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1.  Naringin administration inhibits platelet aggregation and release by reducing blood cholesterol levels and the cytosolic free calcium concentration in hyperlipidemic rabbits 
This study investigated the effects of naringin on platelet aggregation and release in hyperlipidemic rabbits, and the underlying mechanisms. The safety of naringin was also investigated. The rabbits were orally administered 60, 30 or 15 mg/kg of naringin once a day for 14 days after being fed a high fat/cholesterol diet for four weeks. Following the two weeks of drug administration, the degree of platelet aggregation induced by arachidonic acid, adenosine diphosphate and collagen was significantly reduced by naringin at certain doses compared with those in the rabbits of the model group (P<0.01). The levels of P-selectin and platelet factor 4 (PF4) also decreased following treatment with naringin compared with those of the model group. Certain doses of naringin significantly reduced the total cholesterol (TC) levels and elevated the ratio of high-density lipoprotein cholesterol to TC compared with those in the model group, and significantly decreased the cytosolic free calcium concentration ([Ca2+]i). No significant difference in the coagulation function was observed between the control and drug-treatment groups. These results indicate that naringin improved platelet aggregation and inhibited the excessive release of P-selectin and PF4 in hyperlipidemic rabbits. This study suggests that the antiplatelet effect of naringin may be due to its ability to regulate the levels of blood cholesterol and [Ca2+]i in platelets. Naringin also did not cause bleeding in the hyperlipidemic rabbits.
PMCID: PMC4113534  PMID: 25120631
naringin; hyperlipidemic; aggregation; cytosolic free calcium concentration; P-selectin; platelet factor 4
2.  Suppression (but Not Reappraisal) Impairs Subsequent Error Detection: An ERP Study of Emotion Regulation's Resource-Depleting Effect 
PLoS ONE  2014;9(4):e96339.
Past event-related potentials (ERPs) research shows that, after exerting effortful emotion inhibition, the neural correlates of performance monitoring (e.g. error-related negativity) were weakened. An undetermined issue is whether all forms of emotion regulation uniformly impair later performance monitoring. The present study compared the cognitive consequences of two emotion regulation strategies, namely suppression and reappraisal. Participants were instructed to suppress their emotions while watching a sad movie, or to adopt a neutral and objective attitude toward the movie, or to just watch the movie carefully. Then after a mood scale, all participants completed an ostensibly unrelated Stroop task, during which ERPs (i.e. error-related negativity (ERN), post-error positivity (Pe) and N450) were obtained. Reappraisal group successfully decreased their sad emotion, relative to the other two groups. Compared with participants in the control group and the reappraisal group, those who suppressed their emotions during the sad movie showed reduced ERN after error commission. Participants in the suppression group also made more errors in incongruent Stroop trials than the other two groups. There were no significant main effects or interactions of group for reaction time, Pe and N450. Results suggest that reappraisal is both more effective and less resource-depleting than suppression.
PMCID: PMC4002454  PMID: 24777113
3.  Cathepsin L Plays a Role in Quinolinic Acid-Induced NF-Κb Activation and Excitotoxicity in Rat Striatal Neurons 
PLoS ONE  2013;8(9):e75702.
The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-κB) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to assess the contribution of cathepsin L to QA-induced striatal neuron death. Western blot analysis and cathepsin L activity assay were used to assess the changes in the levels of cathepsin L after QA treatment. Western blot analysis was used to assess the changes in the protein levels of inhibitor of NF-κB alpha isoform (IκB-α) and phospho-IκB alpha (p-IκBα) after QA treatment. Immunohistochemical analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced NF-κB. Western blot analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced IκB-α phosphorylation and degradation, changes in the levels of IKKα, p-IKKα, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced loss of striatal neurons were strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced degradation of IκB-α, NF-κB nuclear translocation, up-regulation of NF-κB responsive gene TP53, and activation of caspase-3 was strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced increases in beclin 1, LC3II/LC3I, and down-regulation of p62 were reduced by Z-FF-FMK or NaphthaCHO. These results suggest that cathepsin L is involved in glutamate receptor-induced NF-κB activation. Cathepsin L inhibitors have neuroprotective effects by inhibiting glutamate receptor-induced IκB-α degradation and NF-κB activation.
