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1.  Associations between Two Polymorphisms (FokI and BsmI) of Vitamin D Receptor Gene and Type 1 Diabetes Mellitus in Asian Population: A Meta-Analysis 
PLoS ONE  2014;9(3):e89325.
Background
Vitamin D receptor (VDR) gene polymorphisms are possibly involved in the development of type 1 diabetes mellitus (T1DM). However, the results to date have been inconclusive. We performed a meta-analysis to examine the association between 2 polymorphisms (FokI and BsmI) of the VDR gene and T1DM in the Asian population.
Methods
Literature was retrieved from PubMed, Web of Science, CBM, Embase and Chinese databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random or fixed effect model.
Results
In total, 20 papers (BsmI: 13 studies; FokI: 13 studies) were included. In contrast to the FokI polymorphism, the BsmI polymorphism was associated with an increased risk of T1DM in the Asian population (OR = 1.47, 95% CI = 1.13–1.91, P = 0.004 for B vs. b). Upon stratification by regional geography, an increased risk of T1DM in association with the BsmI polymorphism was observed in the East Asian population (OR = 1.97, 95% CI = 1.38–2.83, P<0.001 for B vs. b), whereas the FokI polymorphism was associated with an increased risk of T1DM in the West Asian population (OR = 1.45, 95% CI = 1.12–1.88, P = 0.004 for F vs. f).
Conclusions
Our meta-analysis suggests that the BsmI polymorphism may be a risk factor for susceptibility to T1DM in the East Asian population, and the FokI polymorphism is associated with an increased risk of T1DM in the West Asian population. However, because the study size was limited, further studies are essential to confirm our results.
doi:10.1371/journal.pone.0089325
PMCID: PMC3945782  PMID: 24603699
2.  TLR7 preconditioning induces robust neuroprotection against stroke by a novel type I interferon-mediated mechanism 
Background and Purpose
Systemic administration of Toll-like receptor 4 (TLR4) and TLR9 agonists prior to cerebral ischemia, have been shown to reduce ischemic injury by reprogramming the brain’s response to stroke. Our goal was to explore the mechanism of TLR induced neuroprotection by determining whether a TLR7 agonist also protects against stroke injury.
Methods
C57Bl/6, TNF−/−, interferon regulatory factor (IRF)7−/−, or type I interferon receptor (IFNAR)−/− mice were subcutaneously administered the TLR7 agonist Gardiquimod (GDQ) 72 hr prior to middle cerebral artery occlusion (MCAO). Infarct volume and functional outcome were determined following reperfusion. Plasma cytokine responses and induction of mRNA for IFN related genes in the brain were measured. IFNAR−/− mice were also treated with the TLR4 agonist (lipopolysaccharide) or the TLR9 agonist (CpG) prior to MCAO and infarct volumes measured.
Results
The results show that GDQ reduces infarct volume as well as functional deficits in mice. GDQ pretreatment provided robust neuroprotection in TNF−/− mice indicating that TNF was not essential. GDQ induced a significant increase in plasma IFNα levels and both IRF7−/− and IFNAR−/− mice failed to be protected, implicating a role for IFN signaling in TLR7 mediated protection.
Conclusion
Our studies provide the first evidence that TLR7 preconditioning can mediate neuroprotection against ischemic injury. Moreover, we show that the mechanism of protection is unique from other TLR preconditioning ligands in that it is independent of TNF and dependent on IFNAR.
doi:10.1161/STROKEAHA.111.641522
PMCID: PMC3943206  PMID: 22403050
Ischemia; Neuroprotection
3.  Notch Gain of Function Inhibits Chondrocyte Differentiation via Rbpj-Dependent Suppression of Sox9 
Notch signaling plays a critical role during development by directing the binary cell fate decision between progenitors and differentiated cells. Previous studies have shown sustained Notch activation in cartilage leads to chondrodysplasia. Genetic evidence indicates that Notch regulates limb bud mesenchymal stem cell differentiation into chondrocytes via an Rbpj-dependent Notch pathway. However, it is still unknown how Notch governs chondrogenesis in the axial skeleton where Notch serves a primary patterning function. We hypothesized that both Rbpj-dependent and Rbpj-independent Notch signaling mechanisms might be involved. Cartilage specific Notch gain-of-function (GOF) mutant mice display chondrodysplasia accompanied by loss of Sox9 expression in vertebrae. To evaluate the contribution of an Rbpj-dependent Notch signaling to this phenotype, we deleted Rbpj on the Notch GOF background. These mice showed persistent spine abnormalities characterized by “butterfly” vertebrae suggesting that removal of Rbpj does not fully rescue the axial skeleton deformities caused by Notch GOF. However, Sox9 protein level was restored in Rbpj deficient Notch GOF mice compared to Notch GOF mutants, demonstrating that regulation of Sox9 expression is canonical or Rbpj-dependent. To further understand the molecular basis of this regulation, we performed chromatin immunoprecipitation (ChIP) assays and detected the recruitment of the Rbpj/NICD transcription complex to Rbpj-binding sites upstream of the Sox9 promoter. The association of the Rbpj/NICD complex with the Sox9 promoter is associated with transcriptional repression of Sox9 in a cellular model of chondrocyte differentiation. Hence, Notch negatively regulates chondrocyte differentiation in the axial skeleton by suppressing Sox9 transcription, and Rbpj-independent Notch signaling mechanisms may also contribute to axial skeletogenesis.
