy and safety of treatment of stable psoriasis vulgaris with calcipotriene ointment in combination with 308 nm excimer laser to 308 nm excimer laser alone. Methods: Randomized, open and self-control trial was conducted in 36 selected patients. The skin lesions from these patients with stable psoriasis vulgaris were divided into two sides along the midline of torso, one side was treated with 308 nm excimer laser, 2 times/week, at meantime Calcipotriene was applied externally, 2 times/day (treatment group); the other side was given 308 nm excimer laser alone, 2 times/week, the treatment period was 6 weeks (control group). Skin lesion area, PASI scores and cumulative doses of 308 nm excimer laser in patients with psoriasis were assessed before treatment and on weeks 2, 4 and 6 after treatment. Results: 32 of 36 patients with stable psoriasis vulgaris completed study, effective rates in two groups were better on week 6 (84.37%, 56.25%) than on week 4 (53.12%, 37.5%) and on week 2 (31.25%, 18.75%) (P < 0.05). Effective rate on week 6 in control group (56.25%) was lower than treatment group (84.37%) (P < 0.05). The two groups showed that PASI scores on weeks 2 and 4 after treatment were significantly lower than before treatments (P < 0.05), and PASI scores on week 6 in treatment group was significantly lower than control group (P < 0.05). The average cumulative laser doses in treatment group at the end of trial was 4.69 (2.03) J/cm2, which was significantly lower than in control group 8.41 (2.42) J/cm (P < 0.05). Treatment efficacies in the head, folds, back, abdomen and limbs were similar and no serious adverse effects, however the number of treatment and irradiation doses in the head and folds were significantly less than in back, abdomen and limbs (P < 0.05). Conclusions: Treatment of psoriasis vulgaris with 308 nm excimer laser in combination with external application of Calcipotriene ointment can improve long-term treatment efficacy, decrease cumulative laser doses, and reduce adverse effects induced by laser irradiations.
PMCID: PMC4211797  PMID: 25356147
Psoriasis; vulgaris; excimer Laser; calcipotriene
13.  Characterization and Plasmid Elimination of NDM-1-Producing Acinetobacter calcoaceticus from China 
PLoS ONE  2014;9(9):e106555.
The presence of multidrug-resistant bacterial pathogens in the environment poses a serious threat to public health. The opportunistic Acinetobacter spp. are among the most prevalent causes of nosocomial infections. Here, we performed complete genome sequencing of the Acinetobacter calcoaceticus strain XM1570, which was originally cultivated from the sputum of a patient diagnosed with pneumonia in Xiamen in 2010. We identified carbapenem resistance associated gene blaNDM-1 located on a 47.3-kb plasmid. Three methods – natural reproduction, sodium dodecyl sulfate treatment and nalidixic acid treatment – were used to eliminate the blaNDM-1-encoding plasmid, which achieved elimination rates of 3.32% (10/301), 83.78% (278/332), and 84.17% (298/354), respectively. Plasmid elimination dramatically increased antibiotic sensitivity, reducing the minimum bacteriostatic concentration of meropenem from 256 µg/ml in the clinical strain to 0.125 µg/ml in the plasmid-eliminated strain. Conjugation transfer assays showed that the blaNDM-1-containing plasmid could be transferred into Escherichia coli DH5α:pBR322 in vitro as well as in vivo in mice. The blaNDM-1 genetic environment was in accordance with that of other blaNDM-1 genes identified from India, Japan, and Hong-Kong. The multilocus sequence type of the isolate was identified as ST-70. Two novel genes encoding intrinsic OXA and ADC were identified and named as OXA-417 and ADC-72. The finding of blaNDM-1 in species like A. calcoaceticus demonstrates the wide spread of this gene in gram-negative bacteria which is possible by conjugative plasmid transfer. The results of this study may help in the development of a treatment strategy for controlling NDM-1 bacterial infection and transmission.
PMCID: PMC4152304  PMID: 25181293
14.  Thermoelectric Seebeck effect in oxide-based resistive switching memory 
Nature Communications  2014;5:4598.
