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1.  Overexpression of Porcine Beta-Defensin 2 Enhances Resistance to Actinobacillus pleuropneumoniae Infection in Pigs 
Infection and Immunity  2015;83(7):2836-2843.
To reduce the need for antibiotics in animal production, alternative approaches are needed to control infection. We hypothesized that overexpression of native defensin genes will provide food animals with enhanced resistance to bacterial infections. In this study, recombinant porcine beta-defensin 2 (PBD-2) was overexpressed in stably transfected PK-15 porcine kidney cells. PBD-2 antibacterial activities against Actinobacillus pleuropneumoniae, an important respiratory pathogen causing porcine contagious pleuropneumonia, were evaluated on agar plates. Transgenic pigs constitutively overexpressing PBD-2 were produced by a somatic cell cloning method, and their resistance to bacterial infection was evaluated by direct or cohabitation infection with A. pleuropneumoniae. Recombinant PBD-2 peptide that was overexpressed in the PK-15 cells showed antibacterial activity against A. pleuropneumoniae. PBD-2 was overexpressed in the heart, liver, spleen, lungs, kidneys, and jejunum of the transgenic pigs, which showed significantly lower bacterial loads in the lungs and reduced lung lesions after direct or cohabitation infection with A. pleuropneumoniae. The results demonstrate that transgenic overexpression of PBD-2 in pigs confers enhanced resistance against A. pleuropneumoniae infection.
PMCID: PMC4468565  PMID: 25916992
2.  Short-Term and Long-Term Survival After Revascularization with or without Mitral Valve Surgery of Patients with Ischemic Mitral Valve Regurgitation: A Meta-Analysis 
There is no consensus on whether mitral valve repair or replacement (MVRR) must be performed to treat ischemic mitral regurgitation (MVR) after myocardial infarction. Our objective in this study was to investigate the efficacy of coronary artery bypass grafting (CABG) combined with or without MVRR for the ischemic MVR.
An article search was performed in OvidSP, PubMed, Cochrane Library, and Embase. In these articles, researchers compared the efficacy of CABG with or without MVRR in treating patients with ischemic MVR after acute coronary syndrome (ACS). We performed a meta-analysis to compare the differences in the short-term and long-term survival rates of patients treated with CABG only and those treated with both CABG and MVRR. Secondary outcomes were compared with the preoperative and postoperative degree of MVR, left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and New York Heart Association (NYHA) class.
Out of the 1183 studies, we selected only 5 articles. A total of 3120 patients were enrolled; the CABG and MVRR group included 575 patients, while the CABG only group included 2545 patients. Long-term survival was higher in the CABG only group (hazard ratio [HR], 1.34; 95% confidence interval [CI] 1.15–1.58, P=0.003). Hospital mortality was similar in both the groups (odds ratio [OR], 2.54; 95% CI, 0.65–9.95; P=0.18). No differences were found in the degree of residual MVR, the mean of LVESV, LVEF, or NYHA class.
In patients with ischemic MVR, the short-term survival rate was similar in both groups. Moreover, there was no significant improvement in the long-term survival rates of patients treated with both CAG and MVRR.
PMCID: PMC4672719  PMID: 26635041
General Surgery; Meta-Analysis; Survival
3.  Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion 
Cell Research  2015;25(12):1285-1298.
Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd−/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd−/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.
PMCID: PMC4670995  PMID: 26611636
GSDMD; inflammasome; pyroptosis; apoptosis; IL-1β; caspase-1; caspase-11
4.  Diagnostic value of SHOX2 DNA methylation in lung cancer: a meta-analysis 
OncoTargets and therapy  2015;8:3433-3439.
The diagnostic value of SHOX2 DNA methylation in patients with lung cancer remains controversial. Thus, we performed a systematic review and meta-analysis to assess diagnostic accuracy of SHOX2 DNA methylation in the lymph node, bronchial aspirates, pleural effusion, plasma, and tumor tissue for lung cancer. We conducted a comprehensive literature search in PubMed, Ovid, the Cochrane library, and Web of Science databases in May 2015. The diagnostic sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were pooled using STATA 12.0 software. A total of 2,296 subjects included 1,129 lung cancer patients in eight studies were recruited in this meta-analysis. The summary estimates for SHOX2 DNA methylation in the diagnosis of lung cancer in these studies were pooled SEN =0.70 (95% confidence interval [CI]: 0.46–0.87), SPE =0.96 (95% CI: 0.91–0.99), PLR 20.01 (95% CI: 6.96–57.52), NLR 0.31 (95% CI: 0.15–0.64), and DOR 65.11 (95% CI: 13.10–323.61), and the area under the curve (AUC) was 0.96 (95% CI: 0.94–0.97). SHOX2 DNA methylation has greater diagnostic value in detecting lung cancer. In addition, considering the potential publication bias and high heterogeneity, further research studies with more well-designed and large sample sizes are needed in the future.