PMCID: PMC3779166  PMID: 24073275
4.  Differential expression and subcellular localization of Prohibitin 1 are related to tumorigenesis and progression of non-small cell lung cancer 
Lung cancer remains the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer. With a variety of biological functions, Prohibitin1 (PHB1) has been proved tumor-associated. But there are conflicting data regarding the involvement of PHB1 in tumorigenesis and few studies regarding the role of PHB1 in lung cancer. The studies reported herein used a combination of clinical observations and molecular methods to investigate the possible role of PHB1 in NSCLC tissues and cell lines. PHB1 expression was evaluated by RT-PCR, RT-qPCR, Western blotting and immunohistochemistry analysis. Flow cytometric analysis was used to determine the surface expression profiles of PHB1 in lung cell lines. The results showed that PHB1 expression were generally increased in lung cancer tissues when compared with matched noncancerous tissues and closely related with tumor differentiation and lymph node invasion. PHB1 expression levels was also increased in three lung cancer cell lines (SK-MES-1, NCI-H157 and NCI-H292) as compared with BEAS-2B cells. Moreover, there were various subcellular localization of PHB1 in different lung cancer cells and the presence of PHB1 on the surface of lung cancer cells was significantly reduced. In conclusion, PHB1 expression is increased in NSCLC and the up-regulation of PHB1 is associated with clinically aggressive phenotype. The different subcellular localization of PHB1 in NSCLC cells and the loss of the membrane-associated PHB1 probably related to the tumorigenesis and progression of NSCLC and suggests that PHB1 may play different roles in various types of NSCLC.
PMCID: PMC3796231  PMID: 24133587
Prohibitin 1; up-regulation; subcellular localization; non-small cell lung cancer
5.  Treatment of radiation-induced hemorrhagic gastritis with prednisolone: A case report 
Radiation-induced gastritis is an infrequent cause of gastrointestinal bleeding. It is a serious complication arising from radiation therapy, and the standard treatment method has not been established. The initial injury is characteristically acute inflammation of gastric mucosa. We presented a 46-year-old male patient with hemorrhagic gastritis induced by external radiotherapy for metastatic retroperitoneal lymph node of hepatocellular carcinoma. The endoscopic examination showed diffuse edematous hyperemicmucosa with telangiectasias in the whole muscosa of the stomach and duodenal bulb. Multiple hemorrhagic patches with active oozing were found over the antrum. Anti-secretary therapy was initiated for hemostasis, but melena still occurred off and on. Finally, he was successfully treated by prednisolone therapy. We therefore strongly argue in favor of perdnisolone therapy to effectively treat patients with radiation-induced hemorrhagic gastritis.
PMCID: PMC3544049  PMID: 23326152
Hemorrhagic gastritis; Radiation; Prednisolone; Hepatocellular carcinoma; Gastrointestinal bleeding
6.  Clinical application of multimodality imaging in radiotherapy treatment planning for rectal cancer 
Cancer Imaging  2013;13(4):495-501.
Radiotherapy plays an important role in the treatment of rectal cancer. Three-dimensional conformal radiotherapy and intensity-modulated radiotherapy are mainstay techniques of radiotherapy for rectal cancer. However, the success of these techniques is heavily reliant on accurate target delineation and treatment planning. Computed tomography simulation is a cornerstone of rectal cancer radiotherapy, but there are limitations, such as poor soft-tissue contrast between pelvic structures and partial volume effects. Magnetic resonance imaging and positron emission tomography (PET) can overcome these limitations and provide additional information for rectal cancer treatment planning. PET can also reduce the interobserver variation in the definition of rectal tumor volume. However, there is a long way to go before these image modalities are routinely used in the clinical setting. This review summarizes the most promising studies on clinical applications of multimodality imaging in target delineation and treatment planning for rectal cancer radiotherapy.
PMCID: PMC3864219  PMID: 24334539
Rectal cancer; radiotherapy treatment planning; computed tomography; magnetic resonance imaging; positron emission tomography/computed tomography
7.  Realizing and characterizing chiral photon flow in a circuit quantum electrodynamics necklace 
Scientific Reports  2015;5:8352.
Gauge theory plays the central role in modern physics. Here we propose a scheme of implementing artificial Abelian gauge fields via the parametric conversion method in a necklace of superconducting transmission line resonators (TLRs) coupled by superconducting quantum interference devices (SQUIDs). The motivation is to synthesize an extremely strong effective magnetic field for charge-neutral bosons which can hardly be achieved in conventional solid-state systems. The dynamic modulations of the SQUIDs can induce effective magnetic fields for the microwave photons in the TLR necklace through the generation of the nontrivial hopping phases of the photon hopping between neighboring TLRs. To demonstrate the synthetic magnetic field, we study the realization and detection of the chiral photon flow dynamics in this architecture under the influence of decoherence. Taking the advantages of its simplicity and flexibility, this parametric scheme is feasible with state-of-the-art technology and may pave an alternative way for investigating the gauge theories with superconducting quantum circuits. We further propose a quantitative measure for the chiral property of the photon flow. Beyond the level of qualitative description, the dependence of the chiral flow on external pumping parameters and cavity decay is characterized.