Reversible resistive switching induced by an electric field in oxide-based resistive switching memory shows a promising application in future information storage and processing. It is believed that there are some local conductive filaments formed and ruptured in the resistive switching process. However, as a fundamental question, how electron transports in the formed conductive filament is still under debate due to the difficulty to directly characterize its physical and electrical properties. Here we investigate the intrinsic electronic transport mechanism in such conductive filament by measuring thermoelectric Seebeck effects. We show that the small-polaron hopping model can well describe the electronic transport process for all resistance states, although the corresponding temperature-dependent resistance behaviours are contrary. Moreover, at low resistance states, we observe a clear semiconductor–metal transition around 150 K. These results provide insight in understanding resistive switching process and establish a basic framework for modelling resistive switching behaviour.
Oxide-based resistive switching memory is known to depend on the formation and rupture of a conducting filament, although the mechanism behind this remains debated. Here, the authors measure the Seebeck effect to understand the intrinsic electronic transport mechanism in the conducting filament.
PMCID: PMC4143917  PMID: 25141267
15.  Primary desmoplastic small round cell tumor of the duodenum 
The desmoplastic small round cell tumor (DSRCT) is an extremely rare tumor that mainly affects adolescents and mostly involves the abdominal and pelvic peritoneum. A 14-year-old girl presented with intermittent epigastric pain; abdominal computed tomography and upper gastrointestinal barium X-ray revealed an 8 cm × 10 cm space-occupying mass in the duodenal region. The patient underwent pancreaticoduodenectomy and the final pathologic diagnosis was DSRCT. Although multi-agent systemic chemotherapy was given, the patient died of metastasis 8 months later. Early diagnosis and surgical treatment with adjuvant chemotherapy seems to be the best treatment choice for this disease.
PMCID: PMC4096735  PMID: 24997683
chemotherapy; desmoplastic small round cell tumor; duodenum; surgery
16.  Nucleolus-tethering system (NoTS) reveals that assembly of photobodies follows a self-organization model 
Molecular Biology of the Cell  2014;25(8):1366-1373.
A nucleolus-tethering system (NoTS) based on nucleolin2 is developed by artificially tethering a protein of interest to the nucleolus for analyzing protein–protein interactions and the initiation of nuclear bodies. The NoTS is used to demonstrate a self-organization model for the biogenesis of photobodies.
Protein–protein interactions play essential roles in regulating many biological processes. At the cellular level, many proteins form nuclear foci known as nuclear bodies in which many components interact with each other. Photobodies are nuclear bodies containing proteins for light-signaling pathways in plants. What initiates the formation of photobodies is poorly understood. Here we develop a nucleolar marker protein nucleolin2 (Nuc2)–based method called the nucleolus-tethering system (NoTS) by artificially tethering a protein of interest to the nucleolus to analyze the initiation of photobodies. A candidate initiator is evaluated by visualizing whether a protein fused with Nuc2 forms body-like structures at the periphery of the nucleolus, and other components are recruited to the de novo–formed bodies. The interaction between two proteins can also be revealed through relocation and recruitment of interacting proteins to the nucleolus. Using the NoTS, we test the interactions among components in photobodies. In addition, we demonstrate that components of photobodies such as CONSTITUTIVELY PHOTOMORPHOGENIC 1, photoreceptors, and transcription factors tethered to the nucleolus have the capacity to form body-like structures at the periphery of the nucleolus, which contain other components of photobodies, suggesting a self-organization model for the biogenesis of photobodies.
PMCID: PMC3983000  PMID: 24554768
17.  A Novel Multi-Unit Tablet for Treating Circadian Rhythm Diseases 
AAPS PharmSciTech  2013;14(2):861-869.
