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1.  Effect of glycemic variability on short term prognosis in acute myocardial infarction subjects undergoing primary percutaneous coronary interventions 
Objective
Glycemic variability (GV) still remains unclear whether acute glycemic excursion has the important prognostic significance in ST-segment elevation myocardial infarction (STEMI) patients undergoing p-PCI. So our aim is to assess the prognostic value of GV in STEMI patients undergoing p-PCI.
Methods
We studied 237 STEMI patients undergoing p-PCI, whose clinical and laboratory data were collected. We used a continuous glucose monitoring system (CGMS) to measure the fluctuations of blood glucose. Participants were grouped into diabetes group and non-diabetes group, and grouped into tertiles of mean amplitude of glycemic excursions (MAGE). The major adverse cardiac events (MACE) of patients was documented during in-hospital and 30-day follow-up. The relationship of MAGE and the incidence of MACE were analyzed.
Results
Data from 237 subjects were incorporated into the statistical analysis, a higher MAGE level was associated with the higher peak CK-MB values (r = 0.374, P <0.01), and the higher peak cTnI values (r = 0.410, P <0.01). The rate of composite MACE by MAGE tertiles (<2.37 mmol/l, 2.37-3.65 mmol/l and >3.65 mmol/l) was 7.5% vs. 14.1% vs. 22.8%, respectively (P = 0.025); STEMI patients with a higher MAGE level had a significantly higher non-IRA revascularization compared with those with lower MAGE levels (32% vs. 15% vs. 21%, P = 0.037). Moreover, diabetic patients with higher MAGE level had significantly higher incidence of composite MACE and non-IRA revascularization, non-diabetic subjects did not show the similar results. In multivariable logistic analysis, the independent predictors of MACE were: MBG, MAGE and LVEF in diabetic subjects and were MBG and MAGE in nondiabetic subjects. Other factors were not significantly associated with MACE.
Conclusions
Greater GV is associated with composite MACE and non-IRA revascularization during in-hospital and 30-day follow-up in unadjusted analyses, especially for diabetic subjects. After multivariable logistic analysis, GV remains an independent prognostic factor for composite MACE in STEMI patients undergoing p-PCI.
doi:10.1186/1758-5996-6-76
PMCID: PMC4091650
Glycemic variability-GV; ST-segment elevation myocardial infarction-STEMI; Primary percutaneous coronary interventions-p-PCI; Mean amplitude of glycemic excursions-MAGE
2.  Complete mitochondrial genome sequences of two parasitic/commensal nemerteans, Gononemertes parasita and Nemertopsis tetraclitophila (Nemertea: Hoplonemertea) 
Parasites & Vectors  2014;7:273.
Background
Most nemerteans (phylum Nemertea) are free-living, but about 50 species are known to be firmly associated with other marine invertebrates. For example, Gononemertes parasita is associated with ascidians, and Nemertopsis tetraclitophila with barnacles. There are 12 complete or near-complete mitochondrial genome (mitogenome) sequences of nemerteans available in GenBank, but no mitogenomes of none free-living nemerteans have been determined so far. In the present paper complete mitogenomes of the above two parasitic/commensal nemerteans are reported.
Methods
The complete mitochondrial genomes (mitogenome) of G. parasita and N. tetraclitophila were amplified by conventional and long PCR. Phylogenetic analyses of maximum likelihood (ML) and Bayesian inference (BI) were performed with both concatenated nucleotide and amino acid sequences.
Results
Complete mitogenomes of G. parasita and N. tetraclitophila are 14742 bp and 14597 bp in size, respectively, which are within the range of published Hoplonemertea mitogenomes. Their gene orders are identical to that of published Hoplonemertea mitogenomes, but different from those of Palaeo- and Heteronemertea species. All the coding genes, as well as major non-coding regions (mNCRs), are AT rich, which is especially pronounced at the third codon position. The AT/GC skew pattern of the coding strand is the same among nemertean mitogenomes, but is variable in the mNCRs. Some slight differences are found between mitogenomes of the present species and other hoplonemerteans: in G. parasita the mNCR is biased toward T and C (contrary to other hoplonemerteans) and the rrnS gene has a unique 58-bp insertion at the 5′ end; in N. tetraclitophila the nad3 gene starts with the ATT codon (ATG in other hoplonemerteans). Phylogenetic analyses of the nucleotide and amino acid datasets show early divergent positions of G. parasita and N. tetraclitophila within the analyzed Distromatonemertea species, and provide strong support for the close relationship between Hoplonemertea and Heteronemertea.