PMCID: PMC4657794  PMID: 26640383
lung cancer; SHOX2; meta-analysis; diagnostic test
6.  Different Approaches for Treating Multilevel Cervical Spondylotic Myelopathy: A Retrospective Study of 153 Cases from a Single Spinal Center 
PLoS ONE  2015;10(10):e0140031.
The optimal surgical treatment for multilevel cervical spondylotic myelopathy (MCSM) remains controversial. This study compared the outcomes of three surgical approaches for MSCM treatment, focusing on the efficacy and safety of a combined approach.
This retrospective study included 153 consecutive MCSM patients (100 men, 53 women; mean age ± standard deviation, 55.7 ± 9.4 years) undergoing operations involving ≥3 intervertebral segments. The patients were divided into three groups according to surgical approach: anterior (n = 19), posterior (n = 76), and combined (n = 58). We assessed demographic variables, perioperative parameters, and clinical outcomes ≥12 months after surgery (20.5 ± 7.6 months), including Japanese Orthopaedic Association (JOA) score, improvement, recovery rate, and complications.
The anterior group had the most favorable preoperative conditions, including the highest preoperative JOA score (12.95 ± 1.86, p = 0.046). In contrast, the combined group had the highest occupancy ratio (48.0% ± 11.6%, p = 0.002). All groups showed significant neurological improvement at final follow-ups, with JOA recovery rates of 59.7%, 54.6%, and 68.9% in the anterior, posterior, and combined groups, respectively (p = 0.163). After multivariable adjustments, the groups did not have significantly different clinical outcomes (postoperative JOA score, p = 0.424; improvement, p = 0.424; recovery rate, p = 0.080). Further, subgroup analyses of patients with occupancy ratios ≥50% showed similar functional outcomes following the posterior and combined approaches. Overall complication rates did not differ significantly among the three approaches (p = 0.600). Occupancy ratios did not have a significant negative influence on postoperative recovery following the posterior approach.
If applied appropriately, all three approaches are effective for treating MCSM. All three approaches had equivalent neurological outcomes, even in subgroups with high occupancy ratios. Further investigations of surgical approaches to MCSM are needed, particularly prospective multicenter studies with long-term follow-up.
PMCID: PMC4604139  PMID: 26460488
7.  Analysis of association among clinical features and shorter leukocyte telomere length in mitochondrial diabetes with m.3243A>G mitochondrial DNA mutation 
BMC Medical Genetics  2015;16:92.
Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondia. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes withm.3243A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length.
Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length.
The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 ± 2.36 kg/m2), early onset of diabetes (35.0 ± 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦25 years, 61.6 ± 20.17 %; 25–45 years, 16.59 ± 8.64 %; >45 years, 6.37 ± 0.59 %; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 ± 0.54 vs. 1.14 ± 0.43 vs. 1.63 ± 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio.
Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes.
PMCID: PMC4599722  PMID: 26449496
Mitochondrial diabetes; m.3243A>G mitochondrial DNA mutation; Clinical features; Leukocyte telomere length
8.  MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia 
Autophagy  2014;10(10):1726-1737.
Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.
PMCID: PMC4198358  PMID: 25126724
autophagy; degradation; leukemia; microRNA; PML-RARA
9.  Yiguanjian decoction and its ingredients inhibit angiogenesis in carbon tetrachloride-induced cirrhosis mice 
Cirrhosis is associated with angiogenesis and disruption of hepatic vascular architecture. Yiguanjian (YGJ) decoction, a prescription from traditional Chinese medicine, is widely used for treating liver diseases. We studied whether YGJ or its ingredients (iYGJ) had an anti-angiogenic effect and explored possible mechanisms underlying this process.
