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1.  In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy 
Science (New York, N.Y.)  2015;351(6271):403-407.
Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the CRISPR/Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR/Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR/Cas9-based genome editing as a potential therapy to treat DMD.
doi:10.1126/science.aad5143
PMCID: PMC4883596  PMID: 26721684
2.  Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects 
Neuron  2015;89(1):147-162.
SUMMARY
Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.
doi:10.1016/j.neuron.2015.11.023
PMCID: PMC4754122  PMID: 26687841
3.  Genome-wide association study identifies COL2A1 locus involved in the hand development failure of Kashin-Beck disease 
Scientific Reports  2017;7:40020.
Kashin-Beck disease (KBD) is a chronic osteochondropathy. The pathogenesis of growth and development failure of hand of KBD remains elusive now. In this study, we conducted a two-stage genome-wide association study (GWAS) of palmar length-width ratio (LWR) of KBD, totally including 493 study subjects. Affymetrix Genome Wide Human SNP Array 6.0 was applied for genome-wide SNP genotyping of 90 KBD patients. Association analysis was conducted by PLINK. Imputation analysis was performed by IMPUTE against the reference panel of the 1000 genome project. Two SNPs were selected for replication in an independent validation sample of 403 KBD patients. In the discovery GWAS, significant association was observed between palmar LWR and rs2071358 of COL2A1 gene (P value = 4.68 × 10−8). In addition, GWAS detected suggestive association signal at rs4760608 of COL2A1 gene (P value = 1.76 × 10−4). Imputation analysis of COL2A1 further identified 2 SNPs with association evidence for palmar LWR. Replication study observed significant association signals at both rs2071358 (P value = 0.017) and rs4760608 (P value = 0.002) of COL2A1 gene. Based on previous and our study results, we suggest that COL2A1 was a likely susceptibility gene involved in the hand development failure of KBD.
doi:10.1038/srep40020
PMCID: PMC5216336  PMID: 28059113
4.  Peak modulation in multicavity-coupled graphene-based waveguide system 
Plasmonically induced transparency (PIT) in a multicavity-coupled graphene-based waveguide system is investigated theoretically and numerically. By using the finite element method (FEM), the multiple mode effect can be achieved, and blue shift is exhibited by tunable altering the chemical potential of the monolayer graphene. We find that the increasing number of the graphene rectangle cavity (GRC) achieves the multiple PIT peaks. In addition, we find that the PIT peaks reduce to just one when the distance between the third cavity and the second one is 100 nm. Easily to be experimentally fabricated, this graphene-based waveguide system has many potential applications for the advancement of 3D ultra-compact, high-performance, and dynamical modulation plasmonic devices.
doi:10.1186/s11671-016-1791-0
PMCID: PMC5216007  PMID: 28058643
Plasmonically induced transparency; Graphene-based waveguide; Multiple peak modulation
5.  A Novel Floating Controlled Release Drug Delivery System Prepared by Hot-Melt Extrusion 
Floating dosage forms are an important formulation strategy for drugs with a narrow absorption window and low intestinal solubility, and for localized gastric treatment. Novel floating pellets were prepared using the hot-melt extrusion (HME) technology. Uniformly foamed strands were created by liquid injection pumping and screw configuration modification. The ammonio methacrylate copolymer (Eudragit® RSPO) foaming structure was formed by a liquid-vapor phase transition inside the strand upon die exiting resulting from the sudden decrease in external pressure, vaporizing the liquid ethanol and vacating the extruded material. This generated uniform vacuous regions in the extrudate. The pellets’ internal structure was investigated using scanning electron microscopy (SEM). The formulation constituents’ and processing parameters’ effects on the drug release profiles, floating force, and the pellets’ micromeritic properties were evaluated by design of experiments: all formulations showed zero lag time and excellent floating strength, indicating immediate-floating pellet formation. The pellets’ drug release profiles were controlled by multiple independent variables at different time points (≤24 h). Drug loading significantly affected drug release within the first hour; the hydroxypropyl methylcellulose (HPMC) content thereafter. Understanding the variables’ effects on the formulations allows for the tailoring of this delivery system to obtain various drug release profiles.