Conclusion
Gene order is highly conserved within the order Monostilifera, particularly within the Distromatonemertea, and the special lifestyle of G. parasita and N. tetraclitophila does not bring significant variations to the overall structures of their mitogenomes in comparison with free-living hoplonemerteans.
doi:10.1186/1756-3305-7-273
PMCID: PMC4081467  PMID: 24946714
Nemertea; Gononemertes parasita; Nemertopsis tetraclitophila; Parasitic/Commensal; Mitochondrial genome; Phylogeny
3.  Folate Intake and the Risk of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Studies 
PLoS ONE  2014;9(6):e100044.
Background
Previous observational studies regarding the existence of an association between folate intake and the risk of breast cancer have been inconsistent. This study aimed to summarize the evidence regarding this relationship using a dose-response meta-analytic approach.
Methodology and Principal Findings
We performed electronic searches of the PubMed, EmBase, and Cochrane Library databases to identify studies published through June 2013. Only prospective observational studies that reported breast cancer effect estimates with 95% confidence intervals (CIs) for more than 2 folate intake categories were included. We excluded traditional case-control studies because of possible bias from various confounding factors. Overall, we included 14 prospective studies that reported data on 677,858 individuals. Folate intake had little effect on the breast cancer risk (relative risk (RR) for highest versus lowest category = 0.97; 95% CI, 0.90–1.05; P = 0.451). Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of breast cancer (RR = 0.99; 95% CI, 0.98–1.01; P = 0.361). Furthermore, we used restricted cubic splines to evaluate the nonlinear relationship between folate intake and the risk of breast cancer, and discovered a potential J-shaped correlation between folate intake and breast cancer risk (P = 0.007) and revealed that a daily folate intake of 200–320 µg was associated with a lower breast cancer risk; however, the breast cancer risk increased significantly with a daily folate intake >400 µg.
Conclusion/Significance
Our study revealed that folate intake had little or no effect on the risk of breast cancer; moreover, a dose-response meta-analysis suggested a J-shaped association between folate intake and breast cancer.
doi:10.1371/journal.pone.0100044
PMCID: PMC4059748  PMID: 24932496
4.  Mouse models uncap novel roles of SSBs 
Cell Research  2013;23(6):744-745.
Three recently published reports, including one in Cell Research, generated Ssb1 knockout mice and demonstrated critical roles of this protein in regulating skeletogenesis, telomere homeostasis and tumor suppression.
doi:10.1038/cr.2013.63
PMCID: PMC3674395  PMID: 23649314
5.  Pre-Clinical Characterization of Dacomitinib (PF-00299804), an Irreversible Pan-ErbB Inhibitor, Combined with Ionizing Radiation for Head and Neck Squamous Cell Carcinoma 
PLoS ONE  2014;9(5):e98557.
Epidermal growth factor receptor (EGFR) is over-expressed in nearly all cases of squamous cell carcinoma of the head and neck (SCCHN), and is an important driver of disease progression. EGFR targeted therapies have demonstrated clinical benefit for SCCHN treatment. In this report, we investigated the pre-clinical efficacy of Dacomitinib (PF-00299804), an irreversible pan-ErbB inhibitor, both alone and in combination with ionizing radiation (IR), a primary curative modality for SCCHN. One normal oral epithelial (NOE) and three SCCHN (FaDu, UT-SCC-8, UT-SCC-42a) cell lines were used to conduct cell viability, clonogenic survival, cell cycle, and immunoblotting assays in vitro, using increasing doses of Dacomitinib (10–500 nM), both with and without IR (2–4 Gy). The FaDu xenograft model was utilized for tumor growth delay assays in vivo, and immunohistochemical analyses were conducted on extracted tumors. A dose-dependent reduction in cell viability and clonogenic survival after Dacomitinib treatment was observed in all three SCCHN models. Treatment led to a significant reduction in EGFR signalling, with a subsequent decrease in phosphorylation of downstream targets such as ERK, AKT, and mTOR. In vivo, Dacomitinib treatment delayed tumor growth, while decreasing phospho-EGFR and Ki-67 immunoexpression. These effects were further enhanced when combined with IR, both in vitro and in vivo. The preclinical data support the further evaluations of Dacomitinib combined with IR for the future management of patients with SCCHN.