doi:10.1002/jbmr.1770
PMCID: PMC3548081  PMID: 22991339
Chondrodysplasia; axial skeleton; genetic mouse model; Notch signaling; Sox9; Chondrocyte
4.  Mapping I-Ag7 restricted epitopes in murine G6PC2 
Immunologic research  2013;55(0):91-99.
G6PC2, also known as islet specific glucose 6-phosphatase catalytic subunit related protein (IGRP), is a major target of autoreactive CD8+ T cells in both diabetic human subjects and the non-obese diabetic (NOD) mouse. However, in contrast to the abundant literature regarding the CD8+ response to this antigen, much less is known about the potential involvement of IGRP-reactive CD4+ T cells in diabetogenesis. The single previous study that examined this question in NOD mice was based upon a candidate epitope approach and identified three I-Ag7-restricted epitopes that each elicited spontaneous responses in these animals. However, given the known inaccuracies of MHC class II epitope prediction algorithms, we hypothesized that additional specificities might also be targeted. To address this issue we immunized NOD mice with membranes from insect cells overexpressing full-length recombinant mouse IGRP, and measured recall responses of purified CD4+ T cells using a library of overlapping peptides encompassing the entire 355aa primary sequence. Nine peptides representing 8 epitopes gave recall responses, only 1 of which corresponded to any of the previously reported sequences. In each case proliferation was blocked by a monoclonal antibody to I-Ag7, but not the appropriate isotype control. Consistent with a role in diabetogenesis, proliferative responses to 4 of the 9 peptides (3 epitopes) were also detected in CD4+ T cells purified from the pancreatic draining lymph nodes of pre-diabetic female animals, but not from peripheral lymph nodes or spleens of the same animals. Intriguingly, one of the newly identified spontaneously reactive epitopes (P8 [IGRP55–72]) is highly conserved between mice and man, suggesting that it might also be a target of HLA-DQ8-restricted T cells in diabetic human subjects, an hypothesis that we are currently testing.
doi:10.1007/s12026-012-8368-5
PMCID: PMC3664523  PMID: 22983906
Autoimmune diabetes; NOD; IGRP; epitope
5.  Association of High Vitamin D Status with Low Circulating Thyroid-Stimulating Hormone Independent of Thyroid Hormone Levels in Middle-Aged and Elderly Males 
Background. A recent study has reported that high circulating 25-hydroxyvitamin D [25(OH)D] is associated with low circulating thyroid-stimulating hormone (TSH) levels, but only in younger individuals. The goal of the present study was to explore the relationship between vitamin D status and circulating TSH levels with thyroid autoimmunity and thyroid hormone levels taken into consideration in a population-based health survey of middle-aged and elderly individuals. Methods. A total of 1,424 Chinese adults, aged 41–78 years, were enrolled in this cross-sectional study. Serum levels of 25(OH)D, TSH, thyroid hormones, and thyroid autoantibodies were measured. Results. The prevalence of vitamin D insufficiency was 94.29% in males and 97.22% in females, and the prevalence of vitamin D deficiency was 55.61% in males and 69.64% in females. Vitamin D status was not associated with positive thyroid autoantibodies after controlling for age, gender, body mass index, and smoking status. Higher 25(OH)D levels were associated with lower TSH levels after controlling for age, FT4 and FT3 levels, thyroid volume, the presence of thyroid nodule(s), and smoking status in males. Conclusion. High vitamin D status in middle-aged and elderly males was associated with low circulating TSH levels independent of thyroid hormone levels.
doi:10.1155/2014/631819
PMCID: PMC3947886
6.  Association of calcaneal quantitative ultrasound parameters with metabolic syndrome in middle-aged and elderly Chinese: a large population-based cross-sectional study 
Background
The possible association between metabolic syndrome (MS) and bone mineral density (BMD) has been highlighted recently. However, the exact effects of MS on calcaneal quantitative ultrasound (QUS) parameters remains uncertain. The aim of this study was to assess the impact of MS states, different componets of MS, as well as the number of MS componets on QUS.
