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1.  Critical Role of Toll-Like Receptor 9 in Morphine and Mycobacterium tuberculosis–Induced Apoptosis in Mice 
PLoS ONE  2010;5(2):e9205.
Background
Although it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive.
Methodology/Principal Findings
We report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-α, IL-1β, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3β in the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3β in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration.
Conclusions/Significance
These data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.
doi:10.1371/journal.pone.0009205
PMCID: PMC2824811  PMID: 20174568
2.  A Nation-Wide Multicenter 10-Year (1999-2008) Retrospective Clinical Study of Endocrine Therapy for Chinese Females with Breast Cancer 
PLoS ONE  2014;9(7):e100159.
Endocrine therapy (ET) is one of the main systemic treatments for patients with breast cancer. To our knowledge, few studies have addressed the performance of ET or relevant influencing factors in cancer treatment in China. By retrospectively analyzing the clinicopathological data on breast cancer collected from representative hospitals of 7 traditional areas in China in one random month from each year between year 1999 and 2008, we found that: 1) The rate of the use of hormone receptor (HR) testing was 83.8% (3529/4211), with the estrogen receptor-positive (ER+) rate and/or the progesterone receptor-positive (PR+) rate being 67.9% (2395/3529), and the ER-PR rate being 32.1% (1134/3529). 2) Of the 1599 patients who had received ET, 999 patients (58.3%) were premenopausal while 600 (41.7%) were postmenopausal; 1598 patients received adjuvant hormonal therapy (AHT), whereas only 1 patient received palliative therapy. The medications mainly administered to patients were anti-estrogen agents (80.3% [1283/1598]), followed by AIs (15.5% [248/1598]). Of the 1598 patients receiving AHT, 1416 patients (88.6%) were positive for ER and/or PR, while 75 (4.7%) were negative for both and 108 patients (6.7%) had unknown HR status. The ratio of the use of endocrine therapy for breast cancer patients with ER+ and/or PR+ status was 60.0% (1416/2395). 3) Results from the logistic regression analysis revealed that geography, occupations, and history of chemotherapy and surgery were dependent factors affecting the application of ET in breast cancer treatment in China (P<0.001). In conclusion, the use of ET on Chinese women with breast cancer is increasingly and gradually accounted into the standardized process. Economic status, occupations, and history of chemotherapy and surgery were key factors affecting the application of ET. People residing in developed areas, engaging in mental labour, having history of chemotherapy and surgery are susceptible to accept ET.
doi:10.1371/journal.pone.0100159
PMCID: PMC4103779  PMID: 25036532
3.  Reversion and T Cell Escape Mutations Compensate the Fitness Loss of a CD8+ T Cell Escape Mutant in Their Cognate Transmitted/Founder Virus 
PLoS ONE  2014;9(7):e102734.
Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity.
doi:10.1371/journal.pone.0102734
PMCID: PMC4100905  PMID: 25028937
4.  Salvage of Failed Protein Targets by Reductive Alkylation 
The growth of diffraction-quality single crystals is of primary importance in protein X-ray crystallography. Chemical modification of proteins can alter their surface properties and crystallization behavior. The Midwest Center for Structural Genomics (MCSG) has previously reported how reductive methylation of lysine residues in proteins can improve crystallization of unique proteins that initially failed to produce diffraction-quality crystals. Recently, this approach has been expanded to include ethylation and isopropylation in the MCSG protein crystallization pipeline. Applying standard methods, 180 unique proteins were alkylated and screened using standard crystallization procedures. Crystal structures of 12 new proteins were determined, including the first ethylated and the first isopropylated protein structures. In a few cases, the structures of native and methylated or ethylated states were obtained and the impact of reductive alkylation of lysine residues was assessed. Reductive methylation tends to be more efficient and produces the most alkylated protein structures. Structures of methylated proteins typically have higher resolution limits. A number of well-ordered alkylated lysine residues have been identified, which make both intermolecular and intramolecular contacts. The previous report is updated and complemented with the following new data; a description of a detailed alkylation protocol with results, structural features, and roles of alkylated lysine residues in protein crystals. These contribute to improved crystallization properties of some proteins.
doi:10.1007/978-1-4939-0354-2_15
PMCID: PMC4078742  PMID: 24590719
Chemical modification; Lysine reductive alkylation; Methylation; Ethylation; Isopropylation; Protein crystallization
5.  Signaling in Pollen Tube Growth: Crosstalk, Feedback, and Missing Links 
Molecular Plant  2013;6(4):1053-1064.