doi:10.1371/journal.pone.0098557
PMCID: PMC4031184  PMID: 24853121
6.  1-Cyclo­hexyl-6,7-dimeth­oxy-1,4-di­hydro­naphthalene 
The title compound, C18H24O2, was isolated from the leaves extract of Ficus carica L. The cyclo­hexane ring displays a chair conformation whereas the cyclo­hexa-1,4-diene ring adopts a flattened boat conformation with methyl C atoms at the prow and stern. In the crystal, mol­ecules are linked by weak C—H⋯O hydrogen bonds into supra­molecular chains propagated along the b-axis direction.
doi:10.1107/S1600536814010204
PMCID: PMC4051087  PMID: 24940252
7.  A Novel DFNA36 Mutation in TMC1 Orthologous to the Beethoven (Bth) Mouse Associated with Autosomal Dominant Hearing Loss in a Chinese Family 
PLoS ONE  2014;9(5):e97064.
Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.
doi:10.1371/journal.pone.0097064
PMCID: PMC4020765  PMID: 24827932
8.  A novel model of double replications and random loss accounts for rearrangements in the Mitogenome of Samariscus latus (Teleostei: Pleuronectiformes) 
BMC Genomics  2014;15(1):352.
Background
Although more than one thousand complete mitochondrial DNA (mtDNA) sequences have been determined in teleostean fishes, only a few gene rearrangements have been observed, and genome-scale rearrangements are even rarer. However, flatfishes (Pleuronectiformes) have been identified as having diverse types of mitochondrial gene rearrangements. It has been reported that tongue soles and the blue flounder mitogenomes exhibit different types of large-scale gene rearrangements.
Results
In the present study, the complete mitochondrial genome of another flatfish, Samariscus latus, was sequenced, and genome-scale rearrangements were observed. The genomic features of this flounder are different from those of any other studied vertebrates, including flatfish species too. The mitogenome of S. latus is characterized by the duplication and translocation of the control region (CR). The genes located between the two CRs are divided into two clusters in which their relative orders are maintained.
Conclusions
We propose a “Double Replications and Random Loss” model to explain the rearrangement events in S. latus mitogenome. This model consists of the following steps. First, the CR was duplicated and translocated. Subsequently, double replications of the mitogenome were successively initiated from the two CRs, leading to the duplication of the genes between the two CRs. Finally, one of each pair of duplicated genes was lost in a random event.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-352) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-352
PMCID: PMC4035078  PMID: 24885702
Flatfish; Flounder; Mitochondrial recombination; Gene order; Molecular rvolution
9.  Fusarium keratitis: genotyping, in vitro susceptibility and clinical outcomes 
Cornea  2013;32(5):667-673.
Purpose
To determine differences in the clinical characteristics and antifungal susceptibility patterns among molecularly characterized ocular Fusarium sp isolates.
Methods
58 Fusarium isolates obtained from 52 eyes of 52 patients were retrieved from the Bascom Palmer Eye Institute’s (BPEI) ocular microbiology laboratory and grown in pure culture. These isolates were characterized based on DNA sequence analysis of the ITS1/2 and rDNA regions. Antifungal susceptibilities were determined for each isolate using broth microdilution methods and the corresponding medical records were reviewed to determine clinical outcomes.
Results
Fusarium (F.) solani isolates had significantly higher voriconazole MIC90 values than F. non-solani organisms (16 and 4ug/ml, respectively). F. solani isolates also exhibited a significantly longer time to cure (65 vs 40.5 days), a worse follow up BCVA (20/118 vs 20/36), and increased need for urgent surgical management (7 vs 0 penetrating keratoplasties) when compared to F. non-solani isolates.
Conclusions
This is the first report to examine the correlation between ocular genotyped Fusarium species and clinical outcomes. It supports the overall worse prognosis for F. solani versus F. non-solani isolates, including higher voriconazole resistance by the former. The clinical implementation of molecular-based diagnostics and antifungal efficacy testing, may yield important prognostic and therapeutic information that could improve the management of fungal ocular infections.
doi:10.1097/ICO.0b013e318277ac74
PMCID: PMC3622819  PMID: 23343947
keratitis; Fusarium sp; genotyping; antifungal; clinical outcomes
10.  Molecular Diagnosis of Putative Stargardt Disease by Capture Next Generation Sequencing 
PLoS ONE  2014;9(4):e95528.