Graphical abstract
doi:10.1016/j.ejpb.2015.11.015
PMCID: PMC4691578  PMID: 26643801
Hot-melt extrusion; Foamed extrudate; Floating drug delivery system; Controlled release; Eudragit® RSPO; Chemical imaging; Theophylline
6.  Autophagy regulates turnover of lipid droplets via ROS-dependent Rab25 activation in hepatic stellate cell 
Redox Biology  2016;11:322-334.
Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis, characterized by dramatic disappearance of lipid droplets (LDs). Although LD disappearance has long been considered one of the hallmarks of HSC activation, the underlying molecular mechanisms are largely unknown. In this study, we sought to investigate the role of autophagy in the process of LD disappearance, and to further examine the underlying mechanisms in this molecular context. We found that LD disappearance during HSC activation was associated with a coordinate increase in autophagy. Inhibition or depletion of autophagy by Atg5 siRNA impaired LD disappearance of quiescent HSCs, and also restored lipocyte phenotype of activated HSCs. In contrast, induction of autophagy by Atg5 plasmid accelerated LD loss of quiescent HSCs. Importantly, our study also identified a crucial role for reactive oxygen species (ROS) in the facilitation of autophagy activation. Antioxidants, such as glutathione and N-acetyl cysteine, significantly abrogated ROS production, and in turn, prevented autophagosome generation and autophagic flux during HSC activation. Besides, we found that HSC activation triggered Rab25 overexpression, and promoted the combination of Rab25 and PI3KCIII, which direct autophagy to recognize, wrap and degrade LDs. Down-regulation of Rab25 activity, using Rab25 siRNA, blocked the target recognition of autophagy on LDs, and inhibited LD disappearance of quiescent HSCs. Moreover, the scavenging of excessive ROS could disrupt the interaction between autophagy and Rab25, and increase intracellular lipid content. Overall, these results provide novel implications to reveal the molecular mechanism of LD disappearance during HSC activation, and also identify ROS-Rab25-dependent autophagy as a potential target for the treatment of liver fibrosis.
Graphical abstract
fx1
Highlights
•Autophagosome generation and autophagic flux are increased during HSC activation.•The inhibition of autophagy blocks LD disappearance of quiescent HSCs.•The induction of autophagy accelerates LD disappearance of quiescent HSCs.•Rab25 activation is required for autophagy to degrade LDs during HSC activation.•Mitochondrial H2O2 production triggers autophagy activation during HSC activation.
doi:10.1016/j.redox.2016.12.021
PMCID: PMC5199192  PMID: 28038427
Autophagy; Lipid droplets; Hepatic stellate cells; ROS; Rab25
7.  Long-Term Alteration of Reactive Oxygen Species Led to Multidrug Resistance in MCF-7 Cells 
Reactive oxygen species (ROS) play an important role in multidrug resistance (MDR). This study aimed to investigate the effects of long-term ROS alteration on MDR in MCF-7 cells and to explore its underlying mechanism. Our study showed both long-term treatments of H2O2 and glutathione (GSH) led to MDR with suppressed iROS levels in MCF-7 cells. Moreover, the MDR cells induced by 0.1 μM H2O2 treatment for 20 weeks (MCF-7/ROS cells) had a higher viability and proliferative ability than the control MCF-7 cells. MCF-7/ROS cells also showed higher activity or content of intracellular antioxidants like glutathione peroxidase (GPx), GSH, superoxide dismutase (SOD), and catalase (CAT). Importantly, MCF-7/ROS cells were characterized by overexpression of MDR-related protein 1 (MRP1) and P-glycoprotein (P-gp), as well as their regulators NF-E2-related factor 2 (Nrf2), hypoxia-inducible factor 1 (HIF-1α), and the activation of PI3K/Akt pathway in upstream. Moreover, several typical MDR mediators, including glutathione S-transferase-π (GST-π) and c-Myc and Protein Kinase Cα (PKCα), were also found to be upregulated in MCF-7/ROS cells. Collectively, our results suggest that ROS may be critical in the generation of MDR, which may provide new insights into understanding of mechanisms of MDR.
doi:10.1155/2016/7053451
PMCID: PMC5183793  PMID: 28058088
8.  Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Promotes Hepatic Stellate Cells Migration via Canonical NF-κB/MMP9 Pathway 
PLoS ONE  2016;11(12):e0167658.