Cirrhosis was induced with carbon tetrachloride (CCl4) (ip) in C57BL/6 mice for 6 weeks. From week 4 to week 6, cirrhotic mice were randomly divided into four groups: sorafenib-treated, YGJ-treated and iYGJ-treated mice and placebo. Serum biochemistries, hydroxyproline (Hyp) content and histopathological changes of hepatic tissues were measured as were α-smooth muscle actin (α-SMA), collagen I, CD31, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) 2 and hypoxia-inducible factor (HIF)-1α.
Both YGJ and iYGJ improved serum biochemistries. Changes of histopathology showed that YGJ and iYGJ reduced hepatic tissue necroinflammatory and collagen fiber deposition in cirrhosis mice. Compared to the CCl4 treated animals, Hyp, α-SMA, collagen I, CD31, VEGF, VEGFR, and HIF-1α expression decreased in YGJ and iYGJ groups.
YGJ and iYGJ inhibited liver angiogenesis in cirrhotic mice treated with CCl4 by inhibiting the HIF-1α/VEGF signaling pathway, suggesting that anti-angiogenic effects of YGJ and iYGJ are associated with improving the hepatic hypoxic microenvironment.
PMCID: PMC4591631  PMID: 26427787
Cirrhosis; Angiogenesis; Yiguanjian
10.  Overexpression of BRCA1 attenuates the sensitivity of PC9 cells to gefitinib 
Gefitinib is an orally active antitumor agent which inhibits uncontrolled cell proliferation by interrupting epidermal growth factor receptor (EGFR) signaling pathways. Various in vitro and in vivo studies have revealed that the upregulated expression of breast cancer susceptibility gene 1 (BRCA1) is associated with chemoresistance and reduced survival following chemotherapies. In this study, a gefitinib-highly-sensitive cell line, PC-9, was used to investigate the effect of BRCA1 expression on the sensitivity of PC-9 cells to gefitinib. PC-9 cells were stably transfected with BRCA-1 (HA-tagged). Transfected and untransfected PC-9 cells were treated with gefitinib, phosphorylated γH2AX was examined by western blot to determine the DNA damages. Following the treatment of gefitinib, the inhibition of proliferation of the PC-9 cells, PC-9-pcDNA3.1 cells, and BRCA1-transfected PC-9 cells were determined. Also, a comet assay was performed to determine the DNA damage caused by gefitinib. The treatment of geftinib for 6 hr, 12 h, and 24 hr significantly increased the cellular expression of phosphorylated γH2AX. With the treatment of gefitinib, the inhibition of proliferation of BRCA-1 overexpressed PC-9 cells was significantly lower than that of the non-transfected PC-9 cells, indicating the overexpression of BRCA1 plays a role in attenuating the sensitivity of PC-9 cells to gefitinib. The comet assay revealed that BRCA1 transfected cells showed a shorter comet tail, indicating the overexpression of BRCA1 attenuated the DNA damages caused by gefitinib. The overexpression of BRCA1 reduced the DNA damages, and enhanced DNA repair mechanisms. Also, gefitinib-mediated inhibition of cell proliferation is attenuated by the expression of BRCA1.
PMCID: PMC4680423  PMID: 26722478
BRCA1; gefitinib; cell proliferation
11.  Prognostic role of neutrophil to lymphocyte ratio in lung cancers: a meta-analysis including 7,054 patients 
OncoTargets and therapy  2015;8:2731-2738.
Neutrophil to lymphocyte ratio (NLR) has recently been reported to be a poor prognostic indicator in lung cancer. However, the prognostic value of the NLR in patients with lung cancer still remains controversial. We performed a meta-analysis to evaluate the prognostic value of NLR in patients with lung cancer.
We performed a comprehensive literature search in PubMed, Ovid, the Cochrane Library, and Web of Science databases in May 2015. Studies were assessed for quality using the Newcastle–Ottawa Scale.
Twenty-two studies with a total of 7,054 patients were included in this meta-analysis. The meta-analysis was performed to generate combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). Our analysis results indicated that high NLR predicted poorer OS (HR, 1.51; 95% confidence interval [CI], 1.33–1.71; P<0.001) and PFS (HR, 1.33; 95% CI, 1.07–1.67; P=0.012) in patients with lung cancer. High NLR was also associated with poor OS in lung cancer treated by surgical resection (HR, 1.59; 95% CI, 1.26–1.99; P<0.001) and chemotherapy (HR, 1.15; 95% CI, 1.08–1.22; P<0.001). In addition, NLR cut-off value =5 (HR, 1.57; 95% CI, 1.16–2.12; P=0.003) and NLR cut-off value <5 (HR, 1.47; 95% CI, 1.28–1.69; P<0.001).