Methods
A total of 7489 Chinese adults aged 40 years or older in Nanjing were enrolled in this cross-sectional study. MS was defined according to recommendations generated by the International Diabetes Federation (IDF) in 2005. QUS was measured for each participant.
Results
The prevalence of MS was 34.6% in men and 42.8% in women (over 40 years old). In postmenopausal women with MS, 25-hydroxyvitamin D[25(OH)D], age adjusted quantitative ultrasound index (QUI) and broadband ultrasound attenuation (BUA) were all lower than those without (p < 0.001, p = 0.023, p = 0.021, respectively), the difference of QUI and BUA disappeared after adjustment for body mass index (BMI) and waist circumference (WC). In stepwise analysis, BMI, WC, high density lipoprotein cholesterol (HDL-C) and fasting plasma glucose (FPG) were related to QUS (p < 0.05). The number of MS components had no influence on QUS. Fragile fracture incidence was higher in women with MS (6.8% VS. 5.3%, P = 0.034).
Conclusion
Chinese postmenopausal women with MS have worse BMD measured by QUS and more chances to develop osteoporotic fractures than the controls, which partially due to central obesity as well as vitamin D deficiency. People having less central obesity, higher FPG or HDL-C are less likely to have bone mineral loss.
doi:10.1186/1472-6823-14-14
PMCID: PMC3925415  PMID: 24529197
Metabolic syndrome; Osteoporosis; Calcaneal quantitative ultrasound; Fragile fractures
7.  Microwave tissue coagulation technique in anatomical liver resection 
Biomedical Reports  2014;2(2):177-182.
Anatomical liver resection is currently the preferred treatment for liver cancer. With the recent introduction of medical microwave coagulation for liver metastases, anatomical hepatectomy may be performed more efficiently. The present study retrospectively reviewed the results of microwave tissue coagulation performed during anatomical liver resection for patients with liver disease at the TangDu Hospital (Xi’an, China) between January, 2009 and June, 2012. A total of 128 patients met the inclusion criteria and were divided into two groups for comparison; those treated with the microwave coagulation technique (n=66) and the conventional group (n=62), who were treated with standard partial hepatectomy. There was no reported perioperative mortality. The univariate analysis revealed that the duration of liver dissection, intraoperative blood loss, intraoperative erythrocyte transfusion volume and alanine aminotransferase levels on the 5th postoperative day were significantly different between the microwave and conventional groups (P<0.05). Therefore, microwave tissue coagulation in anatomical liver resection was shown to be efficacious and safe and, provided proficient skills are developed in this technique, microwave tissue coagulation may be an effective alternative to anatomical hepatectomy.
doi:10.3892/br.2014.227
PMCID: PMC3917738  PMID: 24649092
microwave tissue coagulator; anatomical liver resection; liver cancer; surgical technique
8.  Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice 
Molecular Biology Reports  2014;41:1815-1827.
Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and d-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver.
doi:10.1007/s11033-014-3031-y
PMCID: PMC3933741  PMID: 24442316
Mycelium Cordyceps sinensis; Liver sinusoidal endothelial cells (LSECs); Liver injury; Hepatic sinusoid; MMP-2/9; Oxidative stress
9.  MicroRNA-23a promotes neuroblastoma cell metastasis by targeting CDH1 
Oncology Letters  2014;7(3):839-845.