In the liver, the signal and function of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) have mainly been assessed in association with liver regeneration.
However, the effects of TWEAK on liver fibrosis have not been fully elucidated. To investigate the effects of TWEAK on human hepatic stellate cells (HSCs) and to explore the relevant potential mechanisms, human HSCs line—LX-2 were cultured with TWEAK. Cell migration was detected by transwell assay; cell viability was evaluated by Cell Counting Kit-8; the expression of MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13 gene was identified by quantitative real-time polymerase chain reaction and western blotting; the activity of matrix metalloproteinases (MMPs) was tested by enzyme-linked immuno sorbent assay; small interfering RNA transfection was applied for depletion of MMP9 and p65. The result of transwell assay revealed that TWEAK promoted LX-2 migration. Subsequently, our data testified that the expression and activity of MMP9 was induced by TWEAK in LX-2 cells, which enhanced the migration. Furthermore, our findings showed that TWEAK upregulated the phosphorylation of IκBα and p65 protein to increase MMP9 expression in LX-2 cells. Meanwhile, the alpha-smooth muscle actin, vimentin and desmin expression were upregulated following TWEAK treatment. The results in the present study revealed that TWEAK promotes HSCs migration via canonical NF-κB/MMP9 pathway, which possibly provides a molecular basis targeting TWEAK for the therapy of liver fibrosis.
doi:10.1371/journal.pone.0167658
PMCID: PMC5132172  PMID: 27907201
9.  C2c2 is a single-component programmable RNA-guided RNA-targeting CRISPR effector 
Science (New York, N.Y.)  2016;353(6299):aaf5573.
The CRISPR-Cas adaptive immune system defends microbes against foreign genetic elements via DNA or RNA-DNA interference. We characterize the Class 2 type VI-A CRISPR-Cas effector C2c2 and demonstrate its RNA-guided RNase function. C2c2 from the bacterium Leptotrichia shahii provides interference against RNA phage. In vitro biochemical analysis show that C2c2 is guided by a single crRNA and can be programmed to cleave ssRNA targets carrying complementary protospacers. In bacteria, C2c2 can be programmed to knock down specific mRNAs. Cleavage is mediated by catalytic residues in the two conserved HEPN domains, mutations in which generate catalytically inactive RNA-binding proteins. These results broaden our understanding of CRISPR-Cas systems and suggest that C2c2 can be used to develop new RNA-targeting tools.
doi:10.1126/science.aaf5573
PMCID: PMC5127784  PMID: 27256883
10.  PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia 
Nature Communications  2016;7:13650.
Activin receptor-like kinase 1 (ALK1) is an endothelial serine–threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
Arteriovenous malformations (AVM) is a hallmark of hereditary haemorrhagic telangiectasia type 2, a disease caused by mutations in BMP receptor ALK1. Ola et al. show that AVM can be caused by blocking BMP9 and BMP10 in mice, leading to increased VEGF and PI3K activity, and that pharmacologic inhibition of PI3K prevents AVM development.
doi:10.1038/ncomms13650
PMCID: PMC5141347  PMID: 27897192
11.  Complete Genome Sequences of the SARS-CoV: the BJ Group (Isolates BJ01-BJ04) 
Beijing has been one of the epicenters attacked most severely by the SARS-CoV (severe acute respiratory syndrome-associated coronavirus) since the first patient was diagnosed in one of the city’s hospitals. We now report complete genome sequences of the BJ Group, including four isolates (Isolates BJ01, BJ02, BJ03, and BJ04) of the SARS-CoV. It is remarkable that all members of the BJ Group share a common haplotype, consisting of seven loci that differentiate the group from other isolates published to date. Among 42 substitutions uniquely identified from the BJ group, 32 are non-synonymous changes at the amino acid level. Rooted phylogenetic trees, proposed on the basis of haplotypes and other sequence variations of SARS-CoV isolates from Canada, USA, Singapore, and China, gave rise to different paradigms but positioned the BJ Group, together with the newly discovered GD01 (GD-Ins29) in the same clade, followed by the H-U Group (from Hong Kong to USA) and the H-T Group (from Hong Kong to Toronto), leaving the SP Group (Singapore) more distant. This result appears to suggest a possible transmission path from Guangdong to Beijing/Hong Kong, then to other countries and regions.