This study aimed to develop and evaluate a novel multi-unit tablet that combined a pellet with a sustained-release coating and a tablet with a pulsatile coating for the treatment of circadian rhythm diseases. The model drug, isosorbide-5-mononitrate, was sprayed on microcrystalline cellulose (MCC)-based pellets and coated with Eudragit® NE30D, which served as a sustained-release layer. The coated pellets were compressed with cushion agents (a mixture of MCC PH-200/ MCC KG-802/PC-10 at a ratio of 40:40:20) at a ratio of 4:6 using a single-punch tablet machine. An isolation layer of OpadryII, swellable layer of HPMC E5, and rupturable layer of Surelease® were applied using a conventional pan-coating process. Central-composite design-response surface methodology was used to investigate the influence of these coatings on the square of the difference between release times over a 4 h time period. Drug release studies were carried out on formulated pellets and tablets to investigate the release behaviors, and scanning electron microscopy (SEM) was used to monitor the pellets and tablets and their cross-sectional morphology. The experimental results indicated that this system had a pulsatile dissolution profile that included a lag period of 4 h and a sustained-release time of 4 h. Compared to currently marketed preparations, this tablet may provide better treatment options for circadian rhythm diseases.
PMCID: PMC3666023  PMID: 23649996
central composite design; circadian rhythm diseases; in vitro dissolution study; multi-unit tablet; sustained-release and pulsatile coating
18.  Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics – results from single oral dose studies in healthy volunteers 
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans.
Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2–600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women).
Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4–6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40–80 h. The area under the curve0-24 hours (AUC0–24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC0–24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of −66% and urine NTx/creatinine (uNTx/Cr) of −51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (−70%) and uNTx/Cr (−78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction.
Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.
PMCID: PMC3635595  PMID: 23013236
cathepsin K inhibitor; odanacatib; osteoporosis; pharmacodynamics; pharmacokinetics
19.  Injury to the Endothelial Surface Layer Induces Glomerular Hyperfiltration Rats with Early-Stage Diabetes 
Journal of Diabetes Research  2014;2014:953740.
Glomerular endothelial surface layer (ESL) may play a role in the mechanisms of albuminuria in diabetic nephropathy, which lack evidence in vivo. The effects of high glucose on the passage of albumin across the glomerular ESL were analysed in streptozotocin-induced diabetic Sprague-Dawley rats for 4 weeks. Albuminuria and glomerular mesangial matrix were significantly increased in diabetic rats. The passage of albumin across the ESL, as measured by albumin-colloid gold particle density in the glomerular basement membrane (GBM), was increased significantly in diabetic rats. The thickness of the glomerular ESL, examined indirectly by infusing Intralipid into vessels using an electron microscope, was significantly decreased and the GBM exhibited little change in diabetic rats. In summary, the glomerular ESL may play a role in the pathogenesis of albuminuria in rats with early-stage diabetes.
PMCID: PMC4000657  PMID: 24812636
20.  Cyclin G2 Suppresses Estrogen-Mediated Osteogenesis through Inhibition of Wnt/β-Catenin Signaling 
PLoS ONE  2014;9(3):e89884.
Estrogen plays an important role in the maintenance of bone formation, and deficiency in the production of estrogen is directly linked to postmenopausal osteoporosis. To date, the underlying mechanisms of estrogen-mediated osteogenic differentiation are not well understood. In this study, a pluripotent mesenchymal precursor cell line C2C12 was used to induce osteogenic differentiation and subjected to detection of gene expressions or to manipulation of cyclin G2 expressions. C57BL/6 mice were used to generate bilateral ovariectomized and sham-operated mice for analysis of bone mineral density and protein expression. We identified cyclin G2, an unconventional member of cyclin, is involved in osteoblast differentiation regulated by estrogen in vivo and in vitro. In addition, the data showed that ectopic expression of cyclin G2 suppressed expression of osteoblast transcription factor Runx2 and osteogenic differentiation marker genes, as well as ALP activity and in vitro extracellular matrix mineralization. Mechanistically, Wnt/β-catenin signaling pathway is essential for cyclin G2 to inhibit osteogenic differentiation. To the best of our knowledge, the current study presents the first evidence that cyclin G2 serves as a negative regulator of both osteogenesis and Wnt/β-catenin signaling. Most importantly, the basal and 17β-estradiol-induced osteogenic differentiation was restored by overexpression of cyclin G2. These results taken together suggest that cyclin G2 may function as an endogenous suppressor of estrogen-induced osteogenic differentiation through inhibition of Wnt/β-catenin signaling.