CDH1 inactivation is important in tumor metastasis. In the present study, it was suggested that the mRNA and protein levels of CDH1 decreased in metastatic neuroblastoma (NB) tissues compared with those in primary NB tissues. The aim of the study was to explore the regulatory mechanisms of CDH1 downregulation in metastatic NB. MicroRNAs are small non-coding RNAs (~22 nt in length) that negatively regulate target mRNAs and are involved in various cancer-related processes, including metastasis. In the current study, miR-23a was shown to be upregulated in human metastatic NB tissues compared with primary NB tissues. Inhibition of miR-23a may significantly suppress NB cell migration and invasion. In vitro reporter assay suggested that CDH1 is a direct target gene of miR-23a. Furthermore, blocking the expression of miR-23a partly restored the expression of CDH1 in NB cells. These findings provide evidence that miR-23a is key in promoting NB cell migration and invasion through targeting CDH1, and suggest that exogenous miR-23a may have therapeutic value in treating NB metastasis.
doi:10.3892/ol.2014.1794
PMCID: PMC3919791  PMID: 24520301
miRNA; miR-23a; CDH1; neuroblastoma
10.  Critical assessment of coalescent simulators in modeling recombination hotspots in genomic sequences 
BMC Bioinformatics  2014;15:3.
Background
Coalescent simulation is pivotal for understanding population evolutionary models and demographic histories, as well as for developing novel analytical methods for genetic association studies for DNA sequence data. A plethora of coalescent simulators are developed, but selecting the most appropriate program remains challenging.
Results
We extensively compared performances of five widely used coalescent simulators – Hudson’s ms, msHOT, MaCS, Simcoal2, and fastsimcoal, to provide a practical guide considering three crucial factors, 1) speed, 2) scalability and 3) recombination hotspot position and intensity accuracy. Although ms represents a popular standard coalescent simulator, it lacks the ability to simulate sequences with recombination hotspots. An extended program msHOT has compensated for the deficiency of ms by incorporating recombination hotspots and gene conversion events at arbitrarily chosen locations and intensities, but remains limited in simulating long stretches of DNA sequences. Simcoal2, based on a discrete generation-by-generation approach, could simulate more complex demographic scenarios, but runs comparatively slow. MaCS and fastsimcoal, both built on fast, modified sequential Markov coalescent algorithms to approximate standard coalescent, are much more efficient whilst keeping salient features of msHOT and Simcoal2, respectively. Our simulations demonstrate that they are more advantageous over other programs for a spectrum of evolutionary models. To validate recombination hotspots, LDhat 2.2 rhomap package, sequenceLDhot and Haploview were compared for hotspot detection, and sequenceLDhot exhibited the best performance based on both real and simulated data.
Conclusions
While ms remains an excellent choice for general coalescent simulations of DNA sequences, MaCS and fastsimcoal are much more scalable and flexible in simulating a variety of demographic events under different recombination hotspot models. Furthermore, sequenceLDhot appears to give the most optimal performance in detecting and validating cross-over hotspots.
doi:10.1186/1471-2105-15-3
PMCID: PMC3890628  PMID: 24387001
Coalescent; Population genetics; Linkage disequilibrium; Recombination; Single nucleotide polymorphism
11.  Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance 
Science signaling  2010;3(111):10.1126/scisignal.2000502.
Exposing the brain to sublethal ischemia affects the response to a subsequent, otherwise injurious ischemia, resulting in transcriptional suppression and neuroprotection, a response called ischemic tolerance. Here, we show that the proteomic signature of the ischemic-tolerant brain is characterized by increased abundance of transcriptional repressors, particularly polycomb group (PcG) proteins. Knocking down PcG proteins precluded the induction of ischemic tolerance, whereas in an in vitro model, overexpressing the PcG proteins SCMH1 or BMI1 induced tolerance to ischemia without preconditioning. We found that PcG proteins are associated with the promoter regions of genes encoding two potassium channel proteins that show decreased abundance in ischemic-tolerant brains. Furthermore, PcG proteins decreased potassium currents in cultured neuronal cells and knocking down potassium channels elicited tolerance without preconditioning. These findings reveal a previously unknown mechanism of neuroprotection that involves gene repressors of the PcG family.
doi:10.1126/scisignal.2000502
PMCID: PMC3878609  PMID: 20197544
12.  Defective neuropeptide processing and ischemic brain injury: a study on proprotein convertase 2 and its substrate neuropeptide in ischemic brains 
Using a focal cerebral ischemia model in rats, brain ischemia-induced changes in expression levels of mRNA and protein, and activities of proprotein convertase 2 (PC2) in the cortex were examined. In situ hybridization analyses revealed a transient upregulation of the mRNA level for PC2 at an early reperfusion hour, at which the level of PC2 protein was also high as determined by immunocytochemistry and western blotting. When enzymatic activities of PC2 were analyzed using a synthetic substrate, a significant decrease was observed at early reperfusion hours at which levels of PC2 protein were still high. Also decreased at these reperfusion hours were tissue levels of dynorphin-A(1–8) (DYN-A(1–8)), a PC2 substrate, as determined by radioimmunoassay. Further examination of PC2 protein biosynthesis by metabolic labeling in cultured neuronal cells showed that in ischemic cells, the proteolytic processing of PC2 was greatly attenuated. Finally, in mice, an intracerebroventricular administration of synthetic DYN-A(1–8) significantly reduced the extent of ischemic brain injury. In mice those lack an active PC2, exacerbated brain injury was observed after an otherwise non-lethal focal ischemia. We conclude that brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury.
