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1.  Meta-Analysis of the Adverse Effects of Long-Term Azithromycin Use in Patients with Chronic Lung Diseases 
The adverse effects of azithromycin on the treatment of patients with chronic lung diseases (CLD) were evaluated in the present study. MEDLINE and other databases were searched for relevant articles published until August 2013. Randomized controlled trials that enrolled patients with chronic lung diseases who received long-term azithromycin treatment were selected, and data on microbiological studies and azithromycin-related adverse events were abstracted from articles and analyzed. Six studies were included in the meta-analysis. The risk of bacterial resistance in patients receiving long-term azithromycin treatment was increased 2.7-fold (risk ratio [RR], 2.69 [95% confidence interval {95% CI}, 1.249, 5.211]) compared with the risk in patients receiving placebo treatment. On the other hand, the risk of bacterial colonization decreased in patients receiving azithromycin treatment (RR, 0.551 [95% CI, 0.460, 0.658]). Patients receiving long-term azithromycin therapy were at risk of increased impairment of hearing (RR, 1.168 [95% CI, 1.030, 1.325]). This analysis provides evidence supporting the idea that bacterial resistance can develop with long-term azithromycin treatment. Besides the increasingly recognized anti-inflammatory role of azithromycin used in treating chronic lung diseases, we should be aware of the potential for adverse events with its long-term use.
doi:10.1128/AAC.02067-13
PMCID: PMC3910718  PMID: 24189261
2.  Trim28 Contributes to EMT via Regulation of E-Cadherin and N-Cadherin in Lung Cancer Cell Lines 
PLoS ONE  2014;9(7):e101040.
In previous work, we demonstrated that transcription factor Trim28 (Tripartite motif containing 28) plays a tumor-suppressor role in early-staged adenocarcinoma of the lung due to its ability to restrain transcription of cell cycle-regulating genes. Herein we examine Trim28's role in the epithelial-to-mesenchymal transition (EMT) which is strongly implicated in cancer metastasis. We found that Trim28 plays a role in TGF-β-induced EMT in non-small cell lung cancer cells. Silencing Trim28 with inhibitory RNAs alters the expression of numerous EMT markers, such as E-cadherin and N-cadherin, whereas overexpression of Trim28 has an opposite effect. Trim28 expression is induced following TGF-β treatment at both protein and mRNA levels. Trim28 deficiency impairs TGF-β-induced EMT and decreases cell migration and invasion. Finally, we demonstrate that the expression of Trim28 affects the acetylation and methylation of histones on E-cadherin and N-cadherin promoters. These results suggest that Trim28 contributes to EMT and might be important for tumor metastasis in lung cancer. Taken together with our previous work these results suggest a model in which Trim28 is a tumor suppressor early in the transformation process in lung cancer, but in later stages it functions as an oncogene.
doi:10.1371/journal.pone.0101040
PMCID: PMC4077753  PMID: 24983967
3.  Pathogenicity of Shigella in Chickens 
PLoS ONE  2014;9(6):e100264.
Shigellosis in chickens was first reported in 2004. This study aimed to determine the pathogenicity of Shigella in chickens and the possibility of cross-infection between humans and chickens. The pathogenicity of Shigella in chickens was examined via infection of three-day-old SPF chickens with Shigella strain ZD02 isolated from a human patient. The virulence and invasiveness were examined by infection of the chicken intestines and primary chicken intestinal epithelial cells. The results showed Shigella can cause death via intraperitoneal injection in SPF chickens, but only induce depression via crop injection. Immunohistochemistry and transmission electron microscopy revealed the Shigella can invade the intestinal epithelia. Immunohistochemistry of the primary chicken intestinal epithelial cells infected with Shigella showed the bacteria were internalized into the epithelial cells. Electron microscopy also confirmed that Shigella invaded primary chicken intestinal epithelia and was encapsulated by phagosome-like membranes. Our data demonstrate that Shigella can invade primary chicken intestinal epithelial cells in vitro and chicken intestinal mucosa in vivo, resulting in pathogenicity and even death. The findings suggest Shigella isolated from human or chicken share similar pathogenicity as well as the possibility of human-poultry cross-infection, which is of public health significance.
doi:10.1371/journal.pone.0100264
PMCID: PMC4064985  PMID: 24949637
4.  “I Just Wanted to Tell You That Loperamide WILL WORK”: A Web-Based Study of Extra-Medical Use of Loperamide 
Drug and alcohol dependence  2012;130(0):241-244.