This meta-analysis result suggested that NLR should have significant predictive ability for estimating OS and PFS in patients with lung cancer and may be as a significant biomarker in the prognosis of lung cancer.
PMCID: PMC4599071  PMID: 26491346
NLR; lung cancer; prognosis; meta-analysis
12.  Flos Albiziae aqueous extract and its active constituent quercetin potentiate the hypnotic effect of pentobarbital via the serotonergic system 
Biomedical Reports  2015;3(6):835-838.
Flos albiziae (FA) is reportedly used for treatment of insomnia and anxiety in traditional medicine. The hypnotic effect of an extract of FA (FAE) and its constituent quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, QR] was examined in mice. QR is a widely distributed natural flavonoid abundant in FA flowers and other tissues. The possible mechanisms underlying the hypnotic effects of FAE and QR were investigated using behavioral pharmacology. FAE and QR significantly potentiated pentobarbital-induced [50 mg/kg, intraperitoneal (ip)] sleep (prolonged sleeping time; shortened sleep latency) in a dose-dependent manner, and these effects were augmented by administration of 5-hydroxytryptophan (5-HTP), a precursor of 5-hydroxytryptamine. With a sub-hypnotic dose of pentobarbital (28 mg/kg, ip), FAE and QR significantly increased the rate of sleep onset and were synergistic with 5-HTP (2.5 mg/kg, ip). Pretreatment with p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase, significantly decreased sleeping time and prolonged sleep latency in pentobarbital-treated mice, whereas FAE and QR significantly reversed this effect. Data show that FAE and QR have hypnotic activity, possibly mediated by the serotonergic system. The present study offers a rationale for the use of FA in treating sleep disorders associated with serotonin system dysfunction.
PMCID: PMC4660601  PMID: 26623026
quercetin; hypnotic; serotonergic system
13.  Seasonal Variations of C: N: P Stoichiometry and Their Trade-Offs in Different Organs of Suaeda salsa in Coastal Wetland of Yellow River Delta, China 
PLoS ONE  2015;10(9):e0138169.
Variations of plant C: N: P stoichiometry could be affected by both some environmental fluctuations and plant physiological processes. However, the trade-off mechanism between them and their influencial factors were not understood completely. In this study, C, N, P contents and their stoichiometry of S. salsa’s plant organs (leaves, stems, and roots), together with their environmental factors including salinity, pH, soil N and soil P, were examined in the intertidal and supratidal habitats of coastal wetlands during the different sampling times (May, July, September, November). The results showed that both plant organ and sampling times affected C, N, and P and stoichiometry of S. salsa in the intertidal and supratidal habitats, however, their influencial conditions and mechanisms were different. In the intertidal habitat, the different slopes of C-P and N-P within interspecific organs suggested that plant P, C:P and N:P of S. salsa were modulated by P concentrations that allocated in the specific organs. However, the slopes of C-N were found to be not significant within interspecific organs, but during the sampling times. These differences of plant N and C:N were related with the physiological demand for N in the specific life history stage. In the supratidal habitat, no significant differences were found in the slopes of C-N, C-P, and N-P within interspecific organs. However, different slopes of C-N among the sampling times also indicated a self-regulation strategy for plant N and C:N of S. salsa in different ontogenetic stages. In contrast to the intertidal habitat, seasonal variations of P, C:P and N:P ratios within interspecific organs reflected the soil P characteristics in the supratidal habitat. Our results showed that the stoichiometric constraint strategy of plant S. salsa in this region was strongly correlated with the local soil nutrient conditions.