PMCID: PMC4322363  PMID: 25666884
8.  Decreased light attenuation in cerebral cortex during cerebral edema detected using optical coherence tomography 
Neurophotonics  2014;1(2):025004-.
Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema.
PMCID: PMC4321699
cerebral edema; optical coherence tomography; brain swelling
9.  Anti-CD40-induced inflammatory E-cadherin+ dendritic cells enhance T cell responses and antitumour immunity in murine Lewis lung carcinoma 
Agonistic CD40 antibodies have been demonstrated to activate antigen-presenting cells (APCs) and enhance antitumour T cell responses, thereby providing a new therapeutic option in cancer immunotherapy. In agonistic CD40 antibody-mediated inflammatory responses, a novel subset of E-cadherin + dendritic cells (DCs) has been identified, and little is known about the role of these DCs in tumour immunity. This study investigated the effect of anti-CD40-mediated inflammatory E-cadherin + DCs in murine Lewis lung carcinoma (LLC).
The phenotype and characteristics of anti-CD40-mediated inflammatory E-cadherin + DCs isolated from the anti-CD40 model were assessed in vitro. The antitumour activity of E-cadherin + DCs were evaluated in vivo by promoting the differentiation of effector CD4+ T cells, CEA-specific CD8+ T cells and CD103+ CD8+ T cells and assessing their resistance to tumour challenge, including variations in tumour volume and survival curves.
Here, we demonstrated that anti-CD40-mediated E-cadherin + inflammatory DCs accumulate in the lungs of Rag1 KO mice and were able to stimulate naïve CD4+ T cells to induce Th1 and Th17 cell differentiation and polarisation and to inhibit regulatory T cell and Th2 responses. Importantly, with the adoptive transfer of E-cadherin + DCs into the Lewis lung cancer model, the inflammatory DCs increased the Th1 and Th17 cell responses and reduced the Treg cell and Th2 responses. Interestingly, following the injection of inflammatory E-cadherin + DCs, the CD103+ CD8+ T cell and CEA-specific CD8+ T cell responses increased and exhibited potent antitumour immunity.
These findings indicate that anti-CD40-induced E-cadherin + DCs enhance T cell responses and antitumour activity in non-small cell lung cancer (NSCLC)-bearing mice and may be used to enhance the efficacy of DC-based peptide vaccines against NSCLC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0126-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4323023  PMID: 25651850
E-cadherin; Dendritic cell; T cell; Lung cancer; Activity
10.  The expression dynamics of transforming growth factor-β/Smad signaling in the liver fibrosis experimentally caused by Clonorchis sinensis 
Parasites & Vectors  2015;8:70.
Liver fibrosis is a hallmark of clonorchiasis suffered by millions people in Eastern Asian countries. Recent studies showed that the activation of TGF-β/Smad signaling pathway can potently regulate the hepatic fibrogenesis including Schistosoma spp. and Echinococcus multilocularis-caused liver fibrosis. However, little is known to date about the expression of transforming growth factor-β (TGF-β) and other molecules in TGF-β/Smad signaling pathway which may play an important role in hepatic fibrosis caused by C. sinensis.
A total of 24 mice were individually infected orally with 45 metacercariae, both experimental mice and mocked-infected control mice were anesthetized at 4 week post-infection (wk p.i.), 8 wk p.i. and 16 wk p.i., respectively. For each time-point, the liver and serum from each animal were collected to analyze histological findings and various fibrotic parameters including TGF-β1, TGF-β receptors and down-stream Smads activation, as well as fibrosis markers expression.
The results showed that collagen deposition indicated by hydroxyproline content and Masson’s trichrome staining was increased gradually with the development of infection. The expression of collagen type α1 (Col1a) mRNA transcripts was steadily increased during the whole infection. The mRNA levels of Smad2, Smad3 as well as the protein of Smad3 in the liver of C. sinensis-infected mice were increased after 4 wk p.i. (P < 0.05, compared with normal control) whereas the TGF-β1, TGF-β type I receptor (TGFβRI) and TGF-β type II receptor (TGFβRII) mRNA expression in C. sinensis-infected mice were higher than those of normal control mice after 8 wk p.i. (P < 0.05). However, the gene expression of Smad4 and Smad7 were peaked at 4 wk p.i. (P < 0.05), and thereafter dropped to the basal level at 8 wk p.i., and 16 wk p.i., respectively. The concentrations of TGF-β1 in serum in the C. sinensis-infected mice at 8 wk p.i. and 16 wk p.i (P < 0.05) were significantly higher than those in the control mice.