Stargardt Disease (STGD) is the commonest genetic form of juvenile or early adult onset macular degeneration, which is a genetically heterogeneous disease. Molecular diagnosis of STGD remains a challenge in a significant proportion of cases. To address this, seven patients from five putative STGD families were recruited. We performed capture next generation sequencing (CNGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Seven disease-causing mutations in ABCA4 and two in PROM1 were identified by CNGS, which provides a confident genetic diagnosis in these five families. We also provided a genetic basis to explain the differences among putative STGD due to various mutations in different genes. Meanwhile, we show for the first time that compound heterozygous mutations in PROM1 gene could cause cone-rod dystrophy. Our findings support the enormous potential of CNGS in putative STGD molecular diagnosis.
doi:10.1371/journal.pone.0095528
PMCID: PMC3999032  PMID: 24763286
11.  Use of Targeted Exome Sequencing in Genetic Diagnosis of Chinese Familial Hypercholesterolemia 
PLoS ONE  2014;9(4):e94697.
Familial hypercholesterolemia is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is mainly caused by mutations of the low-density lipoprotein receptor (LDLR) gene. Currently, the methods of whole genome sequencing or whole exome sequencing for screening mutations in familial hypercholesterolemia are not applicable in China due to high cost. We performed targeted exome sequencing of 167 genes implicated in the homozygous phenotype of a proband pedigree to identify candidate mutations, validated them in the family of the proband, studied the functions of the mutant protein, and followed up serum lipid levels after treatment. We discovered that exon 9 c.1268 T>C and exon 8 c.1129 T>G compound heterozygous mutations in the LDLR gene in the proband derived from the mother and father, respectively, in which the mutation of c.1129 T>G has not been reported previously. The mutant LDL-R protein had 57% and 52% binding and internalization functions, respectively, compared with that of the wild type. After 6 months of therapy, the LDL-C level of the proband decreased by more than 50% and the LDL-C of the other family members with heterozygous mutation also reduced to normal. Targeted exome sequencing is an effective method for screening mutation genes in familial hypercholesterolemia. The exon 8 and 9 mutations of the LDLR gene were pedigree mutations. The functions of the mutant LDL-R protein were decreased significantly compared with that of the wild type. Simvastatin plus ezetimibe was proven safe and effective in this preschool-age child.
doi:10.1371/journal.pone.0094697
PMCID: PMC3983231  PMID: 24722143
12.  Pu-Erh Tea Extract Induces the Degradation of FET Family Proteins Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis 
BioMed Research International  2014;2014:254680.
FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.
doi:10.1155/2014/254680
PMCID: PMC3997874  PMID: 24804206
13.  Activation of Synaptic Group II Metabotropic Glutamate Receptors Induces Long-Term Depression at GABAergic Synapses in CNS Neurons 
The Journal of Neuroscience  2013;33(40):15964-15977.
Metabotropic glutamate receptor (mGluR)-dependent homosynaptic long-term depression (LTD) has been studied extensively at glutamatergic synapses in the CNS. However, much less is known about heterosynaptic long-term plasticity induced by mGluRs at inhibitory synapses. Here we report that pharmacological or synaptic activation of group II mGluRs (mGluR II) induces LTD at GABAergic synapses without affecting the excitatory glutamatergic transmission in neurons of the chicken cochlear nucleus. Coefficient of variation and failure rate analysis suggested that the LTD was expressed presynaptically. The LTD requires presynaptic spike activity, but does not require the activation of NMDA receptors. The classic cAMP-dependent protein kinase A signaling is involved in the transduction pathway. Remarkably, blocking mGluR II increased spontaneous GABA release, indicating the presence of tonic activation of mGluR II by ambient glutamate. Furthermore, synaptically released glutamate induced by electrical stimulations that concurrently activated both the glutamatergic and GABAergic pathways resulted in significant and constant suppression of GABA release at various stimulus frequencies (3.3, 100, and 300 Hz). Strikingly, low-frequency stimulation (1 Hz, 15 min) of the glutamatergic synapses induced heterosynaptic LTD of GABAergic transmission, and the LTD was blocked by mGluR II antagonist, indicating that synaptic activation of mGluR II induced the LTD. This novel form of long-term plasticity in the avian auditory brainstem may play a role in the development as well as in temporal processing in the sound localization circuit.
doi:10.1523/JNEUROSCI.0202-13.2013
PMCID: PMC3787505  PMID: 24089501
14.  Spray-coated nanoscale conductive patterns based on in situ sintered silver nanoparticle inks 
Nanoscale Research Letters  2014;9(1):145.