PMCID: PMC4578878  PMID: 26393356
14.  Co-occurrence of Methanosarcina mazei and Geobacteraceae in an iron (III)-reducing enrichment culture 
Methanosaeta harundinacea and Methanosarcina barkeri, known as classic acetoclastic methanogens, are capable of directly accepting electrons from Geobacter metallireducens for the reduction of carbon dioxide to methane, having been revealed as direct interspecies electron transfer (DIET) in the laboratory co-cultures. However, whether their co-occurrences are ubiquitous in the iron (III)-reducing environments and the other species of acetoclastic methanogens such as Methanosarcina mazei are capable of DIET are still unknown. Instead of initiating the co-cultures with pure cultures, two-step cultivation was employed to selectively enrich iron (III)-reducing microorganisms in a coastal gold mining river, Jiehe River, with rich iron content in the sediments. First, iron (III) reducers including Geobacteraceae were successfully enriched by 3-months successive culture on amorphous Fe(III) oxides as electron acceptor and acetate as electron donor. High-throughput Illumina sequencing, terminal restriction fragment length polymorphism (T-RFLP) and clone library analysis based on 16S rRNA genes revealed that the enrichment cultures actively contained the bacteria belong to Geobacteraceae and Bacilli, exclusively dominated by the archaea belong to Methanosarcinaceae. Second, the enrichment cultures including methanogens and Geobacteraceae were transferred with ethanol as alternative electron donor. Remarkably, aggregates were successively formed in the enrichments after three transfers. The results revealed by RNA-based analysis demonstrate that the co-occurrence of Methanosarcina mazei and Geobacteraceae in an iron (III)-reducing enrichment culture. Furthermore, the aggregates, as close physical contact, formed in the enrichment culture, indicate that DIET could be a possible option for interspecies electron transfer in the aggregates.
PMCID: PMC4562271  PMID: 26441876
co-occurrence; Methanosarcina mazei; Geobacteraceae; direct interspecies electron transfer (DIET); iron(III)-reducing microorganisms
15.  Wet-chemical synthesis and applications of non-layer structured two-dimensional nanomaterials 
Nature Communications  2015;6:7873.
There is currently intensive research underway into the development of non-layer structured two dimensional nanomaterials. Here, Zhang et al. review the research progress on the most promising wet-chemical synthesis methods as well as a wide range of applications of this unique class of materials.
Non-layer structured nanomaterials with single- or few-layer thickness have two-dimensional sheet-like structures and possess intriguing properties. Recent years have seen major advances in development of a host of non-layer structured ultrathin two-dimensional nanomaterials such as noble metals, metal oxides and metal chalcogenides. The wet-chemical synthesis has emerged as the most promising route towards high-yield and mass production of such nanomaterials. These nanomaterials are now finding increasing applications in a wide range of areas including catalysis, energy production and storage, sensor and nanotherapy, to name but a few.
PMCID: PMC4560752  PMID: 26303763
Journal of autoimmunity  2014;53:67-77.
Spinal cord pathology with inflammatory, demyelinating lesions spanning three or more vertebral segments is a characteristic feature of neuromyelitis optica (NMO). NMO pathogenesis is thought to involve binding of immunoglobulin G anti-aquaporin-4 autoantibodies (NMO-IgG) to astrocytes, causing complement-dependent cytotoxicity (CDC) and secondary inflammation, demyelination and neuron loss. We investigated the involvement of CD59, a glycophosphoinositol (GPI)-anchored membrane protein on astrocytes that inhibits formation of the terminal C5b-9 membrane attack complex. CD59 inhibition by a neutralizing monoclonal antibody greatly increased NMO-IgG-dependent CDC in murine astrocyte cultures and ex vivo spinal cord slice cultures. Greatly increased NMO pathology was also found in spinal cord slice cultures from CD59 knockout mice, and in vivo following intracerebral injection of NMO-IgG and human complement. Intrathecal injection (at L5-L6) of small amounts of NMO-IgG and human complement in CD59-deficient mice produced robust, longitudinally extensive white matter lesions in lumbar spinal cord. Pathology was most severe at day 2 after injection, showing loss of AQP4 and GFAP, C5b-9 deposition, microglial activation, granulocyte infiltration, and demyelination. Hind limb motor function was remarkably impaired as well. There was partial remyelination and recovery of motor function by day 5. Our results implicate CD59 as an important modulator of the immune response in NMO, and provide a novel animal model of NMO that closely recapitulates human NMO pathology. Upregulation of CD59 on astrocytes may have therapeutic benefit in NMO.
PMCID: PMC4162764  PMID: 24698947
NMO; aquaporin-4; astrocyte; complement-dependent cytotoxicity; demyelination
17.  Optimize the Separation of Fluorinated Amphiles Using High-Performance Liquid Chromatography 
Using the set of fluorinated amphiles that contain the same fluorocarbon moiety but differ in their fluorine content percentage F% (25–45%), the optimal condition for a F%-based separation of these analytes using reverse-phase chromatography was explored. It is found that optimal separation can be achieved by pairing a regular reverse-phase column (such as C8) with a fluorinated eluent (such as trifluoroethanol). Separation is further improved at higher chromatographic temperature with baseline separation achieved at 45°C. This result indicates that the separation of fluorocarbon-tagged molecules can be based on the fluorine content percentage rather than the number of fluorine atoms.