doi:10.1038/jcbfm.2008.161
PMCID: PMC3878611  PMID: 19142196
neuropeptide processing; proprotein convertase 2; dynorphin; brain ischemia; neuroprotection; opioid peptide
13.  Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus 
Gut Microbes  2013;4(1):84-88.
Pathogenic autoinflammatory responses triggered by dysregulated microbial interactions may lead to intestinal disorders and malignancies. Previously, we demonstrated that a lipoteichoic acid (LTA)-deficient Lactobacillus acidophilus strain, NCK2025, ameliorated inflammation-induced colitis, significantly reduced the number of polyps in a colonic polyposis cancer model and restored physiological homeostasis in both cases. Nonetheless, the regulatory signals delivered by NCK2025 to reprogram the gastrointestinal microenvironment, and thus resist colonic cancer progression, remain unknown. Accumulating evidence suggest that epigenetic changes, in the presence and absence of pathogenic inflammation, can result in colorectal cancer (CRC). To test possible epigenetic modifications induced by NCK2025, the expression of epigenetically regulated, CRC-associated genes was measured with and without bacterial treatment. In vivo and in vitro, NCK2025 enhanced the expression of tumor suppressor genes that may regulate CRC development. Therefore, differential epigenetic regulation of CRC-related genes by NCK2025 represents a potential therapy against colitis-associated and sporadic CRC.
doi:10.4161/gmic.22822
PMCID: PMC3555892  PMID: 23137966
colorectal cancer; aberrant epigenetic alterations; DNA methylation; lipoteichoic acid; inflammation
14.  The effects of atmosphere and calcined temperature on photocatalytic activity of TiO2 nanofibers prepared by electrospinning 
Nanoscale Research Letters  2013;8(1):548.
TiO2-based nanofibers were synthesized using a sol–gel method and electrospinning technique. The as-spun composite fibers were heat-treated at different temperatures (500°C, 550°C, 600°C, and 650°C) and atmospheres (ammonia and nitrogen) for 4 h. The fibers had diameters of 50 to 200 nm and mainly featured anatase and rutile phases. The anatase phase decreased and the rutile phase increased with increasing temperature. Different nitrogen conditions exerted minimal effects on the TiO2 crystalline phase. Different nitriding atmospheres during preservation heating yielded various effects on fibers. The effect of nitrogen in ammonia atmosphere is better than that in nitrogen atmosphere. The fibers heat-treated at 600°C and subjected to preservation heating in NH3 showed high photocatalytic activity.
doi:10.1186/1556-276X-8-548
PMCID: PMC3880836  PMID: 24373382
TiO2 nanofibers; Electrospinning; Sol–gel; Photocatalytic activity
15.  Myocardial Scar Identified by Magnetic Resonance Imaging Can Predict Left Ventricular Functional Improvement after Coronary Artery Bypass Grafting 
PLoS ONE  2013;8(12):e81991.
Background
Previous studies have shown that viable myocardium predicts recovery of left ventricular (LV) dysfunction after revascularization. Our aim was to evaluate the prognostic value of myocardial scar assessed by late gadolinium-enhanced cardiovascular magnetic resonance imaging (LGE-CMR) on functional recovery in patients undergoing coronary artery bypass grafting (CABG).
Methods
From November 2009 to September 2012, 63 patients with reduced left ventricular ejection fraction (LVEF) referred for first-time isolated CABG were prospectively enrolled, 52 were included in final analysis. LV functional parameters and scar tissue were assessed by LGE-CMR at baseline and 6 months after surgery. Patency of grafts was evaluated by computed tomography angiography (CTA) 6 months post-CABG. Predictors for global functional recovery were analyzed.