Nanoscale patterns with high conductivity based on silver nanoparticle inks were fabricated using spray coating method. Through optimizing the solution content and spray operation, accurate nanoscale patterns consisting of silver nanoparticles with a square resistance lower than 1 Ω /cm2 were obtained. By incorporating in situ sintering to substitute the general post sintering process, the time consumption could be significantly reduced to one sixth, qualifying it for large-scale and cost-effective fabrication of printed electronics. To testify the application of spray-coated silver nanoparticle inks, an inverted polymer solar cell was also fabricated, which exhibited a power conversion efficiency of 2.76%.
doi:10.1186/1556-276X-9-145
PMCID: PMC3986943  PMID: 24666992
Spray coating; Conductive pattern; Silver nanoparticle ink; Inverted polymer solar cell; In situ sintering process
15.  Molecular Determinants of Lung Development 
Development of the pulmonary system is essential for terrestrial life. The molecular pathways that regulate this complex process are beginning to be defined, and such knowledge is critical to our understanding of congenital and acquired lung diseases. A recent workshop was convened by the National Heart, Lung, and Blood Institute to discuss the developmental principles that regulate the formation of the pulmonary system. Emerging evidence suggests that key developmental pathways not only regulate proper formation of the pulmonary system but are also reactivated upon postnatal injury and repair and in the pathogenesis of human lung diseases. Molecular understanding of early lung development has also led to new advances in areas such as generation of lung epithelium from pluripotent stem cells. The workshop was organized into four different topics, including early lung cell fate and morphogenesis, mechanisms of lung cell differentiation, tissue interactions in lung development, and environmental impact on early lung development. Critical points were raised, including the importance of epigenetic regulation of lung gene expression, the dearth of knowledge on important mesenchymal lineages within the lung, and the interaction between the developing pulmonary and cardiovascular system. This manuscript describes the summary of the discussion along with general recommendations to overcome the gaps in knowledge in lung developmental biology.
doi:10.1513/AnnalsATS.201207-036OT
PMCID: PMC3955361  PMID: 23607856
lung development; lung cell fate; lung cell differentiation; tissue interaction; environmental impact
16.  Post-Impact Fatigue Damage Monitoring Using Fiber Bragg Grating Sensors 
Sensors (Basel, Switzerland)  2014;14(3):4144-4153.
It has been shown that impact damage to composite materials can be revealed by embedded Fiber Bragg Gratings (FBG) as a broadening and splitting of the latter's characteristic narrow peak reflected spectrum. The current work further subjected the impact damaged composite to cyclic loading and found that the FBG spectrum gradually submerged into a rise of background intensity as internal damages progressed. By skipping the impact, directing the impact to positions away from the FBG and examining the extracted fibers, we concluded that the above change is not a result of deterioration/damage of the sensor. It is caused solely by the damages initiated in the composite by the impact and aggravated by fatigue loading. Evolution of the grating spectrum may therefore be used to monitor qualitatively the development of the incurred damages.
doi:10.3390/s140304144
PMCID: PMC4003935  PMID: 24594609
fatigue; impact damage; polymer-matrix composites; health monitoring; fiber Bragg grating
17.  Targeting Aerobic Glycolysis and HIF-1α Expression Enhance Imiquimod-induced Apoptosis in Cancer Cells 
Oncotarget  2014;5(5):1363-1381.
Tumor cells rely on aerobic glycolysis to maintain unconstrained cell growth and proliferation. Imiquimod (IMQ), a synthetic Toll-like receptor (TLR) 7/8 ligand, exerts anti-tumor effects directly by inducing cell death in cancer cells and/or indirectly by activating cellular immune responses against tumor cells. However, whether IMQ modulates glucose metabolism pathways remains unclear. In this study, we demonstrated that IMQ can enhance aerobic glycolysis by up-regulating HIF-1α expression at the transcriptional and translational levels via ROS mediated STAT3- and Akt-dependent pathways, independent of TLR7/8 signaling. The genetic silencing of HIF-1α not only repressed IMQ-induced aerobic glycolysis but also sensitized cells to IMQ-induced apoptosis due to faster ATP and Mcl-1 depletion. Moreover, the glucose analog 2-DG and the Hsp90 inhibitor 17-AAG, which destabilizes the HIF-1α protein, synergized with IMQ to induce tumor cell apoptosis in vitro and significantly inhibited tumor growth in vivo. Thus, we hypothesize that the IMQ-induced up-regulation of HIF-1α and aerobic glycolysis is a protective response to the metabolic stress generated by IMQ treatment, and thus, co-treatment with inhibitors of HIF-1α and/or glycolysis may be a useful therapeutic strategy to enhance the anti-tumor effects of IMQ in clinical settings.