SUMMARY
Pollen tubes represent an attractive model system to investigate polarized cell growth. We will discuss the current state of play of knowledge of the regulatory roles of signaling networks in the cellular activities of the pollen tube tip.
Pollen tubes elongate rapidly at their tips through highly polarized cell growth known as tip growth. Tip growth requires intensive exocytosis at the tip, which is supported by a dynamic cytoskeleton and vesicle trafficking. Several signaling pathways have been demonstrated to coordinate pollen tube growth by regulating cellular activities such as actin dynamics, exocytosis, and endocytosis. These signaling pathways crosstalk to form a signaling network that coordinates the cellular processes required for tip growth. The homeostasis of key signaling molecules is critical for the proper elongation of the pollen tube tip, and is commonly fine-tuned by positive and negative regulations. In addition to the major signaling pathways, emerging evidence implies the roles of other signals in the regulation of pollen tube growth. Here we review and discuss how these signaling networks modulate the rapid growth of pollen tubes.
doi:10.1093/mp/sst070
PMCID: PMC3842152  PMID: 23873928
polarity; pollen development; reproductive biology; signal transduction.
6.  Meta-Analysis of the Adverse Effects of Long-Term Azithromycin Use in Patients with Chronic Lung Diseases 
The adverse effects of azithromycin on the treatment of patients with chronic lung diseases (CLD) were evaluated in the present study. MEDLINE and other databases were searched for relevant articles published until August 2013. Randomized controlled trials that enrolled patients with chronic lung diseases who received long-term azithromycin treatment were selected, and data on microbiological studies and azithromycin-related adverse events were abstracted from articles and analyzed. Six studies were included in the meta-analysis. The risk of bacterial resistance in patients receiving long-term azithromycin treatment was increased 2.7-fold (risk ratio [RR], 2.69 [95% confidence interval {95% CI}, 1.249, 5.211]) compared with the risk in patients receiving placebo treatment. On the other hand, the risk of bacterial colonization decreased in patients receiving azithromycin treatment (RR, 0.551 [95% CI, 0.460, 0.658]). Patients receiving long-term azithromycin therapy were at risk of increased impairment of hearing (RR, 1.168 [95% CI, 1.030, 1.325]). This analysis provides evidence supporting the idea that bacterial resistance can develop with long-term azithromycin treatment. Besides the increasingly recognized anti-inflammatory role of azithromycin used in treating chronic lung diseases, we should be aware of the potential for adverse events with its long-term use.
doi:10.1128/AAC.02067-13
PMCID: PMC3910718  PMID: 24189261
7.  Prognosis of non-small cell lung cancer patients with bone oligometastases treated concurrently with thoracic three-dimensional radiotherapy and chemotherapy 
Background
To evaluate the efficacy of three-dimensional radiotherapy for non-small cell lung cancer (NSCLC) patients with bone metastases.
Methods
Clinical data for 95 NSCLC patients with bone metastases were collected and prognostic factors were analyzed. All patients received radiation to their thoracic primary tumor and ≥2 cycles of chemotherapy.
Results
Of these 95 patients, 47 patients had only bone metastases and 48 had both bone metastases and other organ metastases. Univariate analysis showed that factors that statistically significantly contributed to patients having longer overall survival (OS) included receiving a radiation dose to the primary tumor ≥63 Gy, responding to treatment and receiving ≥4 cycles of chemotherapy (p = 0.001, p = 0.037 and p = 0.009, respectively). A radiation dose to the primary tumor ≥63 Gy remained significant for patients with bone metastases only as well as those with bone and other organ metastases when they were analyzed separately (p = 0.045 and p = 0.012, respectively). For patients with bone metastases only, those with T1-2 tumors had longer OS than those with T3-4 (p = 0.048); and patients who received ≥4 cycles chemotherapy compared with those who received <4 cycles had similar OS (p = 0.385). On multivariate analysis, only a radiation dose ≥63 Gy (p = 0.028) and having only bone metastases (p = 0.006) were independent prognostic factors for better OS.