doi:10.1016/S1672-0229(03)01023-4
PMCID: PMC5172409  PMID: 15629030
SARS; SARS-CoV; haplotype; substitution; phylogeny
12.  Reduction of Polarization Field Strength in Fully Strained c-Plane InGaN/(In)GaN Multiple Quantum Wells Grown by MOCVD 
The polarization fields in c-plane InGaN/(In)GaN multiple quantum well (MQW) structures grown on sapphire substrate by metal-organic chemical vapor deposition are investigated in this paper. The indium composition in the quantum wells varies from 14.8 to 26.5% for different samples. The photoluminescence wavelengths are calculated theoretically by fully considering the related effects and compared with the measured wavelengths. It is found that when the indium content is lower than 17.3%, the measured wavelengths agree well with the theoretical values. However, when the indium content is higher than 17.3%, the measured ones are much shorter than the calculation results. This discrepancy is attributed to the reduced polarization field in the MQWs. For the MQWs with lower indium content, 100% theoretical polarization can be maintained, while, when the indium content is higher, the polarization field decreases significantly. The polarization field can be weakened down to 23% of the theoretical value when the indium content is 26.5%. Strain relaxation is excluded as the origin of the polarization reduction because there is no sign of lattice relaxation in the structures, judging by the X-ray diffraction reciprocal space mapping. The possible causes of the polarization reduction are discussed.
doi:10.1186/s11671-016-1732-y
PMCID: PMC5122532  PMID: 27885621
Polarization field; InGaN/(In)GaN multiple quantum wells; Photoluminescence; Strain relaxation; Reciprocal space mapping
13.  Functional Analysis of the Nitrogen Metabolite Repression Regulator Gene nmrA in Aspergillus flavus 
In Aspergillus nidulans, the nitrogen metabolite repression (NMR) regulator NmrA plays a major role in regulating the activity of the GATA transcription factor AreA during nitrogen metabolism. However, the function of nmrA in A. flavus has not been previously studied. Here, we report the identification and functional analysis of nmrA in A. flavus. Our work showed that the amino acid sequences of NmrA are highly conserved among Aspergillus species and that A. flavus NmrA protein contains a canonical Rossmann fold motif. Deletion of nmrA slowed the growth of A. flavus but significantly increased conidiation and sclerotia production. Moreover, seed infection experiments indicated that nmrA is required for the invasive virulence of A. flavus. In addition, the ΔnmrA mutant showed increased sensitivity to rapamycin and methyl methanesulfonate, suggesting that nmrA could be responsive to target of rapamycin signaling and DNA damage. Furthermore, quantitative real-time reverse transcription polymerase chain reaction analysis suggested that nmrA might interact with other nitrogen regulatory and catabolic genes. Our study provides a better understanding of NMR and the nitrogen metabolism network in fungi.
doi:10.3389/fmicb.2016.01794
PMCID: PMC5122588  PMID: 27933036
Aspergillus flavus; nitrogen metabolism; nmrA; aflatoxins; AreA
14.  The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization 
Nature Communications  2016;7:13517.
Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in Robo4−/− mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that Robo4 deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4ΔCD). Robo4ΔCD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in Robo4−/− mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4ΔCD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients.
Robo4 is a transmembrane protein that regulates vascular permeability. Zhang et al. now reveal the mechanism of Robo4 action and show that Robo4 and UncB are required for VEGF-mediated regulation of vascular barrier by suppressing VEGF-induced phosphorylation of its receptor Vegfr2 on Y949.
doi:10.1038/ncomms13517
PMCID: PMC5123080  PMID: 27882935
15.  A competing-risk-based score for predicting twenty-year risk of incident diabetes: the Beijing Longitudinal Study of Ageing study 
Scientific Reports  2016;6:37248.