PMCID: PMC4012728  PMID: 24658058
imiquimod; aerobic glycolysis; HIF-1α; apoptosis
18.  Pseudo-ischaemic ECG in a patient with amyotrophic lateral sclerosis surviving for a decade 
BMJ Case Reports  2012;2012:bcr0120125543.
A 58-year-old female with no history of heart disease was admitted to our hospital for abnormal ECG mimicking myocardial ischaemia. The ECG revealed persistent T-wave inversion in almost all leads, especially in precordial leads V2–V6. The patient had no complaints of chest pain, chest distress, short of breath or other atypical myocardial ischaemia symptoms. She had a history of amyotrophic lateral sclerosis (ALS) with a disease course more than 20 years. Examinations help rule out other diseases causing persistent T-wave inversion. Importantly, cardiac catheterisation showed nearly normal coronary arteries that could rule out myocardial ischaemia. Accordingly, the authors presumed that the pseudo-ischaemic ECG was associated with ALS in this patient. The findings of the present case provide new evidence that autonomic nervous system may involve in the pathophysiological progress of ALS.
doi:10.1136/bcr.01.2012.5543
PMCID: PMC3291013  PMID: 22665549
19.  Prognostic performance of a series of model for end-stage liver disease and respective Δ scores in patients with hepatitis B acute-on-chronic liver failure 
Molecular Medicine Reports  2014;9(5):1559-1568.
The present study aimed to compare the short-term prognostic performance of a series of model for end-stage liver disease (MELD) and respective delta (Δ) scores scoring systems in a population with acute-on-chronic hepatitis B liver failure (ACHBLF), and to investigate the potential effects from antivirals. A total of 77 patients with ACHBLF of mean age 46 years, 82% male, with 58.4% receiving antivirals, were recruited for this study. The Δ scores for MELDs were defined as the changes one week after admission. Thirty-eight (49%) patients (22 treated with antivirals) died within three months. The mean MELD and ΔMELD scores of the survival group were 19.5±4.4 and 0.2±3.7 respectively, and those of the mortality group were 23.5±5.5 and 7.9±6, respectively. The area under the receiver operating characteristic curve (AUC) for MELD, integrated MELD (iMELD), MELD with the addition of serum sodium (MELD-Na), updated MELD (upMELD), MELD excluding the international normalized ratio (INR; MELD-XI), United Kingdom MELD (UKMELD) and their Δ scores were 0.72, 0.81, 0.77, 0.69, 0.65, 0.77 and 0.86, 0.83, 0.83, 0.82, 0.79 and 0.79, respectively. iMELD and MELD-Na significantly improved the accuracy of MELD (P<0.05). A cut-off value of 41.5 for the iMELD score can prognose 71% of mortalities with a specificity of 85%. In each pair of models, the Δ score was superior to its counterpart, particularly when applied to patients with MELD ≤30. Decreased accuracy was observed for all models in the subset of patients treated with antivirals, although their baseline characteristics were comparable to those of untreated patients, while iMELD, MELD-Na and respective Δ models remained superior with regard to the predictability. The iMELD and MELD-Na models predicted three-month mortality more accurately, while the Δ models were superior to their counterparts when MELD ≤30; however, their performance was altered by antivirals, and thus requires optimization.
doi:10.3892/mmr.2014.1983
PMCID: PMC4020485  PMID: 24573151
acute-on-chronic liver failure; hepatitis B; models for end-stage liver disease; Δ score; prognosis
20.  Effect of Quanzhenyiqitang on apoptosis of alveolar macrophages and expression of histone deacetylase 2 in rats with chronic obstructive pulmonary disease 
This study aimed to investigate the effect of Quanzhenyiqitang on alveolar macrophages (AMs) in a rat model of chronic obstructive pulmonary disease (COPD). In addition, the induction of apoptosis and regulation of histone deacetylase 2 (HDAC2) was studied to elucidate the underlying mechanisms of Quanzhenyiqitang treatment of COPD. Quanzhenyiqitang-treated serum was applied to AMs obtained from rats with COPD. A blank (control) group, an untreated serum group and an aminophylline group were also observed to evaluate the differences in AM apoptosis status, as well as the expression levels of caspase-9, caspase-8 and HDAC2. Compared with the control group, Quanzhenyiqitang-treated serum resulted in higher levels of caspase-9 and caspase-8 expression, increased apoptosis of AMs and increased expression of HDAC2 by AMs. In conclusion, Quanzhenyiqitang is capable of inducing apoptosis of AMs, which are the primary inflammatory cells in COPD, and modulating the expression of the important inflammatory factor HDAC2, producing an overall anti-inflammatory effect.