Conclusions
A radiation dose to the primary tumor ≥63 Gy and having only bone metastases were associated with better OS in NSCLC patients with bone metastases. For patients with bone metastases only, besides radiation dose, T status was also correlated with OS, whereas the number of chemotherapy cycles was not. Therefore, aggressive thoracic radiation may play an important role in improving OS.
doi:10.1186/1748-717X-9-147
PMCID: PMC4082286  PMID: 24962716
Non-small Cell Lung Cancer; Bone Metastases; Thoracic Radiotherapy; Chemotherapy
8.  Detection of genome-wide copy number variations in two chicken lines divergently selected for abdominal fat content 
BMC Genomics  2014;15(1):517.
Background
The chicken (Gallus gallus) is an important model organism that bridges the evolutionary gap between mammals and other vertebrates. Copy number variations (CNVs) are a form of genomic structural variation widely distributed in the genome. CNV analysis has recently gained greater attention and momentum, as the identification of CNVs can contribute to a better understanding of traits important to both humans and other animals. To detect chicken CNVs, we genotyped 475 animals derived from two broiler chicken lines divergently selected for abdominal fat content using chicken 60 K SNP array, which is a high-throughput method widely used in chicken genomics studies.
Results
Using PennCNV algorithm, we detected 438 and 291 CNVs in the lean and fat lines, respectively, corresponding to 271 and 188 CNV regions (CNVRs), which were obtained by merging overlapping CNVs. Out of these CNVRs, 99% were confirmed also by the CNVPartition program. These CNVRs covered 40.26 and 30.60 Mb of the chicken genome in the lean and fat lines, respectively. Moreover, CNVRs included 176 loss, 68 gain and 27 both (i.e. loss and gain within the same region) events in the lean line, and 143 loss, 25 gain and 20 both events in the fat line. Ten CNVRs were chosen for the validation experiment using qPCR method, and all of them were confirmed in at least one qPCR assay. We found a total of 886 genes located within these CNVRs, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed they could play various roles in a number of biological processes. Integrating the results of CNVRs, known quantitative trait loci (QTL) and selective sweeps for abdominal fat content suggested that some genes (including SLC9A3, GNAL, SPOCK3, ANXA10, HELIOS, MYLK, CCDC14, SPAG9, SOX5, VSNL1, SMC6, GEN1, MSGN1 and ZPAX) may be important for abdominal fat deposition in the chicken.
Conclusions
Our study provided a genome-wide CNVR map of the chicken genome, thereby contributing to our understanding of genomic structural variations and their potential roles in abdominal fat content in the chicken.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-517) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-517
PMCID: PMC4092215  PMID: 24962627
Chicken; Copy number variation (CNV); Abdominal fat
9.  Fumanjian, a Classic Chinese Herbal Formula, Can Ameliorate the Impairment of Spatial Learning and Memory through Apoptotic Signaling Pathway in the Hippocampus of Rats with Aβ1–40-Induced Alzheimer's Disease 
Alzheimer's disease (AD) is the most common form of dementia and lacks disease-altering treatments. Fumanjian (FMJ), a famous classic Chinese herbal prescription for dementia, was first recorded in the Complete Works of Jingyue during the Ming Dynasty. This study aimed to investigate whether FMJ could prevent cognitive deficit and take neuroprotective effects in Aβ1–40-induced rat model through apoptotic signaling pathway. AD model was established by bilateral injection of Aβ1–40 into hippocampus in rat. All rats were tested for their capabilities of spatial navigation and memorization by Morris water maze. Apoptosis was tested using TUNEL staining in hippocampus neuronal cells; RT-PCR tested expression of Bcl-2 and Bax mRNA; western blotting tested protein level of cleaved caspase-3. After 14 days of treatment, FMJ significantly improved the escape latency and enhanced platform-cross number compared with the Aβ1–40-injected group (P < 0.05 or P < 0.01). FMJ also significantly decreased number of TUNEL-positive neuronal apoptosis and the expressions of Bax and cleaved Caspase-3 and increased the expression of Bcl-2 (P < 0.01) compared with AD model group. In conclusion, FMJ exerts a protective effect against Aβ1–40-induced learning and memory deficits and neuronal apoptosis, suggesting that FMJ could be used as a potential therapeutic formula for AD.