Aims
Many websites provide a means for individuals to share their experiences and knowledge about different drugs. Such User-Generated Content (UGC) can be a rich data source to study emerging drug use practices and trends. This study examined UGC on extra-medical use of loperamide among illicit opioid users.
Methods
A website that allows for the free discussion of illicit drugs and is accessible for public viewing was selected for analysis. Web-forum posts were retrieved using web crawlers and retained in a local text database. The database was queried to extract posts with a mention of loperamide and relevant brand/slang terms. Over 1,290 posts were identified. A random sample of 258 posts was coded using NVivo to identify intent, dosage, and side-effects of loperamide use.
Results
There has been an increase in discussions related to loperamide’s use by non-medical opioid users, especially in 2010–2011. Loperamide was primarily discussed as a remedy to alleviate a broad range of opioid withdrawal symptoms, and was sometimes referred to as “poor man’s” methadone. Typical doses ranged 70–100 mg per day, much higher than an indicated daily dose of 16 mg.
Conclusions
This study suggests that loperamide is being used extra-medically to self-treat opioid withdrawal symptoms. There is a growing demand among people who are opioid dependent for drugs to control withdrawal symptoms, and loperamide appears to fit that role. The study also highlights the potential of the Web as a “leading edge” data source in identifying emerging drug use practices.
doi:10.1016/j.drugalcdep.2012.11.003
PMCID: PMC3633632  PMID: 23201175
loperamide; web-based research; self-treatment; illicit opiod use
5.  Auricular Acupressure Reduces Anxiety Levels and Improves Outcomes of in Vitro Fertilization: A Prospective, Randomized and Controlled Study 
Scientific Reports  2014;4:5028.
The study was to explore whether auricular acupressure (AA) can relieve anxiety during the period from trans-vaginal oocyte retrieval to the embryo transfer in IVF treatment and whether AA can improve the outcomes of IVF. 305 infertile patients with tubal blockage who were referred for IVF were included. The women were randomized into a control group with 102 cases, a Sham-AA group with 102 cases and an AA group with 101 cases. The anxiety levels were rated with Spielberger's State Trait Anxiety Inventory and the Amsterdam Preoperative Anxiety and Information Scale. Data of clinical pregnancy rate (CPR), implantation rate (IR) and live birth rate (LBR) were obtained. The levels of neuropeptide Y (NPY) and transforming growth factor alpha (TGF-alpha) in the follicular fluids were detected with ELISA. After treatment, in AA group, the levels of state anxiety, preoperative anxiety and need-for-information were significantly lower, whereas CPR, IR, LBR and NPY levels in the follicular fluids were markedly higher than Sham-AA group and control group. We concluded that AA could help to reduce anxiety levels associated with IVF and improves the outcomes of IVF partly through increasing the levels of NPY in the follicular fluids.
doi:10.1038/srep05028
PMCID: PMC4030259  PMID: 24848522
6.  E2F Inhibition Synergizes with Paclitaxel in Lung Cancer Cell Lines 
PLoS ONE  2014;9(5):e96357.
The CDK/Rb/E2F pathway is commonly disrupted in lung cancer, and thus, it is predicted that blocking the E2F pathway would have therapeutic potential. To test this hypothesis, we have examined the activity of HLM006474 (a small molecule pan-E2F inhibitor) in lung cancer cell lines as a single agent and in combination with other compounds. HLM006474 reduces the viability of both SCLC and NSCLC lines with a biological IC50 that varies between 15 and 75 µM, but with no significant difference between the groups. Combination of HLM006474 with cisplatin and gemcitabine demonstrate little synergy; however, HLM006474 synergizes with paclitaxel. Surprisingly, we discovered that brief treatment of cells with HLM006474 led to an increase of E2F3 protein levels (due to de-repression of these promoter sites). Since paclitaxel sensitivity has been shown to correlate with E2F3 levels, we hypothesized that HLM006474 synergy with paclitaxel may be mediated by transient induction of E2F3. To test this, H1299 cells were depleted of E2F3a and E2F3b with siRNA and treated with paclitaxel. Assays of proliferation showed that both siRNAs significantly reduced paclitaxel sensitivity, as expected. Taken together, these results suggest that HLM006474 may have efficacy in lung cancer and may be useful in combination with taxanes.
doi:10.1371/journal.pone.0096357
PMCID: PMC4022639  PMID: 24831239
7.  Human Neural Precursor Cells Promote Neurologic Recovery in a Viral Model of Multiple Sclerosis 
Stem Cell Reports  2014;2(6):825-837.