The results of the present study indicated for the first time that the activation of TGF-β/Smad signaling pathway might contribute to the synthesis of collagen type I which leads to liver fibrosis caused by C. sinensis.
PMCID: PMC4329204  PMID: 25649869
Clonorchis sinensis; Liver fibrosis; Transforming growth factor-β; Smads
11.  Phylogenetic insight into subgenera Idaeobatus and Malachobatus (Rubus, Rosaceae) inferring from ISH analysis 
Rubus is a large and taxonomically complex genus exhibiting agamospermy, polyploidy and frequent hybridization. The objective of this work was to elucidate rDNA disrtibution pattern and investigate genomic composition of polyploids in 16 Rubus taxa (2n = 2x, 3x, 4x, 8x) of two subgenera Idaeobatus and Malachobatus by ISH method.
The basic Rubus genome had one 45S rDNA locus, and all the polyploids (except R. setchuenensis) had the expected multiples of this number. Diploid and tetraploid Rubus taxa carried two 5S rDNA, whereas the triploid and octoploid species only had three. The duplicated 45S rDNA sites tended to be conserved, whereas those of 5S rDNA tended to be eliminated after polyploidization. The accession R03-20 was an autotriploid R. parvifolius, while R03-27 and R03-57 were naturally-occurred triploid hybrids between R. parvifolius and R. coreanus. GISH results suggested that R. parvifolius had close relationship with polyploids from Malachobatus.
The polyploids from Malachobatus were probable allopolyploid. In addition, Rubus parvifolius might be involved in hybridization, polyploidization and speciation of some Idaeobatus and Malachobatus species.
PMCID: PMC4324050
Rubus; Allopolyploid; Hybrid; rDNA-FISH; GISH
12.  Hypoxia-induced MTA1 promotes MC3T3 osteoblast growth but suppresses MC3T3 osteoblast differentiation 
Bone fracture is one of the most common physical injuries in which gene expression and the microenvironment are reprogramed to facilitate the recovery process.
By specific siRNA transfection and MTT assay, we evaluated the effects of metastasis-associated gene 1 (MTA1) in osteoblast growth. To show the role of MTA1 in osteoblast under hypoxia conditions, by overexpressing and silencing MTA1 expression, we performed mineral deposition and alkaline phosphatase activity assay to observe the differentiation status of osteoblast cells. Real-time PCR and Western blot assays were adopted to detect the expression of certain target genes.
Here, we reported that hypoxia-induced MTA1 expression through hypoxia-induced factor 1 alpha (HIF-1α) and stimulated the growth of osteoblast MC3T3 cells. Silencing of MTA1 through specific siRNA suppressed MC3T3 cell growth and elicited cell differentiation and induced alkaline phosphatase activation and the upregulation of bone morphogenetic protein-2 and osteocalcin.
We found that MTA1 was regulated by HIF-1α in hypoxia circumstance to suppress osteoblast differentiation. These findings provide new insights for bone fracture healing and new strategies to develop potential targets to promote fracture healing.
Electronic supplementary material
The online version of this article (doi:10.1186/s40001-015-0084-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4324858  PMID: 25644400
Bone fracture; Fracture healing; Hypoxia-induced MTA1; Osteoblast cell growth; Osteoblast differentiation
13.  The Zeb Proteins δEF1 and Sip1 May Have Distinct Functions in Lens Cells Following Cataract Surgery 
Posterior capsular opacification (PCO), the most prevalent side effect of cataract surgery, occurs when residual lens epithelial cells (LECs) undergo fiber cell differentiation or epithelial-to-mesenchymal transition (EMT). Here, we used a murine cataract surgery model to investigate the role of the Zeb proteins, Smad interacting protein 1 (Sip1) and δ-crystallin enhancer-binding factor 1 (δEF1), during PCO.
Extracapsular extraction of lens fiber cells was performed on wild-type and Sip1 knockout mice. Protein expression patterns were assessed at multiple time points after surgery using confocal immunofluorescence. βB1-Crystallin mRNA levels were measured using quantitative RT-PCR. We used Transfac searches to identify δEF1 binding sites in the βB1-crystallin promoter and transfection analysis to test the ability of δEF1 to regulate βB1-crystallin expression.