doi:10.1155/2014/942917
PMCID: PMC4090451  PMID: 25050129
10.  Production and pathogenicity of hepatitis C virus core gene products 
Hepatitis C virus (HCV) is a major cause of chronic liver diseases, including steatosis, cirrhosis and hepatocellular carcinoma, and its infection is also associated with insulin resistance and type 2 diabetes mellitus. HCV, belonging to the Flaviviridae family, is a small enveloped virus whose positive-stranded RNA genome encoding a polyprotein. The HCV core protein is cleaved first at residue 191 by the host signal peptidase and further cleaved by the host signal peptide peptidase at about residue 177 to generate the mature core protein (a.a. 1-177) and the cleaved peptide (a.a. 178-191). Core protein could induce insulin resistance, steatosis and even hepatocellular carcinoma through various mechanisms. The peptide (a.a. 178-191) may play a role in the immune response. The polymorphism of this peptide is associated with the cellular lipid drop accumulation, contributing to steatosis development. In addition to the conventional open reading frame (ORF), in the +1 frame, an ORF overlaps with the core protein-coding sequence and encodes the alternative reading frame proteins (ARFP or core+1). ARFP/core+1/F protein could enhance hepatocyte growth and may regulate iron metabolism. In this review, we briefly summarized the current knowledge regarding the production of different core gene products and their roles in viral pathogenesis.
doi:10.3748/wjg.v20.i23.7104
PMCID: PMC4064058  PMID: 24966583
Hepatitis C virus; Core protein; Alternative reading frame/core+1 proteins; Insulin resistance; Steatosis; Hepatocellular carcinoma; Interferon
11.  Atorvastatin helps preserve pancreatic β cell function in obese C57BL/6 J mice and the effect is related to increased pancreas proliferation and amelioration of endoplasmic-reticulum stress 
Background
3-Hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitors or statins are competitive inhibitors of the rate-limiting enzyme in cholesterol biosynthesis. Currently, statins are used as first-line therapy in the treatment of diabetic dyslipidemia. However, effects of statins on β cell function remains unclear. This study aims to examine effects of atorvastatin treatment on pancreatic β cell function in obese C57BL/6 J mice and the possible mechanisms.
Methods
Diet-induced obesity (DIO) C57BL/6 J mice were treated with atorvastatin (30 mg/kg/day) for 58 days. β cell function was assessed by hyperglycemic clamp and the area of insulin-positive β cells was examined by immunofluorescence. Gene expression was assessed by RT-PCR, and endoplasmic reticulum (ER) stress related proteins were examined by Western blot. Additionally, cell viability and apoptosis of the cholesterol-loaded NIT-1 cells were investigated after atorvastatin treatment.
Results
Hyperglycemic clamp study revealed that glucose infusion rate (GIR) and insulin stimulation ratio in atorvastatin-treated DIO mice were markedly higher than control mice (P < 0.05, P < 0.01 vs. con), indicating preserved β-cell sensitivity to glucose. Lipid profiles of plasma triglyceride (TG), pancreas TG and plasma cholesterol (CHO) were improved. Pancreas weight and weight index were improved significantly after atorvastatin treatment (P < 0.05 vs. con). Immunofluorescence results showed that atorvastatin-treated mice had significantly larger insulin-positive β cell area (P < 0.05 vs. con). Furthermore, RT-PCR and western blot showed that the mRNA and protein expression of pancreatic and duodenal homeobox 1 (Pdx1) in the pancreas were upregulated (P < 0.001, P < 0.01 vs. con). Moreover, the expression level of ER stress markers of activating transcription factor 4 (ATF4), CCAAT-enhancer-binding protein homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2α (eIF2α) were downregulated in the pancreas of atorvastatin-treated mice (P < 0.001, P < 0.01, P < 0.01 vs. con). Besides, atorvastatin protected the pancreatic β cell line of NIT-1 from cholesterol-induced apoptosis. Western blot showed increased expression of anti-apoptotic protein of B-cell lymphoma 2 (Bcl-2).
Conclusion
Pancreatic β cell function of obese C57BL/6 J mice was preserved after atorvastatin treatment, and this improvement may be attributed to enhanced pancreas proliferation and amelioration of pancreatic ER stress.
doi:10.1186/1476-511X-13-98
PMCID: PMC4078942  PMID: 24950764
Atorvastatin; Diabetes; Pancreatic β cell function; Proliferation; ER stress; Apoptosis
12.  Anatomical and functional outcomes after Densiron 68 heavy silicone oil tamponade for complicated retinal detachment in Chinese eyes 
AIM
To evaluate the safety and efficacy of Densiron 68 heavy silicone oil (HSO) tamponade for complicated retinal detachment (RD) in Chinese eyes.