Summary
Using a viral model of the demyelinating disease multiple sclerosis (MS), we show that intraspinal transplantation of human embryonic stem cell-derived neural precursor cells (hNPCs) results in sustained clinical recovery, although hNPCs were not detectable beyond day 8 posttransplantation. Improved motor skills were associated with a reduction in neuroinflammation, decreased demyelination, and enhanced remyelination. Evidence indicates that the reduced neuroinflammation is correlated with an increased number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords. Coculture of hNPCs with activated T cells resulted in reduced T cell proliferation and increased Treg numbers. The hNPCs acted, in part, through secretion of TGF-β1 and TGF-β2. These findings indicate that the transient presence of hNPCs transplanted in an animal model of MS has powerful immunomodulatory effects and mediates recovery. Further investigation of the restorative effects of hNPC transplantation may aid in the development of clinically relevant MS treatments.
Highlights
•Spinal cord transplantation of hNPCs results in recovery in a viral model of MS•hNPC-mediated recovery occurs in the absence of engrafted cells•hNPCs are immunomodulatory through increasing the frequency of Tregs in the CNS•hNPCs increase Treg frequency via a TGF-β1- and TGF-β2-dependent pathway
Intraspinal transplantation of hESC-derived neural precursor cells (hNPCs) into an immunocompetent mouse model of multiple sclerosis results in sustained clinical recovery. Although hNPCs were rejected within 8 days, the treated mice exhibited long-lasting reduction in neuroinflammation and enhancement of remyelination. The hNPCs appear to mediate recovery through transiently secreted anti-inflammatory and promyelination factors.
doi:10.1016/j.stemcr.2014.04.005
PMCID: PMC4050357  PMID: 24936469
8.  Novel Characterization and Live Imaging of Schlemm's Canal Expressing Prox-1 
PLoS ONE  2014;9(5):e98245.
Schlemm's canal is an important structure of the conventional aqueous humor outflow pathway and is critically involved in regulating the intraocular pressure. In this study, we report a novel finding that prospero homeobox protein 1 (Prox-1), the master control gene for lymphatic development, is expressed in Schlemm's canal. Moreover, we provide a novel in vivo method of visualizing Schlemm's canal using a transgenic mouse model of Prox-1-green fluorescent protein (GFP). The anatomical location of Prox-1+ Schlemm's canal was further confirmed by in vivo gonioscopic examination and ex vivo immunohistochemical analysis. Additionally, we show that the Schlemm's canal is distinguishable from typical lymphatic vessels by lack of lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expression and absence of apparent sprouting reaction when inflammatory lymphangiogenesis occurred in the cornea. Taken together, our findings offer new insights into Schlemm's canal and provide a new experimental model for live imaging of this critical structure to help further our understanding of the aqueous humor outflow. This may lead to new avenues toward the development of novel therapeutic intervention for relevant diseases, most notably glaucoma.
doi:10.1371/journal.pone.0098245
PMCID: PMC4020937  PMID: 24827370
9.  Proteomic Identification of Nrf2-Mediated Phase II Enzymes Critical for Protection of Tao Hong Si Wu Decoction against Oxygen Glucose Deprivation Injury in PC12 Cells 
Chinese herbal medicine formula Tao Hong Si Wu decoction (THSWD) is traditionally used in China for cerebrovascular diseases. However, the molecular mechanisms of THSWD associated with the cerebral ischemia reperfusion injury are largely unknown. The current study applied the two-dimensional gel electrophoresis-based proteomics to investigate the different protein profiles in PC12 cells with and without the treatment of THSWD. Twenty-six proteins affected by THSWD were identified by MALDI-TOF mass spectrometry. Gene ontology analysis showed that those proteins participated in several important biological processes and exhibited diverse molecular functions. In particular, six of them were found to be phase II antioxidant enzymes, which were regulated by NF-E2-related factor-2 (Nrf2). Quantitative PCR further confirmed a dose-dependent induction of the six phase II enzymes by THSWD at the transcription level. Moreover, the individual ingredients of THSWD were discovered to synergistically contribute to the induction of phase II enzymes. Importantly, THSWD's protection against oxygen-glucose deprivation-reperfusion (OGD-Rep) induced cell death was significantly attenuated by antioxidant response element (ARE) decoy oligonucleotides, suggesting the protection of THSWD may be likely regulated at least in part by Nrf2-mediated phase II enzymes. Thus, our data will help to elucidate the molecular mechanisms underlying the neuroprotective effect of THSWD.
doi:10.1155/2014/945814
PMCID: PMC4037622  PMID: 24949080
10.  Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations 
FEBS Open Bio  2014;4:393-406.