δEF1, which, in other systems, can activate fibrotic genes (e.g., α-smooth muscle actin) and repress epithelial genes, upregulates by 48 hours after fiber cell removal. In culture, δEF1 repressed βB1-crystallin promoter activity, suggesting that it may also turn off lens gene expression following surgery, contributing to “fibrotic PCO” development. Sip1 also upregulates in LECs by 48 hours, but analysis of Sip1 knockout lenses demonstrated that Sip1 does not play a major role in EMT or fiber cell differentiation after surgery. However, Sip1 knockout LECs do express the ectodermal marker keratin 8, suggesting that Sip1 may limit the reprogramming of residual LECs to an embryonic state.
Zeb transcription factors likely play important, but distinct roles in PCO development after cataract surgery.
Zeb transcription factor expression upregulates following lens fiber cell removal in an animal model. The results presented correlate δEF1 expression with lens epithelial fibrosis while Sip1 upregulation appears to prevent dedifferentiation of lens cells to a precursor fate.
PMCID: PMC4148927  PMID: 25082886
cataract surgery; epithelial-to-mesenchymal transition; lens regeneration; mouse disease model; posterior capsular opacification; Zeb
14.  qFibrosis: A fully-quantitative innovative method incorporating histological features to facilitate accurate fibrosis scoring in animal model and chronic hepatitis B patients 
Journal of hepatology  2014;61(2):260-269.
Background & Aims
There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients.
qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison.
qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p <0.001) and human biopsies (p <0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93–0.99 for animal samples: 1–16 mm2; AUC: 0.84–0.97 for biopsies: 10–44 mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15 mm) and under- and over-scoring by different pathologists (p <0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p = 0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts.
qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice.
PMCID: PMC4278959  PMID: 24583249
Liver fibrosis assessment; qFibrosis; Chronic hepatitis B; Liver biopsy; Image analysis
15.  Vector analysis of low to moderate astigmatism with small incision lenticule extraction (SMILE): results of a 1-year follow-up 
BMC Ophthalmology  2015;15:8.
To evaluate the refractive outcomes for the correction of low to moderate astigmatism up to 1 year following small incision lenticule extraction (SMILE) surgery.
This retrospective study enrolled 98 eyes from 98 patients who underwent SMILE surgery for the correction of myopia and astigmatism. Only right eyes were included in this study to avoid the bias of orientation errors. The vector method was used to analyze the outcomes of astigmatism at 1 month, 6 months and 12 months after the procedure, including the double-angle plots, correction index (CI), index of success (IOS), angle of error (AofE) and magnitude of error (MofE). The effectiveness, safety, stability and predictability were also investigated during the 12-month follow-up.
The preoperative cylinder ranged from -2.75 D to -0.25 D (average of -0.90 ± 0.68 D), and the mean postoperative cylinder values were -0.24 ± 0.29 D, -0.24 ± 0.29 D, and -0.20 ± 0.27 D at 1 month, 6 months, and 12 months, respectively. The mean astigmatism in vector form was -0.14 D × 27.19° at 1 month, -0.13 D × 27.29° at 6 months, and -0.10 D × 28.63° at 12 months after surgery. The CI was 1.00 ± 0.32 and IOS was 0.29 ± 0.44 at the 12-month follow-up. Significant negative correlations were found between the CI and absolute target induced astigmatism (TIA) value, and positive correlations were found between the IOS and absolute AofE value (P < 0.05). The MofE was limited within ±1.00 D at the 12-month follow-up. Fifty-six eyes (57.1%) gained one line in corrected distance visual acuity (CDVA) and five eyes (5.1%) gained two lines. There were no significant differences observed in the refractive outcomes among time points.
SMILE surgery was effective and safe in correcting low to moderate astigmatism, and stable refractive outcomes were observed at the long-term follow-up. The undercorrection of astigmatism could possibly be influenced by attempted astigmatism correction preoperatively, the axis rotation during the surgery or wound healing postoperatively. This study suggested that nomograms should be adjusted in correcting astigmatism with SMILE surgery.
PMCID: PMC4328987  PMID: 25618419
Vector analysis; Astigmatism; Femtosecond laser; Small incision lenticule extraction; Refractive surgery; Long-term
16.  Evolutionary analysis of rubella viruses in mainland China during 2010–2012: endemic circulation of genotype 1E and introductions of genotype 2B 
Scientific Reports  2015;5:7999.