Few risk tools have been proposed to quantify the long-term risk of diabetes among middle-aged and elderly individuals in China. The present study aimed to develop a risk tool to estimate the 20-year risk of developing diabetes while incorporating competing risks. A three-stage stratification random-clustering sampling procedure was conducted to ensure the representativeness of the Beijing elderly. We prospectively followed 1857 community residents aged 55 years and above who were free of diabetes at baseline examination. Sub-distribution hazards models were used to adjust for the competing risks of non-diabetes death. The cumulative incidence function of twenty-year diabetes event rates was 11.60% after adjusting for the competing risks of non-diabetes death. Age, body mass index, fasting plasma glucose, health status, and physical activity were selected to form the score. The area under the ROC curve (AUC) was 0.76 (95% Confidence Interval: 0.72–0.80), and the optimism-corrected AUC was 0.78 (95% Confidence Interval: 0.69–0.87) after internal validation by bootstrapping. The calibration plot showed that the actual diabetes risk was similar to the predicted risk. The cut-off value of the risk score was 19 points, marking mark the difference between low-risk and high-risk patients, which exhibited a sensitivity of 0.74 and specificity of 0.65.
doi:10.1038/srep37248
PMCID: PMC5110955  PMID: 27849048
16.  Discovery and functional characterization of diverse Class 2 CRISPR-Cas systems 
Molecular cell  2015;60(3):385-397.
Microbial CRISPR-Cas systems are divided into Class 1, with multisubunit effector complexes, and Class 2, with single protein effectors. Currently, only two Class 2 effectors, Cas9 and Cpf1, are known. We describe here three distinct Class 2 CRISPR-Cas systems. The effectors of two of the identified systems, C2c1 and C2c3, contain RuvC-like endonuclease domains distantly related to Cpf1. The third system, C2c2, contains an effector with two predicted HEPN RNase domains. Whereas production of mature CRISPR RNA (crRNA) by C2c1 depends on tracrRNA, C2c2 crRNA maturation is tracrRNA-independent. We found that C2c1 systems can mediate DNA interference in a 5’-PAM-dependent fashion analogous to Cpf1. However, unlike Cpf1, which is a single-RNA-guided nuclease, C2c1 depends on both crRNA and tracrRNA for DNA cleavage. Finally, comparative analysis indicates that Class 2 CRISPR-Cas systems evolved on multiple occasions through recombination of Class 1 adaptation modules with effector proteins acquired from distinct mobile elements.
Graphical abstract
doi:10.1016/j.molcel.2015.10.008
PMCID: PMC4660269  PMID: 26593719
CRISPR-Cas adaptive immunity; Cas9; Cpf1; crRNA; tracrRNA; PAM; RuvC-like endonuclease; HEPN domain; computational discovery pipeline; RNA-seq
17.  Engineering and optimising deaminase fusions for genome editing 
Nature Communications  2016;7:13330.
Precise editing is essential for biomedical research and gene therapy. Yet, homology-directed genome modification is limited by the requirements for genomic lesions, homology donors and the endogenous DNA repair machinery. Here we engineered programmable cytidine deaminases and test if we could introduce site-specific cytidine to thymidine transitions in the absence of targeted genomic lesions. Our programmable deaminases effectively convert specific cytidines to thymidines with 13% efficiency in Escherichia coli and 2.5% in human cells. However, off-target deaminations were detected more than 150 bp away from the target site. Moreover, whole genome sequencing revealed that edited bacterial cells did not harbour chromosomal abnormalities but demonstrated elevated global cytidine deamination at deaminase intrinsic binding sites. Therefore programmable deaminases represent a promising genome editing tool in prokaryotes and eukaryotes. Future engineering is required to overcome the processivity and the intrinsic DNA binding affinity of deaminases for safer therapeutic applications.