PMCID: PMC3940656  PMID: 24595300
21.  Longitudinal Variability of Phosphorus Fractions in Sediments of a Canyon Reservoir Due to Cascade Dam Construction: A Case Study in Lancang River, China 
PLoS ONE  2013;8(12):e83329.
Dam construction causes the accumulation of phosphorus in the sediments of reservoirs and increases the release rate of internal phosphorus (P) loading. This study investigated the longitudinal variability of phosphorus fractions in sediments and the relationship between the contents of phosphorus fractions and its influencing factors of the Manwan Reservoir, Lancang River, Yunnan Province, China. Five sedimentary phosphorus fractions were quantified separately: loosely bound P (ex-P); reductant soluble P (BD-P); metal oxide-bound P (NaOH-P); calcium-bound P (HCl-P), and residual-P. The results showed that the total phosphorus contents ranged from 623 to 899 µg/g and were correlated positively with iron content in the sediments of the reservoir. The rank order of P fractions in sediments of the mainstream was HCl-P>NaOH-P>residual-P>BD-P>ex-P, while it was residual-P>HCl-P>NaOH-P>BD-P>ex-P in those of the tributaries. The contents of bio-available phosphorus in the tributaries, including ex-P, BD-P and NaOH-P, were significantly lower than those in the mainstream. The contents of ex-P, BD-P, NaOH-P showed a similar increasing trend from the tail to the head of the Manwan Reservoir, which contributed to the relatively higher content of bio-available phosphorus, and represents a high bio-available phosphorus releasing risk within a distance of 10 km from Manwan Dam. Correlation and redundancy analyses showed that distance to Manwan Dam and the silt/clay fraction of sediments were related closely to the spatial variation of bio-available phosphorus.
PMCID: PMC3873304  PMID: 24386180
22.  Type I J-Domain NbMIP1 Proteins Are Required for Both Tobacco Mosaic Virus Infection and Plant Innate Immunity 
PLoS Pathogens  2013;9(10):e1003659.
Tm-22 is a coiled coil-nucleotide binding-leucine rich repeat resistance protein that confers durable extreme resistance against Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV) by recognizing the viral movement protein (MP). Here we report that the Nicotiana benthamiana J-domain MIP1 proteins (NbMIP1s) associate with tobamovirus MP, Tm-22 and SGT1. Silencing of NbMIP1s reduced TMV movement and compromised Tm-22-mediated resistance against TMV and ToMV. Furthermore, silencing of NbMIP1s reduced the steady-state protein levels of ToMV MP and Tm-22. Moreover, NbMIP1s are required for plant resistance induced by other R genes and the nonhost pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. In addition, we found that SGT1 associates with Tm-22 and is required for Tm-22-mediated resistance against TMV. These results suggest that NbMIP1s function as co-chaperones during virus infection and plant immunity.
Author Summary
Plant pathogens cause considerable yield losses in many vegetables and crops; therefore, understanding the mechanisms of disease resistance can enable crop improvements and provide substantial economic benefits. Here, we examine the signaling pathways of Tm-22, a tomato resistance protein that confers resistance to Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV) by detecting the presence of their movement proteins (MPs). We found that in Nicotiana benthamiana, Tm-22-mediated resistance against TMV and ToMV requires MIP1s (NbMIP1s), a group of J-domain proteins that may act as molecular chaperones to assist protein folding and maintain protein structure. Intriguingly, MIP1s are required for both TMV resistance and TMV infection. NbMIP1s interact with and are essential for protein stability of both Tm-22 and the viral MP. NbMIP1s are required for resistance mediated by other resistance proteins and resistance to the bacterial nonhost pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. These new insights into the mechanisms of viral infection and disease resistance may enable future advances in crop protection.