Results
The baseline LVEF was 32.7±9.2%, which improved to 41.6±11.0% 6 months later and 32/52 patients improved LVEF by ≥5%. Multivariate logistic regression analysis showed that the most significant negative predictor for global functional recovery was the number of scar segments (Odds ratio 2.864, 95% Confidence Interval 1.172–6.996, p = 0.021). Receiver-Operator-Characteristic (ROC) analysis demonstrated that ≤4 scar segments predicted global functional recovery with a sensitivity and specificity of 85.0% and 87.5%, respectively (AUC = 0.91, p<0.001). Comparison of ROC curves also indicated that scar tissue was superior to viable myocardium in predicting cardiac functional recovery (p<0.001).
Conclusions
Our findings indicated that scar tissue on LGE-CMR is an independent negative predictor of cardiac functional recovery in patients with impaired LV function undergoing CABG. These observations may be helpful for clinicians and cardiovascular surgeons to determine which patients are most likely to benefit from surgical revascularization.
doi:10.1371/journal.pone.0081991
PMCID: PMC3864907  PMID: 24358136
16.  Restoration of LRIG1 suppresses bladder cancer cell growth by directly targeting EGFR activity 
Background
Recently, leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a negative regulator of EGFR, was discovered is a novel agent for suppressing bladder cancer. The aim of this study was to investigate the impact of LRIG1 on the biological features of aggressive bladder cancer cells and the possible mechanisms of enhanced apoptosis induced by upregulation of LRIG1.
Methods
In this study, we examined the mRNA and protein expression of LRIG1 and EGFR in bladder cancers and normal bladder. Meanwhile, we overexpressed LRIG1 with adenovirus vector in T24/5637 bladder cancer cell lines, and we used real time-PCR, western blot, and co-immunoprecipitation analysis in order to examine the effects of LRIG1 gene on EGFR. Furthermore, we evaluate the impact of LRIG1 gene on the function of human bladder cancer cells and EGFR signaling.
Results
The expression of LRIG1 was decreased, while the expression of EGFR was increased in the majority of bladder cancer, and the ratio of EGFR/LRIG1 was increased in tumors versus normal tissue. We found that upregulation of LRIG1 induced cell apoptosis and cell growth inhibition, and further reversed invasion in bladder cancer cell lines in vitro by inhibiting phosphorylation of downstream MAPK and AKT signaling pathway.
Conclusion
Taken together, our findings provide us with an insight into LRIG1 function, and we conclude that LRIG1 evolved in bladder cancer as a rare feedback negative attenuator of EGFR, thus could offer a novel therapeutic target to treat patients with bladder cancer.
doi:10.1186/1756-9966-32-101
PMCID: PMC3880093  PMID: 24314030
LRIG1; EGFR; Apoptosis; Invasion; Bladder cancer
17.  Inhibition of Increased Circulating Tfh Cell by Anti-CD20 Monoclonal Antibody in Patients with Type 1 Diabetes 
PLoS ONE  2013;8(11):e79858.
Objectives
Follicular helper T (Tfh) cells exert an important role in autoimmune diseases. Whether it might be involved in type 1 diabetes (T1D) is unknown. Our aim was to investigate the role of Tfh cells in patients with T1D and the effect of anti-CD20 monoclonal antibody (rituximab) on Tfh cells from T1D patients.
Patients and Methods
Fifty-four patients with T1D and 37 healthy controls were enrolled in the current study. 20 of those patients were treated with rituximab. The frequencies of circulating CD4+CXCR5+ICOS+T cells were analyzed by flow cytometry. The serum autoantibodies were detected by radioligand assay. The levels of IL-21, IL-6 and BCL-6 were assessed using ELISA and/or real-time PCR.
Results
Increased frequencies of circulating Tfh cells together with enhanced expression of IL-21 were detected in patients. The correlation between the frequencies of circulating Tfh cells and the serum autoantibodies or C-peptide level was comfirmed. After rituximab therapy, follow-up analysis demonstrated that the frequencies of circulating Tfh cell and serum IA2A were decreased. The levels of IL-21, IL-6 and Bcl-6 mRNA were decreased after treatment. Furthermore, beta cell function in 10 of 20 patients was improved.
Conclusions
These data indicate Tfh cells may participate in the T1D-relatede immune responses and B cells might play a role in the development of Tfh responses in the disease progression.
doi:10.1371/journal.pone.0079858
PMCID: PMC3835920  PMID: 24278195
18.  Stereo-selective neuroprotection against stroke with vitamin A derivatives 
Brain research  2008;1241:10.1016/j.brainres.2008.09.020.