Precision genome engineering using homology donors and the endogenous DNA break repair machinery and recently CRISPR-Cas9 targeted APOBECs have been demonstrated. Here the authors design zinc-finger and TALE chimeric deaminases and investigate editing efficiency and off-target effects.
doi:10.1038/ncomms13330
PMCID: PMC5097136  PMID: 27804970
18.  Development of an Internet Self-Management Intervention for Intermittent Urinary Catheter Users with Spinal Cord Injury 
While web-based interventions have proliferated recently, information in the literature is often lacking of how the intervention was developed. In response to that gap, this is a report of the development of a web-based self-management intervention for intermittent urinary catheter users and the pretesting with four adults with spinal cord injury living in the community. Two websites were created, one for recruitment and the other for the intervention itself. The intervention involved developing new web-based technology, including an interactive urinary diary (with fluid intake/urine output and a journal), extensive catheter products information, three intervention nurse phone call consultations, and user-community discussion forums. Study participants completed an online survey and were interviewed twice about the enrollment process and their perceptions of their involvement in the intervention. Suggestions from the pretesting participants were used to revise the website applications prior to the next stage of research (a feasibility study). Numerous recommendations and comments were received related to content, interactivity of components, and usability. This paper provides a description of how the websites were developed (including the technology and software programs used), issues encountered and what was done to address them, and how the web-based intervention was modified for improvements.
doi:10.1097/CIN.0000000000000182
PMCID: PMC4654633  PMID: 26361267
nursing interventions; intervention studies; intermittent urethral catheterization; self-management; nursing informatics
19.  Neural Correlates of Task-Irrelevant First and Second Language Emotion Words – Evidence from the Emotional Face–Word Stroop Task 
Frontiers in Psychology  2016;7:1672.
Emotionally valenced words have thus far not been empirically examined in a bilingual population with the emotional face–word Stroop paradigm. Chinese-English bilinguals were asked to identify the facial expressions of emotion with their first (L1) or second (L2) language task-irrelevant emotion words superimposed on the face pictures. We attempted to examine how the emotional content of words modulated behavioral performance and cerebral functioning in the bilinguals’ two languages. The results indicated that there were significant congruency effects for both L1 and L2 emotion words, and that identifiable differences in the magnitude of the Stroop effect between the two languages were also observed, suggesting L1 is more capable of activating the emotional response to word stimuli. For event-related potentials data, an N350–550 effect was observed only in the L1 task with greater negativity for incongruent than congruent trials. The size of the N350–550 effect differed across languages, whereas no identifiable language distinction was observed in the effect of conflict slow potential (conflict SP). Finally, more pronounced negative amplitude at 230–330 ms was observed in L1 than in L2, but only for incongruent trials. This negativity, likened to an orthographic decoding N250, may reflect the extent of attention to emotion word processing at word-form level, while the N350–550 reflects a complicated set of processes in the conflict processing. Overall, the face–word congruency effect has reflected identifiable language distinction at 230–330 and 350-550 ms, which provides supporting evidence for the theoretical proposals assuming attenuated emotionality of L2 processing.
doi:10.3389/fpsyg.2016.01672
PMCID: PMC5088204  PMID: 27847485
emotion word; emotionality; emotional conflict control; bilingualism; emotional Stroop; emotional face–word Stroop
20.  Down-Regulation of MicroRNA-133b Suppresses Apoptosis of Lens Epithelial Cell by Up-Regulating BCL2L2 in Age-Related Cataracts 
Background
MicroRNA-133b (miR-133b) has been reported to be involved in many diseases, including ovarian cancer and osteosarcoma. Accumulating evidence suggests that miR-133b plays important roles in human disease. In this study, we aimed to investigate the molecular mechanism, including the potential regulator and signaling pathways, of BCL2L2.
Material/Methods
We first searched the online miRNA database (www.mirdb.org) using the “seed sequence” located within the 3′-UTR of the target gene, and then performed luciferase assay to test the regulatory relationship between miR-133b and BCL2L2. Western blot and real-time PCR were used to determine the expression of BCL2L2 in human samples or cells treated with miRNA mimics or inhibitors. Flow cytometry was conducted to evaluate the apoptosis status of the cells.
Results
We validated BCL2L2 to be the direct gene using a luciferase reporter assay. We also conducted real-time PCR and Western blot analyses to study the mRNA and protein expression level of BCL2L2 among different groups (control: n=29, cataract: n=33) or cells treated with scramble control, miR-133b mimics, BCL2L2 siRNA, and miR-133b inhibitors, and identified the negative regulatory relationship between miR-133b and BCL2L2. We also conducted experiments to investigate the influence of miR-133b and BCL2L2 on the viability and apoptosis of cells. The results showed that miR-133b positively interfered with the viability of cells, while BCL2L2 negatively interfered with the viability of cells, and that miR-133b inhibited apoptosis while BCL2L2 accelerated apoptosis.