METHODS
Twenty-one eyes of 21 patients with complicated RD were included in this retrospective study. All patients underwent pars plana vitrectomy with an internal tamponade using Densiron 68 HSO. Anatomical and functional results and complications were evaluated, including retinal status, visual acuity (VA), intraocular pressure (IOP), intraocular inflammation, lens opacity, and HSO emulsification.
RESULTS
All the patients were followed up for 3mo to 1y (5.8±1.16mo). Retinal reattachment was achieved in 19 of 21 patients (90.5%). VA improved in 18 of 21 patients (85.7%), from 1.93 logMAR (±0.48) to 1.52 logMAR (±0.45) (P=0.001). Postoperative complications included early dispersion of HSO in 7 eyes (38.8%), cataract in 10 of 18 phakic eyes (55.5%), moderate postoperative inflammation reaction in 10 eyes (47.6%), and elevated IOP in 5 eyes (23.8%), all of which were controlled by medication or by surgery.
CONCLUSION
High anatomical and functional success rates can be achieved with primary vitrectomy for complicated RD by using Densiron 68 HSO; however, it should not be ignored that Densiron 68 HSO can cause some complications in the eye.
doi:10.3980/j.issn.2222-3959.2014.03.15
PMCID: PMC4067661  PMID: 24967193
complicated retinal detachment; heavy silicone oil; intraocular tamponade; vitreoretinal surgery
13.  Prevalence and associated factors of corneal blindness in Ningxia in northwest China 
AIM
To describe the prevalence and demographic characteristics of corneal blindness in an urban and rural region of Ningxia, located in the northwest part of China.
METHODS
A stratified, randomized sampling procedure was employed in the study, including urban and rural area of all age group. Visual acuity, anterior segment and ocular fundus were checked. Related factor of corneal disease, including age, gender, education status, ethnic group, location and occupation, were identified according to uniform customized protocol. An eye was defined to be corneal blindness if the visual acuity was <20/400 due to a corneal disease.
RESULTS
Three thousand individuals (1290 from urban area and 1710 from rural area) participated in the investigation, with a response rate of 80.380%. The prevalence of corneal blindness was 0.023% in both eyes and 0.733% in at least one eye. The blindness in at least one eye with varied causes was present in 106 participants (3.533%) and in bilateral eyes in 34 participants (1.133%). The corneal diseases accounted for 20.754% of blindness in at least one eye and 20.588% of bilateral blindness. The prevalence of corneal disease was higher in older and Han ethnic group, especially those who occupied in agriculture and outdoor work. People with corneal blindness were more likely to be older and lower education. Rural population were more likely to suffer from bilateral corneal blindness than the urban population in ≥59-year group (χ2=6.716, P=0.019). Infectious, trauma and immune corneal disease were the three leading causes of corneal disease. Trauma corneal disease was more likely leading to blindness in one eye. However, infectious and immune corneal diseases make more contribution to the bilateral corneal blindness.
CONCLUSION
Corneal blindness is a significant burden of in Ningxia population, encompassing a variety of corneal infections and trauma; the majority of those were avoidable. Health promotion strategies and good hygienic conditions have to be developed.
doi:10.3980/j.issn.2222-3959.2014.03.30
PMCID: PMC4067676  PMID: 24967208
corneal disease; epidemiology; blindness; infectious keratitis; trauma
14.  Enhancing the light absorbance of polymer solar cells by introducing pulsed laser-deposited CuIn0.8Ga0.2Se2 nanoparticles 
Nanoscale Research Letters  2014;9(1):308.
Evenly separated crystalline CuIn0.8Ga0.2Se2 (CIGS) nanoparticles are deposited on ITO-glass substrate by pulsed laser deposition. Such CIGS layers are introduced between conjugated polymer layers and ITO-glass substrates for enhancing light absorbance of polymer solar cells. The P3HT:PCBM absorbance between 300 and 650 nm is enhanced obviously due to the introduction of CIGS nanoparticles. The current density-voltage curves of a P3HT:PCBM/CIGS solar cell demonstrate that the short-circuit current density is improved from 0.77 to 1.20 mA/cm2. The photoluminescence spectra show that the excitons in the polymer are obviously quenched, suggesting that the charge transfer between the P3HT:PCBM and CIGS occurred. The results reveal that the CIGS nanoparticles may exhibit the localized surface plasmon resonance effect just as metallic nanostructures.