PMCID: PMC4136531  PMID: 25147409
reverse-phase chromatography; HPLC; fluorinated amphiles; fluorous; hetero-pairing; homo-pairing
18.  Novel X-ray Communication Based XNAV Augmentation Method Using X-ray Detectors 
Sensors (Basel, Switzerland)  2015;15(9):22325-22342.
The further development of X-ray pulsar-based NAVigation (XNAV) is hindered by its lack of accuracy, so accuracy improvement has become a critical issue for XNAV. In this paper, an XNAV augmentation method which utilizes both pulsar observation and X-ray ranging observation for navigation filtering is proposed to deal with this issue. As a newly emerged concept, X-ray communication (XCOM) shows great potential in space exploration. X-ray ranging, derived from XCOM, could achieve high accuracy in range measurement, which could provide accurate information for XNAV. For the proposed method, the measurement models of pulsar observation and range measurement observation are established, and a Kalman filtering algorithm based on the observations and orbit dynamics is proposed to estimate the position and velocity of a spacecraft. A performance comparison of the proposed method with the traditional pulsar observation method is conducted by numerical experiments. Besides, the parameters that influence the performance of the proposed method, such as the pulsar observation time, the SNR of the ranging signal, etc., are analyzed and evaluated by numerical experiments.
PMCID: PMC4610565  PMID: 26404295
XNAV augmentation; X-ray communication; X-ray ranging; X-ray detector; measurement model
19.  Trans-Corneal Subretinal Injection in Mice and Its Effect on the Function and Morphology of the Retina 
PLoS ONE  2015;10(8):e0136523.
To introduce a practical method of subretinal injection in mice and evaluate injection-induced retinal detachment (RD) and damage using a dynamic imaging system, electrophysiology, and histology.
After full dilation of a 2-month-old C57BL/6J mouse pupil, the cornea near the limbus was punctured with a 30 ½-gague disposable beveled needle. A 33 ½-gauge blunt needle was inserted through the corneal perforation into the anterior chamber, avoiding the lens before going deeper into the vitreous cavity, and penetrating the inner retina to reach the subretinal space. The mice were divided into four groups: in group 1, about 80–100% of the retina was filled with subretinally injected solution; in group 2, approximately 50–70% of the retina was filled with injected solution; in group 3, the procedures were stopped before solution injection; and non-injected eyes were used as the negative control in group 4. An optical coherence tomography (OCT) imaging system was used to monitor retinal reattachment during the first three days following the injections. Histological and functional changes were examined by light microscopy and electroretinography (ERG) at five weeks post-injection.
After a short-term training, a 70% success rate with 50% or more coverage (i.e., retinal blebs occupied 50% or more retinal area and filled with the injected solution) with minimal injection-related damages can be achieved. Bleb formation was associated with retinal detachment (RD) between the neuroretina and the retinal pigment epithelium (RPE) layer. Partial RD could be observed at post-injection day 1, and by day 2 most of the retina had reattached. At 5 weeks post-injection, compared to uninjected control group 4, the b-wave amplitudes of ERG decreased 22% in group 1, 16% in group 2, and 7% in group 3; the b-wave amplitudes were statistically different between the uninjected group and the groups with either 50–70% or 80–100% coverage. The subretinal injection-induced RD reattached and became stable at five weeks post-injection, although some photoreceptor damage could still be observed in and around the injection sites, especially in 80–100% coverage group.
Trans-corneal subretinal injection is effective and practical, although subretinal injection-related damages can cause some morphological and functional loss.
PMCID: PMC4552822  PMID: 26317758
20.  Hierarchical Ni-Mo-S nanosheets on carbon fiber cloth: A flexible electrode for efficient hydrogen generation in neutral electrolyte 
Science Advances  2015;1(7):e1500259.
A flexible cloth-like electrode, which can efficiently split water to produce H2 at neutral pH, is successfully demonstrated.