Conclusions
BCL2L2 was the virtual target of miR-133b, and we found a negative regulatory relationship between miR-133b and BCL2L2. MiR-133b and BCL2L2 interfered with the viability and apoptosis of cells.
doi:10.12659/MSM.896975
PMCID: PMC5094470  PMID: 27802259
Genes, bcl-2; Apoptosis; MicroRNAs; Lenses
21.  The Novel miR-9600 Suppresses Tumor Progression and Promotes Paclitaxel Sensitivity in Non–small-cell Lung Cancer Through Altering STAT3 Expression 
MicroRNAs have been identified to be involved in center stage of cancer biology. They accommodate cell proliferation and migration by negatively regulate gene expression either by hampering the translation of targeted mRNAs or by promoting their degradation. We characterized and identified the novel miR-9600 and its target in human non–small-cell lung cancer (NSCLC). Our results demonstrated that the miR-9600 were downregulated in NSCLC tissues and cells. It is confirmed that signal transducer and activator of transcription 3 (STAT3), a putative target gene, is directly inhibited by miR-9600. The miR-9600 markedly suppressed the protein expression of STAT3, but with no significant influence in corresponding mRNA levels, and the direct combination of miR-9600 and STAT3 was confirmed by a luciferase reporter assay. miR-9600 inhibited cell growth, hampered expression of cell cycle-related proteins and inhibited cell migration and invasion in human NSCLC cell lines. Further, miR-9600 significantly suppressed tumor growth in nude mice. Similarly, miR-9600 impeded tumorigenesis and metastasis through directly targeting STAT3. Furthermore, we identified that miR-9600 augmented paclitaxel and cisplatin sensitivity by downregulating STAT3 and promoting chemotherapy-induced apoptosis. These data demonstrate that miR-9600 might be a useful and novel therapeutic target for NSCLC.
doi:10.1038/mtna.2016.96
PMCID: PMC5155328  PMID: 27845771
drug resistance; miR-9600; non–small-cell lung cancer; STAT3; tumorigenesis
22.  Partial Splenic Embolization has Beneficial Effects for the Management of Gastroesophageal Variceal Hemorrhage 
Background/Aims:
Partial splenic embolization (PSE) is used in the management of gastroesophageal variceal hemorrhage (GEVH). However, it is uncertain whether it has beneficial effects for GEVH patients in preventing variceal recurrence and variceal hemorrhage, as well as promoting overall survival (OS), when it is combined with conventional therapies.
Materials and Methods:
The databases including PubMed, EMBASE, Web of Science, Google scholar, and Cochrane Central Register of Controlled Trials were searched up to 11th of November, 2015. Meta-analyses were performed by using Review Manager 5.3 software for analyzing the risk of bias, Newcastle-Ottawa Scale for assessing the bias of cohort studies, and GRADEprofiler software for assessing outcomes obtained from the meta-analyses.
Results:
A total of 1505 articles were reviewed, and 1 randomized controlled trial and 5 cohort studies with 244 participants were eligible for inclusion. The pooled hazard ratio (HR) of variceal recurrence is 0.50 (95% confidence interval (CI) 0.37, 0.68; P< 0.00001; I2 = 0%). The pooled HR of variceal hemorrhage is 0.24 (95% CI 0.15, 0.39; P< 0.00001; I2 = 0%). The pooled HR of OS is 0.50 (95% CI 0.33, 0.67; P< 0.00001; I2 = 0%). Meta-analyses demonstrated statistically significant superiority of combinational therapies over conventional therapies in preventing variceal recurrence and variceal hemorrhage and prolonging OS. The complications related to PSE were mild or moderate and nonfatal.