Rubella remains a significant burden in mainland China. In this report, 667 viruses collected in 24 of 31 provinces of mainland China during 2010–2012 were sequenced and analyzed, significantly extending previous reports on limited numbers of viruses collected before 2010. Only viruses of genotypes 1E and 2B were found. Genotype 1E viruses were found in all 24 provinces. Genotype 1E viruses were likely introduced into mainland China around 1997 and endemic transmission of primarily one lineage became established. Viruses reported here from 2010–2012 are largely in a single cluster within this lineage. Genotype 2B viruses were rarely detected in China prior to 2010. This report documents a previously undetected 2B lineage, which likely became endemic in eastern provinces of China between 2010 and 2012. Bayesian analyses were performed to estimate the evolutionary rates and dates of appearance of the genotype 1E and 2B viral linages in China. A skyline plot of viral population diversity did not provide evidence of reduction of diversity as a result of vaccination, but should be useful as a baseline for such reductions as vaccination programs for rubella become widespread in mainland China.
PMCID: PMC4303870  PMID: 25613734
17.  TLR3 Signaling in Macrophages Is Indispensable for the Protective Immunity of Invariant Natural Killer T Cells against Enterovirus 71 Infection 
PLoS Pathogens  2015;11(1):e1004613.
Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.
Author Summary
Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease. EV71 infection occurs mainly in children but rarely in adults. The factors that determine the susceptibility of children to EV71 infection remain elusive. Here, we found that the paucity of invariant natural killer T (iNKT) cells in new-born mice was associated with their susceptibility to EV71 infection. Furthermore, iNKT cells played a critical role in protecting older young mice from EV71 infection before their adaptive immune systems were fully developed. Mechanistically, TLR3 signaling in macrophages, but not in dendritic cells, was essentially required for iNKT cell activation during EV71 infection. Both interleukin (IL)-12 production and endogenous lipid antigens presented by macrophages were required for full iNKT cell activation. iNKT cells tended to prevent the dissemination of EV71 into central nervous system. Taken together, our findings provide a new insight into the susceptibility of children to EV71 infection, and imply that the manipulation of iNKT cells might represent a potential therapeutic strategy for HFMD and other viral infectious diseases in children.
PMCID: PMC4304831  PMID: 25615690
18.  A novel 11p13 microdeletion encompassing PAX6 in a Chinese Han family with aniridia, ptosis and mental retardation 
To explore possible genetic aberrations in a Chinese family with aniridia, ptosis and mental retardation, and provide genetic evidence for the prenatal diagnosis.
14 exons of PAX6 in the proband were sequenced by the Sanger sequencing technique. Multiplex ligation-dependent probe amplification (MLPA) technique was employed to further explore gene alterations of PAX6. Single nucleotide polymorphisms-array (SNP-array) assay was applied to screen potential pathologic genome-wide copy number variations (CNV).
There were no detectable pathogenic mutations in the 14 exons of PAX6 in the proband. MLPA indicated a heterozygous deletion encompassing all PAX6 gene regions covered and a partial upstream region. SNP-array assay detected a heterozygous 11p13 microdeletion with a length of 518 kb in the proband, spanning two whole annotated genes, elongation factor protein 4 (ELP4), the paired box gene 6 (PAX6), and partial IMP1 inner-mitochondrial membrane (IMMP1L) gene. SNP-array revealed her affected brother carried the identical deletion.
The 518 kb heterozygous deletion in 11p13 encompassing PAX6 should be the genetic etiology for the familial aniridia.
PMCID: PMC4307215  PMID: 25628759
PAX6; 11p13 deletion; Mental retardation; Aniridia; SNP-array
19.  An intestinal commensal symbiosis factor controls neuroinflammation via TLR2-mediated CD39 signaling 
Nature communications  2014;5:4432.
The mammalian immune system constitutively senses vast quantities of commensal bacteria and their products through pattern recognition receptors, yet excessive immune reactivity is prevented under homeostasis. Intestinal microbiome can influence host susceptibility to extra-intestine autoimmune disorders. Here we report that polysaccharide A (PSA), a symbiosis factor for human intestinal commensal Bacteroides fragilis, protects against central nervous system demyelination and inflammation during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, through toll-like receptor 2 (TLR2). TLR2 mediates tissue-specific expansion of a critical regulatory CD39+ CD4 T cell subset by PSA. Ablation of CD39 signaling abrogates PSA control of EAE manifestations and inflammatory cytokine responses. Further, CD39 confers immune-regulatory phenotypes to total CD4 T cells and Foxp3+ CD4 Tregs. Importantly, CD39-deficient CD4 T cells show an enhanced capability to drive EAE progression. Our results demonstrate the therapeutic potential and underlying mechanism by which an intestinal symbiont product modulates CNS-targeted demyelination.