PACS
61.46. + w; 61.41.e; 81.15.Fg; 81.07.b
doi:10.1186/1556-276X-9-308
PMCID: PMC4067071  PMID: 24994961
CuIn0.8Ga0.2Se2 nanoparticles; P3HT:PCBM; Pulsed laser deposition; Absorption; Polymer solar cells; Photoluminescence
15.  Metalloproteinase-disintegrin ADAM12 is associated with a breast tumor-initiating cell phenotype 
Breast cancer research and treatment  2013;139(3):10.1007/s10549-013-2602-2.
Members of the ADAM family of proteases have been associated with mammary tumorigenesis. Gene profiling of human breast tumors identified several intrinsic subtypes of breast cancer, which differ in terms of their basic biology, response to chemotherapy/radiation, preferential sites of metastasis, and overall patient survival. Whether or not the expression of individual ADAM proteases is linked to a particular subtype of breast cancer and whether the functions of these ADAMs are relevant to the cancer subtype have not been investigated. We analyzed several transcriptomic datasets and found that ADAM12L is specifically up-regulated in claudin-low tumors. These tumors are poorly differentiated, exhibit aggressive characteristics, have molecular signatures of epithelial-tomesenchymal transition (EMT), and are rich in markers of breast tumor-initiating cells (BTICs). Consistently, we find that ADAM12L, but not the alternative splice variant ADAM12S, is a part of stromal, mammosphere, and EMT gene signatures, which are all associated with BTICs. In patients with estrogen receptor-negative tumors, high expression of ADAM12L, but not ADAM12S, is predictive of resistance to neoadjuvant chemotherapy. Using MCF10DCIS.com breast cancer cells, which express the endogenous ADAM12L and efficiently form mammospheres when plated at the density of single cell per well, we show that ADAM12L plays an important role in supporting mammosphere growth. We postulate that ADAM12L may serve as a novel marker and/or a novel therapeutic target in BTICs.
doi:10.1007/s10549-013-2602-2
PMCID: PMC3844617  PMID: 23771733
Metalloprotease; Disintegrin; Claudin-low tumors; Tumor-initiating cells; Epithelial-to-mesenchymal transition; Mammospheres
16.  Accumulated hippocampal formaldehyde induces age-dependent memory decline 
Age  2012;35(3):583-596.
Aging is an important factor in memory decline in aged animals and humans and in Alzheimer’s disease and is associated with the impairment of hippocampal long-term potentiation (LTP) and down-regulation of NR1/NR2B expression. Gaseous formaldehyde exposure is known to induce animal memory loss and human cognitive decline; however, it is unclear whether the concentrations of endogenous formaldehyde are elevated in the hippocampus and how excess formaldehyde affects LTP and memory formation during the aging process. In the present study, we report that hippocampal formaldehyde accumulated in memory-deteriorating diseases such as age-related dementia. Spatial memory performance was gradually impaired in normal Sprague–Dawley rats by persistent intraperitoneal injection with formaldehyde. Furthermore, excess formaldehyde treatment suppressed the hippocampal LTP formation by blocking N-methyl-d-aspartate (NMDA) receptor. Chronic excess formaldehyde treatment over a period of 30 days markedly decreased the viability of the hippocampus and down-regulated the expression of the NR1 and NR2B subunits of the NMDA receptor. Our results indicate that excess endogenous formaldehyde is a critical factor in memory loss in age-related memory-deteriorating diseases.
doi:10.1007/s11357-012-9388-8
PMCID: PMC3636394  PMID: 22382760
Alzheimer’s disease (AD); Aging; Endogenous formaldehyde; Long-term potentiation (LTP); Long-term memory (LTM); NMDA receptor
17.  Prevalence of Nonpolio Enteroviruses in the Sewage of Guangzhou City, China, from 2009 to 2012 
Applied and Environmental Microbiology  2013;79(24):7679-7683.