Highlights
•Familial Alzheimer disease (FAD) mutations affect presenilin membrane integration.•The transmembrane domains around the catalytic site are vulnerable to changes.•All FAD mutations cause changes in the active site of the γ-secretase complex.•The FAD mutants lead to a complex processing pattern of the amyloid precursor protein.
The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37–43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ species produced (the Aβ42/Aβ40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the Aβ42/Aβ40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the Aβ42/Aβ40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total Aβ production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased Aβ42/Aβ40 ratio are associated with a decrease in total γ-secretase activity.
doi:10.1016/j.fob.2014.04.006
PMCID: PMC4050182  PMID: 24918054
APP, amyloid precursor protein; Aβ, amyloid-β peptide; AICD, amyloid precursor protein intracellular domain; AD, Alzheimer disease; FAD, familial AD; TMD, transmembrane domains; PS, presenilin; NTF, N-terminal fragment; CTF, C-terminal fragment; ER, endoplasmic reticulum; Lep, leader peptidase; BD8, blastocyst-derived embryonic stem cells; GVP, Gal4VP16; GCB, γ-secretase inhibitor coupled to biotin; WT, wild type; FLIM/FRET, Fluorescence Lifetime Imaging/ Fluorescence Resonance Energy Transfer; CHAPSO, 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid; Bis-Tris, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol; MSD, Meso Scale Discovery; RM, rough microsomes; CRM, column-washed dog pancreas rough microsomes; Endo H, endoglycosidase H; MGD, minimal glycosylation distance; Alzheimer disease; γ-Secretase; Membrane integration; Amyloid β-peptide; Protein structure
11.  The Effects of Early-Life Predator Stress on Anxiety- and Depression-Like Behaviors of Adult Rats 
Neural Plasticity  2014;2014:163908.
Childhood emotional trauma contributes significantly to certain psychopathologies, such as post-traumatic stress disorder. In experimental animals, however, whether or not early-life stress results in behavioral abnormalities in adult animals still remains controversial. Here, we investigated both short-term and long-term changes of anxiety- and depression-like behaviors of Wistar rats after being exposed to chronic feral cat stress in juvenile ages. The 2-week predator stress decreased spontaneous activities immediately following stress but did not increase depression- or anxiety-like behaviors 4 weeks after the stimulation in adulthood. Instead, juvenile predator stress had some protective effects, though not very obvious, in adulthood. We also exposed genetic depression model rats, Wistar Kyoto (WKY) rats, to the same predator stress. In WKY rats, the same early-life predator stress did not enhance anxiety- or depression-like behaviors in both the short-term and long-term. However, the stressed WKY rats showed slightly reduced depression-like behaviors in adulthood. These results indicate that in both normal Wistar rats and WKY rats, early-life predator stress led to protective, rather than negative, effects in adulthood.
doi:10.1155/2014/163908
PMCID: PMC4009288  PMID: 24839560
12.  Correcting for Differential Transcript Coverage Reveals a Strong Relationship between Alternative Splicing and Organism Complexity 
Molecular Biology and Evolution  2014;31(6):1402-1413.
What at the genomic level underlies organism complexity? Although several genomic features have been associated with organism complexity, in the case of alternative splicing, which has long been proposed to explain the variation in complexity, no such link has been established. Here, we analyzed over 39 million expressed sequence tags available for 47 eukaryotic species with fully sequenced genomes to obtain a comparable index of alternative splicing estimates, which corrects for the distorting effect of a variable number of transcripts per species—an important obstacle for comparative studies of alternative splicing. We find that alternative splicing has steadily increased over the last 1,400 My of eukaryotic evolution and is strongly associated with organism complexity, assayed as the number of cell types. Importantly, this association is not explained as a by-product of covariance between alternative splicing with other variables previously linked to complexity including gene content, protein length, proteome disorder, and protein interactivity. In addition, we found no evidence to suggest that the relationship of alternative splicing to cell type number is explained by drift due to reduced Ne in more complex species. Taken together, our results firmly establish alternative splicing as a significant predictor of organism complexity and are, in principle, consistent with an important role of transcript diversification through alternative splicing as a means of determining a genome’s functional information capacity.