PMCID: PMC4118494  PMID: 25043484
20.  Experimental infection of Z:ZCLA Mongolian gerbils with human hepatitis E virus 
AIM: To investigate whether Z:ZCLA Mongolian gerbils are readily susceptible to infection by human hepatitis E virus (HEV).
METHODS: Z:ZCLA Mongolian gerbils were infected with a clinical HEV strain isolated from an acute hepatitis E patient, and virus pathogenesis was assessed in this host. Non-infected gerbils served as the control group. Feces samples from gerbils were collected weekly for reverse transcription-nested polymerase chain reaction. Serum anti-HEV IgG and alanine aminotransferase (ALT) were detected by enzyme linked immunosorbent assay. At sacrifice, each animal’s liver, spleen and kidney were collected for histopathologic examination.
RESULTS: HEV-infected gerbils showed fatigue, with histopathological changes observed in the liver, spleen and kidney. HEV RNA was detected in fecal samples taken at day 7 after inoculation and the detectable levels lasted out to day 42 after inoculation. Interestingly, ALT levels were only moderately increased in the HEV-infected animals compared with the non-infected control group.
CONCLUSION: Z:ZCLA Mongolian gerbils are susceptible to human HEV.
PMCID: PMC4299338  PMID: 25624719
Hepatitis E virus; Mongolian gerbils; Infection; Interspecies transmission; Zoonosis
21.  Regional covariance patterns of gray matter alterations in Alzheimer’s disease and its replicability evaluation 
Journal of magnetic resonance imaging : JMRI  2013;39(1):10.1002/jmri.24143.
To identify regional network covariance patterns of gray matter associated with Alzheimer’s disease (AD) and to further evaluate its replicability and stability.
Materials and Methods
This study applied a multivariate analytic approach based on scaled subprofile modeling (SSM) to structural MRI data from 19 patients with AD and 19 healthy controls (HC). We further applied the derived covariance patterns to examine the replicability and stability of AD-associated covariance patterns in an independent dataset [13 AD and 14 HC] acquired with a different scanner.
The AD-associated covariance patterns identified from SSM combined principal components mainly involved the temporal lobe and parietal lobe. The expression of covariance patterns was significantly higher in AD patients than HC (t(36) = 5.84, p= 5.75E–7) and predicted the AD/HC group membership (84% sensitivity and 90% specificity). In replicability evaluation, the expression of the forward applied covariance patterns was still statistically significant and had acceptable discriminability (69% sensitivity and 71% specificity).
AD patients showed regional gray matter alterations in a reliable covariance manner. The results suggest that SSM has utility for characterizing covariant features, therefore, can assist us with further understanding covariance patterns of gray matter in AD based on the view of the network.
PMCID: PMC3732807  PMID: 23589138
multivariate analysis; scaled subprofile model; Alzheimer’s disease; structural MRI; voxel-based morphometry
22.  Dynamics of histone variant H3.3 and its coregulation with H2A.Z at enhancers and promoters 
Nucleus  2014;5(1):21-27.
In eukaryotes, genomic DNA is hierarchically packaged into chromatin by histones. A defined organization of the genome into chromatin with specific patterns of epigenetic modifications is crucial for transcriptional regulation, cell fate determination, and maintenance, in which the histone variant incorporation has been characterized as one of the most key players. The diversity of histone variants results in structural plasticity of chromatin and highlights functionally distinct chromosomal domains. Here we focus on the role of histone variant H3.3 and its coregulation with H2A.Z in chromatin dynamics at enhancers and promoters and transcriptional regulation.
PMCID: PMC4028350  PMID: 24637397
histone variant; H3.3; H2A.Z; chromatin dynamics; transcriptional regulation
23.  Chitosan/siRNA Nanoparticles Targeting Cyclooxygenase Type 2 Attenuate Unilateral Ureteral Obstruction-induced Kidney Injury in Mice 
Theranostics  2015;5(2):110-123.