PMCID: PMC3789785  PMID: 24098120
23.  CBrowse: a SAM/BAM-based contig browser for transcriptome assembly visualization and analysis 
Bioinformatics  2012;28(18):2382-2384.
Summary: To address the impending need for exploring rapidly increased transcriptomics data generated for non-model organisms, we developed CBrowse, an AJAX-based web browser for visualizing and analyzing transcriptome assemblies and contigs. Designed in a standard three-tier architecture with a data pre-processing pipeline, CBrowse is essentially a Rich Internet Application that offers many seamlessly integrated web interfaces and allows users to navigate, sort, filter, search and visualize data smoothly. The pre-processing pipeline takes the contig sequence file in FASTA format and its relevant SAM/BAM file as the input; detects putative polymorphisms, simple sequence repeats and sequencing errors in contigs and generates image, JSON and database-compatible CSV text files that are directly utilized by different web interfaces. CBowse is a generic visualization and analysis tool that facilitates close examination of assembly quality, genetic polymorphisms, sequence repeats and/or sequencing errors in transcriptome sequencing projects.
Availability: CBrowse is distributed under the GNU General Public License, available at
Contact: or;
Supplementary Information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3436847  PMID: 22789590
24.  Recombinant Rat CC10 Protein Inhibits PDGF-Induced Airway Smooth Muscle Cells Proliferation and Migration 
BioMed Research International  2013;2013:690937.
Abnormal migration and proliferation of airway smooth muscle cells (ASMCs) in the airway cause airway wall thickening, which is strongly related with the development of airway remodeling in asthma. Clara cell 10 kDa protein (CC10), which is secreted by the epithelial clara cells of the pulmonary airways, plays an important role in the regulation of immunological and inflammatory processes. Previous studies suggested that CC10 protein had great protective effects against inflammation in asthma. However, the effects of CC10 protein on ASMCs migration and proliferation in airway remodeling were poorly understood. In this study, we constructed the pET-22b-CC10 recombinant plasmid, induced expression and purified the recombinant rat CC10 protein from E. coli by Ni2+ affinity chromatography and ion exchange chromatography purification. We investigated the effect of recombinant rat CC10 protein on platelet-derived growth factor (PDGF)-BB-induced ASMCs proliferation and migration. Our results demonstrated that the recombinant CC10 protein could inhibit PDGF-BB-induced cell viability, proliferation and migration. Western blot analysis showed that PDGF-BB-induced activation of cyclin D1 was inhibited by CC10. These findings implicated that CC10 could inhibit increased ASMCs proliferation, and migration induced by PDGF-BB, and this suppression effect might be associated with inhibition of cyclin D1 expression, which might offer hope for the future treatment of airway remodeling.
PMCID: PMC3784082  PMID: 24106713
25.  Protein phosphorylation-acetylation cascade connects growth factor deprivation to autophagy 
Autophagy  2012;8(9):1385-1386.
Different from unicellular organisms, metazoan cells require the presence of extracellular growth factors to utilize environmental nutrients. However, the underlying mechanism was unclear. We have delineated a pathway, in which glycogen synthase kinase 3 (GSK3) in cells deprived of growth factors phosphorylates and activates the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to elicit autophagy. Cells with the Kat5/Tip60 gene replaced with Kat5S86A that cannot be phosphorylated by GSK3 are resistant to serum starvation-induced autophagy. Acetylation sites on ULK1 were mapped to K162 and K606, and the acetylation-defective mutant ULK1K162,606R displays reduced kinase activity and fails to rescue autophagy in Ulk1−/− mouse embryonic fibroblasts, indicating that acetylation is vital to the activation of ULK1. The GSK3-KAT5-ULK1 cascade seems to be specific for cells to sense growth factors, as KAT5 phosphorylation is not enhanced under glucose deprivation. Distinct from the glucose starvation-autophagy pathway that is conserved in all eukaryotic organisms, the growth factor deprivation response pathway is perhaps unique to metazoan organisms.
PMCID: PMC3442885  PMID: 22717509
GSK3; Tip60; Ulk1; acetylation; autophagy; growth factor; phosphorylation

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