doi:10.1093/molbev/msu083
PMCID: PMC4032128  PMID: 24682283
organism complexity; alternative splicing; genome evolution; transcriptome evolution; expressed sequence tags
13.  Improving protein function prediction using domain and protein complexes in PPI networks 
BMC Systems Biology  2014;8:35.
Background
Characterization of unknown proteins through computational approaches is one of the most challenging problems in silico biology, which has attracted world-wide interests and great efforts. There have been some computational methods proposed to address this problem, which are either based on homology mapping or in the context of protein interaction networks.
Results
In this paper, two algorithms are proposed by integrating the protein-protein interaction (PPI) network, proteins’ domain information and protein complexes. The one is domain combination similarity (DCS), which combines the domain compositions of both proteins and their neighbors. The other is domain combination similarity in context of protein complexes (DSCP), which extends the protein functional similarity definition of DCS by combining the domain compositions of both proteins and the complexes including them. The new algorithms are tested on networks of the model species of Saccharomyces cerevisiae to predict functions of unknown proteins using cross validations. Comparing with other several existing algorithms, the results have demonstrated the effectiveness of our proposed methods in protein function prediction. Furthermore, the algorithm DSCP using experimental determined complex data is robust when a large percentage of the proteins in the network is unknown, and it outperforms DCS and other several existing algorithms.
Conclusions
The accuracy of predicting protein function can be improved by integrating the protein-protein interaction (PPI) network, proteins’ domain information and protein complexes.
doi:10.1186/1752-0509-8-35
PMCID: PMC3994332  PMID: 24655481
14.  MicroRNA-566 activates EGFR signaling and its inhibition sensitizes glioblastoma cells to nimotuzumab 
Molecular Cancer  2014;13:63.
Background
Epidermal growth factor receptor (EGFR) is amplified in 40% of human glioblastomas. However, most glioblastoma patients respond poorly to anti-EGFR therapy. MicroRNAs can function as either oncogenes or tumor suppressor genes, and have been shown to play an important role in cancer cell proliferation, invasion and apoptosis. Whether microRNAs can impact the therapeutic effects of EGFR inhibitors in glioblastoma is unknown.
Methods
miR-566 expression levels were detected in glioma cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate VHL as a direct target gene of miR-566. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm whether miR-566 inhibition could sensitize anti-EGFR therapy.
Results
In this study, we demonstrated that miR-566 is up-regulated in human glioma cell lines and inhibition of miR-566 decreased the activity of the EGFR pathway. Lentiviral mediated inhibition of miR-566 in glioblastoma cell lines significantly inhibited cell proliferation and invasion and led to cell cycle arrest in the G0/G1 phase. In addition, we identified von Hippel-Lindau (VHL) as a novel functional target of miR-566. VHL regulates the formation of the β-catenin/hypoxia-inducible factors-1α complex under miR-566 regulation.
Conclusions
miR-566 activated EGFR signaling and its inhibition sensitized glioblastoma cells to anti-EGFR therapy.
doi:10.1186/1476-4598-13-63
PMCID: PMC3999939  PMID: 24650032
EGFR; Glioblastoma; miR-566; Nimotuzumab; Combination therapy
15.  Complete Genome Sequence of Porcine Encephalomyocarditis Virus from an Aardvark in China 
Genome Announcements  2014;2(1):e00017-14.
A strain of encephalomyocarditis virus, HNXX13, was isolated from an aardvark in central China. The complete genome was sequenced and analyzed, and phylogenetic analysis suggests that HNXX13 belongs to encephalomyocarditis virus group 1.
doi:10.1128/genomeA.00017-14
PMCID: PMC3924359  PMID: 24526627
16.  Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells 
Cancer gene therapy  2013;20(8):469-477.
Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally (i.t.) as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous (s.c.) MCA205 sarcomas in vivo. Optimal anti-tumor efficacy of mDC.Tbet-based gene therapy was dependent on host NK cells and CD8+ T cells, and required mDC.Tbet expression of MHC class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce pro-inflammatory cytokines (IL-12 family members or IFN-γ) or to migrate to tumor-draining lymph nodes (TDLN) based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3−/−) deficiency in host antigen crosspresenting DC did not diminish the therapeutic action of i.t.-delivered wild-type mDC.Tbet. Interestingly, we observed that i.t delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naïve CD45RB+ T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after i.t. delivery of mDC.Tbet-based gene therapy.
doi:10.1038/cgt.2013.42
PMCID: PMC3775601  PMID: 23846252
Dendritic Cell; Gene Therapy; T-bet; Sarcoma; Immunotherapy; Chemokines
17.  Targeting microRNAs with small molecules: Between Dream and Reality 
doi:10.1038/clpt.2010.46
PMCID: PMC3902962  PMID: 20428111
microRNA; metastases; targeted cancer therapy; computational modeling; drug discovery; small molecule inhibitors
18.  A Critical Assessment of Combined Ligand-based and Structure-based Approaches to hERG Channel Blocker Modeling 
Blockade of hERG channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining QSAR modeling, pharmacophore analysis, and molecular docking. Our consensus models demonstrated high predictive capacity and improved enrichment, and they could correctly classify 91.8% of 147 hERG blockers from 351 inactives. To further enhance our modeling effort, hERG homology models were constructed and molecular docking studies were conducted, resulting in high correlations (R2=0.81) between predicted and experimental binding affinities. We expect our unique models can be applied to efficient screening for hERG blockades, and our extensive understanding of the hERG-inhibitor interactions will facilitate the rational design of drugs devoid of hERG channel activity and hence with reduced cardiac toxicities.
doi:10.1021/ci200271d
PMCID: PMC3894065  PMID: 21902220
19.  Rapid Suppression of Inhibitory Synaptic Transmission by Retinoic Acid 
The Journal of Neuroscience  2013;33(28):11440-11450.
In brain, properly balanced synaptic excitation and inhibition is critically important for network stability and efficient information processing. Here, we show that retinoic acid (RA), a synaptic signaling molecule whose synthesis is activated by reduced neural activity, induces rapid internalization of synaptic GABAA receptors in mouse hippocampal neurons, leading to significant reduction of inhibitory synaptic transmission. Similar to its action at excitatory synapses, action of RA at inhibitory synapses requires protein translation and is mediated by a nontranscriptional function of the RA-receptor RARα. Different from RA action at excitatory synapses, however, RA at inhibitory synapses causes a loss instead of the gain of a synaptic protein (i.e., GABAARs). Moreover, the removal of GABAARs from the synapses and the reduction of synaptic inhibition do not require the execution of RA's action at excitatory synapses (i.e., downscaling of synaptic inhibition is intact when upscaling of synaptic excitation is blocked). Thus, the action of RA at inhibitory and excitatory synapses diverges significantly after the step of RARα-mediated protein synthesis, and the regulations of GABAAR and AMPAR trafficking are independent processes. When both excitatory and inhibitory synapses are examined together in the same neuron, the synaptic excitation/inhibition ratio is significantly enhanced by RA. Importantly, RA-mediated downscaling of synaptic inhibition is completely absent in Fmr1 knock-out neurons. Thus, RA acts as a central organizer for coordinated homeostatic plasticity in both excitatory and inhibitory synapses, and impairment of this overall process alters the excitatory/inhibitory balance of a circuit and likely represents a major feature of fragile X-syndrome.
doi:10.1523/JNEUROSCI.1710-13.2013
PMCID: PMC3724332  PMID: 23843516
20.  TRAF5 and TRAF3IP2 Gene Polymorphisms Are Associated with Behçet's Disease and Vogt-Koyanagi-Harada Syndrome: A Case-Control Study 
PLoS ONE  2014;9(1):e84214.
Background
TRAF5 and TRAF3IP2 have been reported to be associated with several autoimmune diseases. Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome are two autoimmune uveitis entities whereby both genetic and environmental factors are thought to be involved.
Objective
The role of TRAF5 and TRAF3IP2 in BD and VKH has not yet been reported and was therefore the subject of this study.
Methods
The study included 789 BD patients, 940 VKH patients and 1601 healthy unrelated individuals. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or TaqMan® SNP Genotyping Assay. Real-Time PCR was used to detect mRNA expression from PBMCs obtained from healthy controls with (n = 22) or without (n = 79) stimulation. Levels of TNF-α, IL-6 and IL-8 in culture supernatants were measured by ELISA (n = 22).