Conclusions:
The results indicate that PSE has beneficial effects for GEVH patients, however, future investigation with a larger number of subjects in clinical trials is warranted.
doi:10.4103/1319-3767.195553
PMCID: PMC5184739  PMID: 27976634
Gastroesophageal variceal hemorrhage; hypersplenism; overall survival; partial splenic embolization; variceal recurrence
23.  Huge focal nodular hyperplasia presenting in a 6-year-old child: A case presentation 
Highlights
•FNH is a benign lesion of the liver which is rare in children.•We report the case of a 6-year-old child (male) with a huge FNH which size is more than 10 cm. This could be the biggest FNH among all children’s FNH cases ever reported.•When pediatric FNH patients accord with (1) clinical symptoms; (2) indefinite diagnosis or hepatitis B virus carriage; (3) tumor size >5 cm, surgical treatment could be considered.
Introduction
Focal nodular hyperplasia (FNH) is a benign lesion of the liver which is usually found in healthy adults, however, FNH is rare in children, and comprises only 2% of all pediatric liver tumors. Herein, we report the case of a 6-year-old child (male) with a huge FNH which size is more than 10 cm. This could be the biggest FNH among all children’s FNH cases ever reported.
Case presentation
A 6-year-old boy was found a hepatic space-occupying lesion two years ago. As the time went by, the lesion became bigger gradually. The last CT examination showed the size of the tumor to be 10.5 × 9.9 cm in the right hepatic lobe. This child underwent surgical resection of the tumor which was confirmed as FNH (11 × 8 × 7 cm) by pathology.
Conclusion
FNH is a benign lesion of the liver, and it is characterized by hepatocyte hyperplasia and a central stellate scar. It is uncommon for FNH to be diagnosed in children. Such huge FNH (about 11 cm) is extremely rare. Surgical operation may be the effective method to cure huge FNH.
doi:10.1016/j.ijscr.2016.10.053
PMCID: PMC5099262  PMID: 27825058
FNH, focal nodular hyperplasia; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed tomography; Focal nodular hyperplasia; Child; Benign liver tumors; Computed tomography
24.  Cpf1 is a single RNA-guided endonuclease of a Class 2 CRISPR-Cas system 
Cell  2015;163(3):759-771.
The microbial adaptive immune system CRISPR mediates defense against foreign genetic elements through two classes of RNA-guided nuclease effectors. Class 1 effectors utilize multi-protein complexes, whereas Class 2 effectors rely on single-component effector proteins such as the well-characterized Cas9. Here we report characterization of Cpf1, a putative Class 2 CRISPR effector. We demonstrate that Cpf1 mediates robust DNA interference with features distinct from Cas9. Cpf1 is a single RNA-guided endonuclease lacking tracrRNA, and it utilizes a T-rich protospacer adjacent motif. Moreover, Cpf1 cleaves DNA via a staggered DNA double stranded break. Out of 16 Cpf1-family proteins, we identified two candidate enzymes, from Acidominococcus and Lachnospiraceae, with efficient genome editing activity in human cells. Identifying this mechanism of interference broadens our understanding of CRISPR-Cas systems and advances their genome editing applications.
Graphical Abstract
doi:10.1016/j.cell.2015.09.038
PMCID: PMC4638220  PMID: 26422227
25.  Boosting Power Density of Microbial Fuel Cells with 3D Nitrogen‐Doped Graphene Aerogel Electrode 
Advanced Science  2016;3(8):1600097.
A 3D nitrogen‐doped graphene aerogel (N‐GA) as an anode material for microbial fuel cells (MFCs) is reported. Electron microscopy images reveal that the N‐GA possesses hierarchical porous structure that allows efficient diffusion of both bacterial cells and electron mediators in the interior space of 3D electrode, and thus, the colonization of bacterial communities. Electrochemical impedance spectroscopic measurements further show that nitrogen doping considerably reduces the charge transfer resistance and internal resistance of GA, which helps to enhance the MFC power density. Importantly, the dual‐chamber milliliter‐scale MFC with N‐GA anode yields an outstanding volumetric power density of 225 ± 12 W m−3 normalized to the total volume of the anodic chamber (750 ± 40 W m−3 normalized to the volume of the anode). These power densities are the highest values report for milliliter‐scale MFCs with similar chamber size (25 mL) under the similar measurement conditions. The 3D N‐GA electrode shows great promise for improving the power generation of MFC devices.
doi:10.1002/advs.201600097
PMCID: PMC5074258  PMID: 27818911
microbial fuel cells; nitrogen‐doped graphene aerogels; power density; Shewanella oneidensis

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