In this study we evaluated the neuroprotective potential of vitamin A (all-trans retinol), and its geometric isomers, all-trans retinoic acid and 9-cis retinoic acid, in a focal model of ischemia. A 60 minute middle cerebral artery occlusion in C57 mice resulted in over 50% hemispheric infarction. Vitamin A (retinol) and its derivatives were administered as two i.p. injections immediately prior to and following ischemia. A reduction in infarct volume was observed with all-trans retinol, in a dose dependent manner: maximum protection was observed with a 10 mg/kg dose. A similar protective profile was observed with all-trans retinol, but not the stereoisomer 9-cis retinoic acid. Administration of the derivatives 1 hour following ischemia did not produce significant protection. Taken together these data suggest a possible use of vitamin A derivatives as an acute neuroprotective strategy for stroke.
doi:10.1016/j.brainres.2008.09.020
PMCID: PMC3829682  PMID: 18824156
Retinoid; ischemia; Retinol; C57; stroke
19.  Petrophysical Properties (Density and Magnetization) of Rocks from the Suhbaatar-Ulaanbaatar-Dalandzadgad Geophysical Profile in Mongolia and Their Implications 
The Scientific World Journal  2013;2013:791918.
Petrophysical properties of 585 rock samples from the Suhbaatar-Ulaanbaatar-Dalandzadgad geophysical profile in Mongolia are presented. Based on the rock classifications and tectonic units, petrophysical parameters (bulk density, magnetic susceptibility, intensity of natural remanent magnetization, and Köenigsberger ratio) of these rocks are summarized. Results indicate that (1) significant density contrast of different rocks would result in variable gravity anomalies along the profile; (2) magnetic susceptibility and natural remanent magnetization of all rocks are variable, covering 5-6 orders of magnitude, which would make a variable induced magnetization and further links to complex magnetic anomalies in ground surface; (3) the distribution of rocks with different lithologies controls the pattern of lithospheric magnetic anomaly along the profile. The petrophysical database thus provides not only one of the keys to understand the geological history and structure of the profile, but also essential information for analysis and interpretation of the geophysical (e.g., magnetic and gravity) survey data.
doi:10.1155/2013/791918
PMCID: PMC3842065  PMID: 24324382
20.  PAI-1 -675 4G/5G Polymorphism in Association with Diabetes and Diabetic Complications Susceptibility: a Meta-Analysis Study 
PLoS ONE  2013;8(11):e79150.
A meta-analysis was performed to assess the association between the PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg’s and Egger’s test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes (REM OR 1.07, 95% CI 0.96, 1.20), DN (REM OR 1.10, 95% CI 0.98, 1.25), DR (REM OR 1.09, 95% CI 0.97, 1.22) or diabetic CAD risk (REM OR 1.07, 95% CI 0.81, 1.42), and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies.
doi:10.1371/journal.pone.0079150
PMCID: PMC3818463  PMID: 24223897
21.  Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling 
Journal of neurochemistry  2012;123(Suppl 2):75-85.
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection while less attention has been paid to the cerebrovascular compartment whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain-barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) β mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.
doi:10.1111/j.1471-4159.2012.07946.x
PMCID: PMC3481200  PMID: 23050645
preconditioning; blood-brain barrier; interferon-β; ischemia; stroke
22.  Association of GRM7 Variants with Different Phenotype Patterns of Age-Related Hearing Impairment in an Elderly Male Han Chinese Population 
PLoS ONE  2013;8(10):e77153.
Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age-related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case-control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ‘‘flat shape (FL)’’, ‘‘sloping shape (SL)’’, ‘‘2-4 kHz abrupt loss (AL) shape’’ and ‘‘8 kHz dip (8D) shape’’. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p= 0.000472, OR= 1.599, 95%CI= 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p= 9.41E-05, OR= 1.945, 95%CI= 1.393~2.715; p= 0.000109, OR= 1.915, 95%CI= 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn’t significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns.
doi:10.1371/journal.pone.0077153
PMCID: PMC3795658  PMID: 24146964
23.  The neuroprotective effect of immune serum of adeno-associated virus vaccine containing Aβ1-15 gene on amyloid toxicity 
Objective:
The aim of this study was to explore the effect of adeno-associated virus (AAV) serotype 2 vector vaccine containing amyloid-β peptide (Aβ) 1-15 gene fragment (AAV-Aβ15) immunized mice sera on counteracting Aβ1-42 peptide toxicity towards a primary culture cortical neurons.