Results
Three SNPs (rs6540679, rs12569232, rs10863888) of TRAF5 and rs13210247 of TRAF3IP2 were significantly associated with Behçet's disease and VKH syndrome (corrected P values ranging from 9.45×10−12 to 0.027). TRAF3IP2 rs33980500 and rs13190932 were not polymorphic in Han Chinese. Following stimulation by lipopolysaccharide (LPS), carriers of the GG genotype of rs6540679/TRAF5 had a higher TRAF5 mRNA expression (p = 0.004) and an increased TNF-α (p = 0.0052) and IL-6 (p = 0.0014) level compared with AA and AG genotype carriers.
Conclusion
This study provides evidence that TRAF5 and TRAF3IP2 genes are involved in the development of BD and VKH syndrome. Functional research suggested that TRAF5 gene polymorphisms may regulate TRAF5 expression and downstream inflammatory cytokines such as TNF-α and IL-6.
doi:10.1371/journal.pone.0084214
PMCID: PMC3885545  PMID: 24416204
21.  Is there a difference in cognitive development between preschool singletons and twins born after intracytoplasmic sperm injection or in vitro fertilization?*  
Objective: To explore whether there exist differences in cognitive development between singletons and twins born after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Methods: A total of 566 children were recruited for the study, including 388 children (singletons, n=175; twins, n=213) born after IVF and 178 children (singletons, n=87; twins, n=91) born after ICSI. The cognitive development was assessed using the Chinese-Wechsler Intelligence Scale for Children (C-WISC). Results: For all pre-term offspring, all the intelligence quotient (IQ) items between singletons and twins showed no significant differences no matter if they were born after IVF or ICSI. There was a significant difference in the cognitive development of IVF-conceived full-term singletons and twins. The twins born after IVF obtained significantly lower scores than the singletons in verbal IQ (containing information, picture & vocabulary, arithmetic, picture completion, comprehension, and language), performance IQ (containing maze, visual analysis, object assembly, and performance), and full scale IQ (P<0.05). The cognitive development of full-term singletons and twins born after ICSI did not show any significant differences. There was no significant difference between the parents of the singletons and twins in their characteristics where data were collected, including the age of the mothers, the current employment status, the educational backgrounds, and areas of residence. There were also no consistent differences in the duration of pregnancy, sex composition of the children, age, and height between singletons and twins at the time of our study although there existed significant differences between the two groups in the sex composition of the full-term children born after ICSI (P<0.05). Conclusions: Compared to the full-term singletons born after IVF, the full-term twins have lower cognitive development. The cognitive development of full-term singletons and twins born after ICSI did not show any significant differences. For all pre-term offspring, singletons and twins born after IVF or ICSI, the results of the cognitive development showed no significant differences.
doi:10.1631/jzus.B1300229
PMCID: PMC3891118  PMID: 24390744
Cognitive development; Intelligence quotient (IQ); In vitro fertilization (IVF); Intracytoplasmic sperm injection (ICSI); Singleton; Twins
22.  Novel Insights of Structure-based Modeling for RNA-targeted Drug Discovery 
Journal of chemical information and modeling  2012;52(10):10.1021/ci300320t.
Substantial progress in RNA biology highlights the importance of RNAs (e.g., microRNAs) in diseases and the potential of targeting RNAs for drug discovery. However, the lack of RNA-specific modeling techniques demands for development of new tools for RNA-targeted rational drug design. Herein, we implemented integrated approaches of accurate RNA modeling and virtual screening for RNA inhibitor discovery with the most comprehensive evaluation to date of five docking and 11 scoring methods. For the first time, statistical analysis was heavily employed to assess the significance of our predictions. We found that GOLD:GOLD Fitness and rDock:rDock_solv could accurately predict the RNA ligand poses, and ASP rescoring further improved the ranking of ligand binding poses. Due to the weak correlations (R2<0.3) of existing scoring with experimental binding affinities, we implemented two new RNA-specific scoring functions, iMDLScore1 and iMDLScore2, and obtained better correlations with R2=0.70 and 0.79, respectively. We also proposed a multi-step virtual screening approach and demonstrated that rDock:rDock_solv together with iMDLScore2 rescoring obtained the best enrichment on the flexible RNA targets, whereas GOLD:GOLD Fitness combined with rDock_solv rescoring outperformed other methods for rigid RNAs. This study provided practical strategies for RNA modeling and offered new insights into RNA-small molecule interactions for drug discovery.
doi:10.1021/ci300320t
PMCID: PMC3869234  PMID: 22947071
RNA-ligand interactions; molecular docking; scoring function; virtual screening; statistical analysis
23.  A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family 
AIM
To investigate the genetic findings and phenotypic characteristics of a Chinese family with Norrie disease (ND).