Cyclooxygenase type 2 (COX-2) plays a predominant role in the progression of kidney injury in obstructive nephropathy. The aim of this study was to test the efficacy of chitosan/small interfering RNA (siRNA) nanoparticles to knockdown COX-2 specifically in macrophages to prevent kidney injury induced by unilateral ureteral obstruction (UUO). Using optical imaging techniques and confocal microscopy, we demonstrated that chitosan/siRNA nanoparticles accumulated in macrophages in the obstructed kidney. Consistent with the imaging data, the obstructed kidney contained a higher amount of siRNA and macrophages. Chitosan-formulated siRNA against COX-2 was evaluated on RAW macrophages demonstrating reduced COX-2 expression and activity after LPS stimulation. Injection of COX-2 chitosan/siRNA nanoparticles in mice subjected to three-day UUO diminished the UUO-induced COX-2 expression. Likewise, macrophages in the obstructed kidney had reduced COX-2 immunoreactivity, and histological examination showed lesser tubular damage in COX-2 siRNA-treated UUO mice. Parenchymal inflammation, assessed by tumor necrosis factor-alpha (TNF-α) and interleukin 6 mRNA expression, was attenuated by COX-2 siRNA. Furthermore, treatment with COX-2 siRNA reduced heme oxygenase-1 and cleaved caspase-3 in UUO mice, indicating lesser oxidative stress and apoptosis. Our results demonstrate a novel strategy to prevent UUO-induced kidney damage by using chitosan/siRNA nanoparticles to knockdown COX-2 specifically in macrophages.
PMCID: PMC4278998  PMID: 25553102
Cyclooxygenase type 2; siRNA; chitosan; unilateral ureteral obstruction; mice.
24.  Analysis of synonymous codon usage in enterovirus 71 
Virusdisease  2014;25(2):243-248.
Enterovirus 71 (EV71) is the major cause of hand-foot-and-mouth disease in children. In our study, using the complete genome sequences of 42 EV71 representing all three genotypes, we analyzed synonymous codon usage and the relative dinucleotide abundance in EV71 genome. The general correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in EV71 genome. Furthermore, we observed that the relative abundance of dinucleotides in EV71 is independent of the overall base composition but is still the result of differential mutational pressure, which also shapes codon usage. In addition, other factors, such as hydrophobicity and aromaticity, also influence the codon usage variation among the genomes of EV71. This study represents the most comprehensive analysis of EV71 codon usage patterns and provides a basic understanding of the mechanisms for codon usage bias.
PMCID: PMC4188181
EV71; Synonymous codon usage; Mutational bias; Dinucleotide bias; Subgenotype
25.  SDF-1α/CXCR4 Axis Mediates The Migration of Mesenchymal Stem Cells to The Hypoxic-Ischemic Brain Lesion in A Rat Model 
Cell Journal (Yakhteh)  2015;16(4):440-447.
Transplantation of mesenchymal stem cells (MSCs) can promote functional recovery of the brain after hypoxic-ischemic brain damage (HIBD). However, the mechanism regulating MSC migration to a hypoxic-ischemic lesion is poorly understood. Interaction between stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXC chemokine receptor 4 (CXCR4) is crucial for homing and migration of multiple stem cell types. In this study, we investigate the potential role of SDF-1α/CXCR4 axis in mediating MSC migration in an HIBD model.
Materials and Methods
In this experimental study, we first established the animal model of HIBD using the neonatal rat. Bone marrow MSCs were cultured and labeled with 5-bromo-21-deoxyuridine (BrdU) after which 6×106 cells were intravenously injected into the rat. BrdU positive MSCs in the hippocampus were detected by immunohistochemical analyses. The expression of hypoxia-inducible factor-1α (HIF-1α) and SDF-1α in the hippocampus of hypoxic-ischemic rats was detected by Western blotting. To investigate the role of hypoxia and SDF-1α on migration of MSCs in vitro, MSCs isolated from normal rats were cultured in a hypoxic environment (PO2=1%). Migration of MSCs was detected by the transwell assay. The expression of CXCR4 was tested using Western blotting and flow cytometry.
BrdU-labeled MSCs were found in the rat brain, which suggested that transplanted MSCs migrated to the site of the hypoxic-ischemic brain tissue. HIF-1α and SDF-1α significantly increased in the hippocampal formations of HIBD rats in a time-dependent manner. They peaked on day 7 and were stably expressed until day 21. Migration of MSCs in vitro was promoted by SDF-1α under hypoxia and inhibited by the CXCR4 inhibitor AMD3100. The expression of CXCR4 on MSCs was elevated by hypoxia stimulation as well as microdosage treatment of SDF-1α.
This observation illustrates that SDF-1α/CXCR4 axis mediate the migration of MSCs to a hypoxic-ischemic brain lesion in a rat model.
PMCID: PMC4297482
Mesenchymal Stem Cells; Migration; SDF-1α; CXCR 4

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