A unique functional electrode made of hierarchal Ni-Mo-S nanosheets with abundant exposed edges anchored on conductive and flexible carbon fiber cloth, referred to as Ni-Mo-S/C, has been developed through a facile biomolecule-assisted hydrothermal method. The incorporation of Ni atoms in Mo-S plays a crucial role in tuning its intrinsic catalytic property by creating substantial defect sites as well as modifying the morphology of Ni-Mo-S network at atomic scale, resulting in an impressive enhancement in the catalytic activity. The Ni-Mo-S/C electrode exhibits a large cathodic current and a low onset potential for hydrogen evolution reaction in neutral electrolyte (pH ~7), for example, current density of 10 mA/cm2 at a very small overpotential of 200 mV. Furthermore, the Ni-Mo-S/C electrode has excellent electrocatalytic stability over an extended period, much better than those of MoS2/C and Pt plate electrodes. Scanning and transmission electron microscopy, Raman spectroscopy, x-ray diffraction, x-ray photoelectron spectroscopy, and x-ray absorption spectroscopy were used to understand the formation process and electrocatalytic properties of Ni-Mo-S/C. The intuitive comparison test was designed to reveal the superior gas-evolving profile of Ni-Mo-S/C over that of MoS2/C, and a laboratory-scale hydrogen generator was further assembled to demonstrate its potential application in practical appliances.
PMCID: PMC4643797  PMID: 26601227
Hierarchical Ni-Mo-S Nanosheets; Carbon Fiber Cloth; Flexible Electrodes; Hydrogen Generation; Neutral Electrolyte
21.  Creative arts program as an intervention for PTSD: a randomized clinical trial with motor vehicle accident survivors 
The aim of this study is to determine whether the creative arts program (HA) is effective in preventing the onset of Posttraumatic stress disorder (PTSD). PTSD develops in 10-20% of motor vehicle accident survivors (MVAs). MVAs in the initial months after the accident were randomly assigned to receive 8-week HA intervention (n = 26) or wait the list (WL, n = 26). The arts program consisted of writing and drawing. PTSD severity was assessed at 2, 6, and 12 months post injury with a clinical interview (Clinician-Administered PTSD Scale, CAPS) and self-report instrument (Impact of Event Scale-Revised, IES-R). Secondary outcomes were post-traumatic growth (PTG), depression and anxiety symptoms. Repeated measures analysis of variance indicated that both HA and WL group exhibited a significant effect of time (P < 0.01) on CAPS, but no significant group differences over time. There were no group differences on depression or anxiety over time. Pessimists did not benefit more from attending the HA than they did from attending the WL. Our results fail to support the hypothesis that the creative arts program is effect in avoiding MVA-related PTSD symptoms. But it only seems to be a short-term, rather than a long-term effect.
PMCID: PMC4612983  PMID: 26550298
Art therapy; life orientation; motor vehicle accidents; posttraumatic stress disorder
22.  STIM2 protects hippocampal mushroom spines from amyloid synaptotoxicity 
Alzheimer disease (AD) is a disease of lost memories. Mushroom postsynaptic spines play a key role in memory storage, and loss of mushroom spines has been proposed to be linked to memory loss in AD. Generation of amyloidogenic peptides and accumulation of amyloid plaques is one of the pathological hallmarks of AD. It is important to evaluate effects of amyloid on stability of mushroom spines.
In this study we used in vitro and in vivo models of amyloid synaptotoxicity to investigate effects of amyloid peptides on hippocampal mushroom spines. We discovered that application of Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into hippocampal region resulted in reduction of mushroom spines and activity of synaptic calcium-calmodulin-dependent kinase II (CaMKII). We further discovered that expression of STIM2 protein rescued CaMKII activity and protected mushroom spines from amyloid toxicity in vitro and in vivo.
Obtained results suggest that downregulation of STIM2-dependent stability of mushroom spines and reduction in activity of synaptic CaMKII is a mechanism of hippocampal synaptic loss in AD model of amyloid synaptotoxicity and that modulators/activators of this pathway may have a potential therapeutic value for treatment of AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13024-015-0034-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4536802  PMID: 26275606
Alzheimer disease; Abeta peptides; STIM2; Mushroom spines; Synapse
23.  Chilling- and Freezing- Induced Alterations in Cytosine Methylation and Its Association with the Cold Tolerance of an Alpine Subnival Plant, Chorispora bungeana 
PLoS ONE  2015;10(8):e0135485.