METHODS
Molecular genetic analysis and clinical examinations were performed on a Chinese family with ND. Mutations in the Norrie disease pseudoglioma (NDP) gene were detected by direct sequencing. Haplotypes were constructed and compared with the phenotypes in the family. Evolutionary comparisons and mutant open reading frame (ORF) prediction were also undertaken.
RESULTS
Two family members with ocular manifestations were diagnosed with ND. No signs of sensorineural hearing loss were observed in either patient, while one of them showed signs of mild mental retardation. A novel heterozygous mutation in the NDP gene, c.-1_2delAAT, was detected in both patients. The mutation and the mutation bearing haplotype co-segregated with the ND phenotype in males and was transmitted from their mothers and/or grandmothers (II:2). The male without ND did not harbor the mutation. The mutation occurred at the highly conserved nucleotides. ORF finder predicted that the mutation would lead to the production of a truncated protein that lacks the first 11 N-terminal amino acids.
CONCLUSION
A novel mutation, c.-1_2delAAT in the NDP gene, was identified in a Chinese family with ND. This mutation caused ND without obvious sensorineural hearing loss. Mental disorder was found in one but not the other patients. The clinical heterogeneity in the family indicated that other genetic variants and epigenetic factors may also play a role in the disease presentation.
doi:10.3980/j.issn.2222-3959.2013.06.01
PMCID: PMC3874509  PMID: 24392318
Norrie disease; pseudoglioma; mutation; Chinese
24.  Microarray analysis provides new insights into the function of apolipoprotein O in HepG2 cell line 
Background
Apolipoprotein O (apoO) is a new member of the apolipoprotein family. However, data on its physiological functions are limited and inconsistent. Using a microarray expression analysis, this study explored the function of apoO in liver cells.
Methods
HepG2 cells were treated either with oleic acid or tumor necrosis factor-α for 24 h. mRNA and protein expression of apoO were assessed by quantitative real-time PCR (qRT-PCR) and Western blot respectively. An efficient lentiviral siRNA vector targeting the human apoO gene was designed and constructed. The gene expression profile of HepG2 human hepatocellular carcinoma cells transfected with the apoO silencing vector was investigated using a whole-genome oligonucleotide microarray. The expression levels of some altered genes were validated using qRT-PCR.
Results
ApoO expression in HepG2 cells was dramatically affected by lipid and inflammatory stimuli. A total of 282 differentially expressed genes in apoO-silenced HepG2 cells were identified by microarray analysis. These genes included those participating in fatty acid metabolism, such as ACSL4, RGS16, CROT and CYP4F11, and genes participating in the inflammatory response, such as NFKBIZ, TNFSF15, USP2, IL-17, CCL23, NOTCH2, APH-1B and N2N. The gene Uncoupling protein 2 (UCP2), which is involved in both these metabolic pathways, demonstrated significant changes in mRNA level after transfection.
Conclusions
It is likely that apoO participates in fatty acid metabolism and the inflammatory response in HepG2 cells, and UCP2 may act as a mediator between lipid metabolism and inflammation in apoO-silenced HepG2 cells.
doi:10.1186/1476-511X-12-186
PMCID: PMC3878747  PMID: 24341743
Apolipoprotein O; Inflammation; Lipid metabolism; Fatty acids
25.  Impact of Low-Dose Involved-Field Radiation Therapy on Pediatric Patients with Lymphocyte-Predominant Hodgkin Lymphoma Treated with Chemotherapy: A Report from the Children’s Oncology Group 
Pediatric blood & cancer  2012;59(7):1284-1289.
Background
Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma.
Procedure
Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT).
Results
The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have > 5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT.
Conclusions
This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.
doi:10.1002/pbc.24258
PMCID: PMC3468707  PMID: 22847767
Lymphocyte-Predominant Hodgkin Lymphoma

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