Materials and Methods:
BALB/c mice were vaccinated via the intramuscular immunization route with AAV-Aβ15. The anti-Aβ antibody titer of immunized mice sera was quantified by sandwich Enzyme-Linked ImmunoSorbent Assay. The toxicity of Aβ1-42 peptide on neurons was assessed by morphology with an inverse microscopy and cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay.
Results:
AAV-Aβ15 could induce an Aβ-specific immunoglobulin G (IgG) humoral immune response in /c mice the anti-Aβ antibodies were detectable at 1 month after immunization, significantly increased at 2 and 4 months after immunization, and the immunized sera could attenuate cytotoxicity of Aβ1-42 peptide on primary culture cortical neurons.
Conclusions:
The immune serum of AAV-Aβ15 could play a neuroprotective effect against Aβ1-42 peptide toxicity, which would be beneficial for Alzheimer's disease patients.
doi:10.4103/0972-2327.120489
PMCID: PMC3841610  PMID: 24339589
Alzheimer's disease; amyloid-beta; immunotherapy; vaccine
24.  Psychological status and diabetes-related distress of Chinese type 1 diabetes patients in Jiangsu province, China 
Journal of Biomedical Research  2013;27(5):380-385.
We sought to assess the psychological status and diabetes-related distress of Chinese type 1 diabetes patients in Jiangsu province, China. According to the World Health Organization criteria, 42 patients with type 1 diabetes were enrolled in the study and assessed with the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) and Diabetes Distress Scale (DDS). All data were tabulated and statistical analyses were performed. The study summarized cases of 42 patients with type 1 diabetes, including 17 males and 25 females with a mean age of 23±12 years and a mean duration of diabetes of 7±6 years. Compared to the Chinese normative data, the SAS standard score was significantly higher, whereas SDS standard score had no statistical significance. The SAS standard score was most highly correlated with diabetes duration (γ = 0.547, P = 0.011). Additionally, 19.5% of the patients had moderate or even severe diabetes-related distress and 21.4% had moderate or even severe emotional burden while 26.2% had regimen-related distress. Multiple stepwise regression analysis showed that the mean correlation between DDS and the four domains was high, particularly the emotional burden domain (estimated β = 0.363, P < 0.001) and regimen-related distress domain (estimated β = 0.356, P < 0.001). The correlation between SAS and DDS was positive (estimated β = 0.039, P = 0.027). In conclusion, the results showed the importance of psychological aspects in Chinese individuals with type 1 diabetes. Screening and treatment of psychological aspects may result in better adherence and increased quality of life for patients with diabetes.
doi:10.7555/JBR.27.20120112
PMCID: PMC3783823  PMID: 24086171
type 1 diabetes; anxiety; depression; diabetes-related distress
25.  The Organic Cation Transporter, OCTN1, Expressed in the Human Heart, Potentiates Antagonism of the HERG Potassium Channel 
Background
Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.
Methods and Results
Reverse transcriptase–polymerase chain reaction identified expression in the human atrium and ventricle of 14 of 31 candidate drug uptake and efflux transporters, including OCTN1 (SLC22A4), a known uptake transporter of the HERG channel blocker quinidine. In situ hybridization and immunostaining localized OCTN1 expression to cardiomyocytes. The IC50 for quinidine block of IKr in CHO cells transfected with HERG alone was significantly higher than cells transfected with HERG + OCTN1 (0.66 ± 0.15 μM versus 0.14 ± 0.06 μM [52% absolute increase in drug block; 95% confidence interval, 0.4–0.64 μM]), and this effect was further potentiated by a common genetic variant of OCTN1, L503F. In the absence of OCTN1, quinidine block could be 91% ± 5% washed out, but with the transporter, washout was incomplete (57% ± 6%). OCTN1 coexpression also facilitated HERG block by flecainide and ibutilide, but not erythromycin.
Conclusions
Coexpression of the organic cation transporter, OCTN1, expressed in human cardiac myocytes, intensifies quinidine-induced HERG block. These findings establish a critical hypothesis that variable drug transporter activity may be a potential risk factor for torsade de pointes.
doi:10.1097/FJC.0b013e3181abc288
PMCID: PMC3745652  PMID: 19528813
antiarrhythmia agents; arrhythmia; pharmacology; pharmacokinetics; ion channels

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