doi:10.3892/etm.2014.1585
PMCID: PMC3991511  PMID: 24940433
chronic obstructive pulmonary disease; alveolar macrophage; Quanzhenyiqitang
21.  Oocytes with a Dark Zona Pellucida Demonstrate Lower Fertilization, Implantation and Clinical Pregnancy Rates in IVF/ICSI Cycles 
PLoS ONE  2014;9(2):e89409.
The morphological assessment of oocytes is important for embryologists to identify and select MII oocytes in IVF/ICSI cycles. Dysmorphism of oocytes decreases viability and the developmental potential of oocytes as well as the clinical pregnancy rate. Several reports have suggested that oocytes with a dark zona pellucida (DZP) correlate with the outcome of IVF treatment. However, the effect of DZP on oocyte quality, fertilization, implantation, and pregnancy outcome were not investigated in detail. In this study, a retrospective analysis was performed in 268 infertile patients with fallopian tube obstruction and/or male factor infertility. In 204 of these patients, all oocytes were surrounded by a normal zona pellucida (NZP, control group), whereas 46 patients were found to have part of their retrieved oocytes enclosed by NZP and the other by DZP (Group A). In addition, all oocytes enclosed by DZP were retrieved from 18 patients (Group B). No differences were detected between the control and group A. Compared to the control group, the rates of fertilization, good quality embryos, implantation and clinical pregnancy were significantly decreased in group B. Furthermore, mitochondria in oocytes with a DZP in both of the two study groups (A and B) were severely damaged with several ultrastructural alterations, which were associated with an increased density of the zona pellucida and vacuolization. Briefly, oocytes with a DZP affected the clinical outcome in IVF/ICSI cycles and appeared to contain more ultrastructural alterations. Thus, DZP could be used as a potential selective marker for embryologists during daily laboratory work.
doi:10.1371/journal.pone.0089409
PMCID: PMC3933533  PMID: 24586757
22.  CXCR4 Inhibition Ameliorates Severe Obliterative Pulmonary Hypertension and Accumulation of C-Kit+ Cells in Rats 
PLoS ONE  2014;9(2):e89810.
Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit+ cells and severe pulmonary arterial hypertension. We detected c-kit+­ cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit+ α-smooth muscle actin+ cells and pulmonary arterial muscularization and did not affect c-kit+ von Willebrand Factor+ cell numbers. Both c-kit+ cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit+ α-smooth muscle actin+ cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit+ von Willebrand Factor+ cells is largely independent of CXC chemokine receptor 4.
doi:10.1371/journal.pone.0089810
PMCID: PMC3933653  PMID: 24587052
23.  Analysis of Notch Signaling-Dependent Gene Expression in Developing Airways Reveals Diversity of Clara Cells 
PLoS ONE  2014;9(2):e88848.
Clara cells (CCs) are a morphologically and operationally heterogeneous population of Secretoglobin Scgb1a1-expressing secretory cells that are crucial for airway homeostasis and post-injury repair. Analysis of the extent and origin of CC diversity are limited by knowledge of genes expressed in these cells and their precursors. To identify novel putative markers of CCs and explore the origins of CC diversity, we characterized global changes in gene expression in embryonic lungs in which CCs do not form due to conditional disruption of Notch signaling (RbpjkCNULL). Microarray profiling, Real Time PCR (qRT-PCR), and RNA in situ hybridization (ISH) identified eleven genes downregulated in the E18.5 airways of Rbpjkcnull compared to controls, nearly half not previously known to mark CCs. ISH revealed that several genes had overlapping but distinct domains of expression of in the normal developing lung (E18.5). Notably, Reg3g, Chad, Gabrp and Lrrc26 were enriched in proximal airways, Hp in the distal airways and Upk3a in clusters of cells surrounding Neuroepithelial Bodies (NEBs). Seven of the eleven genes, including Reg3g, Hp, and Upk3a, were expressed in the adult lung in CCs in a pattern similar to that observed in the developing airways. qRT-PCR-based analysis of gene expression of CCs isolated from different airway regions of B1-EGFP reporter mice corroborated the spatial enrichment in gene expression observed by ISH. Our study identifies candidate markers for CC-precursors and CCs and supports the idea that the diversification of the CC phenotype occurs already during embryonic development.