Chilling (0–18°C) and freezing (<0°C) are two distinct types of cold stresses. Epigenetic regulation can play an important role in plant adaptation to abiotic stresses. However, it is not yet clear whether and how epigenetic modification (i.e., DNA methylation) mediates the adaptation to cold stresses in nature (e.g., in alpine regions). Especially, whether the adaptation to chilling and freezing is involved in differential epigenetic regulations in plants is largely unknown. Chorispora bungeana is an alpine subnival plant that is distributed in the freeze-thaw tundra in Asia, where chilling and freezing frequently fluctuate daily (24 h). To disentangle how C. bungeana copes with these intricate cold stresses through epigenetic modifications, plants of C. bungeana were treated at 4°C (chilling) and -4°C (freezing) over five periods of time (0–24 h). Methylation-sensitive amplified fragment-length polymorphism markers were used to investigate the variation in DNA methylation of C. bungeana in response to chilling and freezing. It was found that the alterations in DNA methylation of C. bungeana largely occurred over the period of chilling and freezing. Moreover, chilling and freezing appeared to gradually induce distinct DNA methylation variations, as the treatment went on (e.g., after 12 h). Forty-three cold-induced polymorphic fragments were randomly selected and further analyzed, and three of the cloned fragments were homologous to genes encoding alcohol dehydrogenase, UDP-glucosyltransferase and polygalacturonase-inhibiting protein. These candidate genes verified the existence of different expressive patterns between chilling and freezing. Our results showed that C. bungeana responded to cold stresses rapidly through the alterations of DNA methylation, and that chilling and freezing induced different DNA methylation changes. Therefore, we conclude that epigenetic modifications can potentially serve as a rapid and flexible mechanism for C. bungeana to adapt to the intricate cold stresses in the alpine areas.
PMCID: PMC4535906  PMID: 26270551
24.  Use of a Novel Integrase-Deficient Lentivirus for Targeted Anti-Cancer Therapy With Survivin Promoter-Driven Diphtheria Toxin A 
Medicine  2015;94(31):e1301.
Supplemental Digital Content is available in the text
As an immunotoxin, diphtheria toxin has been widely used in gene therapy and gene function assays for its roles in protein synthesis inhibition, and the aim of our study is to set up a nonintegrating lentiviral system for specific expression of diphtheria toxin A (DTA) used in cancer gene therapy.
Here, we established a lentiviral system that could coordinately express fluorescent protein and DTA driven by the cytomegalovirus (CMV) promoter, which is convenient for us to precisely trace the expression of DTA and monitor the process of lentivirus packaging. To achieve safer cancer therapy, we replaced the CMV promoter with the Survivin promoter, a specific promoter that is dramatically activated in cancer tissues and cells, but not in normal tissues and cells, and that will impose greater therapeutic potential because a significant expression difference occurred between these 2 groups. Meanwhile, we obtained integrase-deficient lentivirus (IDLV) after packaging with the integrase mutant, which expresses defective integrase RRK262263264AAH, to minimize the side effects that derived from the insertional mutagenesis of the host genome.
Our results suggest that the IDLV system that we generated possesses therapeutic potential in cancers in vitro and in vivo.
PMCID: PMC4616595  PMID: 26252309
25.  Stabilization of 4H hexagonal phase in gold nanoribbons 
Nature Communications  2015;6:7684.
Gold, silver, platinum and palladium typically crystallize with the face-centred cubic structure. Here we report the high-yield solution synthesis of gold nanoribbons in the 4H hexagonal polytype, a previously unreported metastable phase of gold. These gold nanoribbons undergo a phase transition from the original 4H hexagonal to face-centred cubic structure on ligand exchange under ambient conditions. Using monochromated electron energy-loss spectroscopy, the strong infrared plasmon absorption of single 4H gold nanoribbons is observed. Furthermore, the 4H hexagonal phases of silver, palladium and platinum can be readily stabilized through direct epitaxial growth of these metals on the 4H gold nanoribbon surface. Our findings may open up new strategies for the crystal phase-controlled synthesis of advanced noble metal nanomaterials.
Noble metals typically crystallize with the face-centered cubic structure. Here, the authors report the synthesis of gold nanoribbons in the 4H hexagonal polytype, a previously unreported, metastable phase of gold, and use it to stabilize 4H hexagonal phases of silver, palladium and platinum.
PMCID: PMC4525209  PMID: 26216712

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