doi:10.1371/journal.pone.0088848
PMCID: PMC3931645  PMID: 24586412
24.  Factors Associated with Impairment of Quadriceps Muscle Function in Chinese Patients with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2014;9(2):e84167.
Background
Quadriceps muscle dysfunction is well confirmed in chronic obstructive pulmonary disease (COPD) and reported to be related to a higher risk of mortality. Factors contributing to quadriceps dysfunction have been postulated, while not one alone could fully explain it and there are few reports on it in China. This study was aimed to investigate the severity of quadriceps dysfunction in patients with COPD, and to compare quadriceps muscle function in COPD and the healthy elderly.
Methods
Quadriceps strength and endurance capabilities were investigated in 71 COPD patients and 60 age-matched controls; predicted values for quadriceps strength and endurance were calculated using regression equations (incorporating age, gender, anthropometric measurements and physical activities), based on the data from controls. Potential parameters related to quadriceps dysfunction in COPD were identified by stepwise regression analysis.
Results
Mean values of quadriceps strength was 46% and endurance was 38% lower, in patients with COPD relative to controls. Gender, physical activities and anthropometric measurements were predictors to quadriceps function in the controls. While in COPD, forced expiratory volume in 1 second percentage of predicted value (FEV1% pred), nutritional depletion, gender and physical inactivity were identified as independent factors to quadriceps strength (R2 = 0.72); FEV1%pred, thigh muscle mass, serum levels of tumor necrosis factor-alpha (TNF-α) and gender were correlated to quadriceps endurance variance, with each p<0.05.
Conclusion
Quadriceps strength and endurance capabilities are both substantially impaired in Chinese COPD patients, with strength most affected. For the controls, physical activity is most important for quadriceps function. While for COPD patients, quadriceps dysfunction is related to multiple factors, with airflow limitation, malnutrition and muscle disuse being the main ones.
doi:10.1371/journal.pone.0084167
PMCID: PMC3928035  PMID: 24558357
25.  The Untranslated Regions of Classic Swine Fever Virus RNA Trigger Apoptosis 
PLoS ONE  2014;9(2):e88863.
Classical swine fever virus (CSFV) causes a broad range of disease in pigs, from acute symptoms including high fever and hemorrhages, to chronic disease or unapparent infection, depending on the virus strain. CSFV belongs to the genus Pestivirus of the family Flaviviridae. It carries a single-stranded positive-sense RNA genome. An internal ribosomal entry site (IRES) in the 5′ untranslated region (UTR) drives the translation of a single open reading frame encoding a 3898 amino acid long polypeptide chain. The open reading frame is followed by a 3′ UTR comprising four highly structured stem-loops. In the present study, a synthetic RNA composed of the 5′ and 3′ UTRs of the CSFV genome devoid of any viral coding sequence and separated by a luciferase gene cassette (designated 5′UTR-Luc-3′UTR) triggered apoptotic cell death as early as 4 h post-transfection. The apoptosis was measured by DNA laddering analysis, TUNEL assay, annexin-V binding determined by flow cytometry, and by analysis of caspase activation. Contrasting with this, only trace DNA laddering was observed in cells transfected with the individual 5′ or 3′ UTR RNA; even when the 5′ UTR and 3′ UTR were co-transfected as separate RNA molecules, DNA laddering did not reach the level induced by the chimeric 5′UTR-Luc-3′UTR RNA. Interestingly, RNA composed of the 5′UTR and of stem-loop I of the 3′UTR triggered much stronger apoptosis than the 5′ or 3′UTR alone. These results indicate that the 5′ and 3′ UTRs act together in cis induce apoptosis. We furthered obtained evidence that the UTR-mediated apoptosis required double-stranded RNA and involved translation shutoff possibly through activation of PKR.
doi:10.1371/journal.pone.0088863
PMCID: PMC3923050  PMID: 24533157

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