The human-pathogenic viruses in urban sewage have been extensively monitored to obtain information on circulating viruses in human communities. Enteroviruses (EVs) excreted by patients who present with diverse clinical syndromes can remain infectious in the environment for several weeks, and limited data on circulating environmental EVs are available. A 4-year (2009 to 2012) surveillance study was conducted to detect nonpolio enteroviruses (NPEVs) in the urban sewage of Guangzhou city, China. After the viruses in the sewage samples were concentrated and isolated, molecular identification was used to detect and type the NPEVs. During the 4-year study, 17 different NPEV serotypes were identified in the sewage of Guangzhou city. The most common serotypes were echovirus 11 (ECHO11), ECHO6, ECHO7, and ECHO12 and coxsackie group B viruses 5 (CVB5) and CVB3. The predominant serotypes were influenced by spatial and temporal factors and differed each year. CVB5 was commonly detected in 2009 and 2010 but was rarely isolated in 2011 and 2012. In contrast, CVB3 was not observed in 2009 and 2010 but was increasingly detected in 2011 and 2012. Our study provides an overview of the serotype distribution and circulation patterns of NPEVs in the sewage of Guangzhou, China. In the absence of a systematic EV disease surveillance system, the detection and characterization of sewage-borne NPEVs will help us better understand the changes in EV disease trends and the epidemic background of circulating EVs, which could help interpret the EV trends and warn of future outbreaks in this area.
doi:10.1128/AEM.02058-13
PMCID: PMC3837794  PMID: 24096418
18.  Novel antisense oligonucleotides containing hydroxamate linkages: targeted iron-triggered chemical nucleases 
Antisense oligonucleotides with iron binding hydroxamate linkages are designed to act as sequence-selective cleaving agents of complementary nucleic acids through Fenton chemistry. Oligothymidylate analogs with hydroxamate linkages were efficiently synthesized from coupling of nucleoside intermediates, activated as p-nitrophenyl carbonates, with hydroxylamine derivatized nucleosides. Iron binding studies showed that hydroxamate linked oligonucleotides are effective iron chelators when there are three nonadjacent internucleosidic hydroxamate linkages available in the same oligonucleotide molecule. However, analysis of the CD spectra of an oligothymidylate 16mer, which contained complete substitution of all phosphates with hydroxamates, indicated that the hydroxamate linkage was too rigid to allow the analog to base pair with the complementary DNA d(A16). Syntheses of mix-linked thymidine oligomers with up to three hydroxamate linkages incorporated in the center of the sequence are also reported. Iron binding of the thymidine oligomer with hydroxamate linkages was confirmed by matrix assisted laser desorption mass spectrometry analysis. Nuclease stability assays showed that the modified oligonucleotides have enhanced resistance toward nuclease S1 (endonuclease) compared to natural oligonucleotides. A thymidine 16mer with three hydroxamate linkages incorporated in the center of the sequence was shown to be able to bind with both iron and its complementary polyA strand. A small destablizing effect was observed when the phosphodiester linkage was changed to the hydroxamate linkage. Under Fenton chemistry conditions, this novel iron binding oligothymidylate analog cleaved the complementary DNA strand sequence-selectively.
doi:10.1007/s10534-009-9206-7
PMCID: PMC4030709  PMID: 19184459
Hydroxamic acid; Iron binding; Fenton chemistry; Antisense oligonucleotides; Chemical nucleases
19.  Effects of Early Blood Pressure Lowering on Early and Long-Term Outcomes after Acute Stroke: An Updated Meta-Analysis 
PLoS ONE  2014;9(5):e97917.
Background
Hypertension is common after acute stroke onset. Previous studies showed controversial effects of early blood pressure (BP) lowering on stroke outcomes. The aim of this study is to assess the effects of early BP lowering on early and long-term outcomes after acute stroke.
Methods
A meta-analysis was conducted with prospective randomized controlled trials assessing the effects of early BP lowering on early and long-term outcomes after acute stroke compared with placebo. Literature searching was performed in the databases from inception to December 2013. New evidence from recent trials were included. Outcomes were analyzed as early (within 30 days) and long-term (from 3 to 12 months) endpoints using summary estimates of relative risks (RR) and their 95% confidence intervals (CI) with the fixed-effect model or random-effect model.
Results
Seventeen trials providing data from 13236 patients were included. Pooled results showed that early BP lowering after acute stroke onset was associated with more death within 30 days compared with placebo (RR: 1.34 and 95% CI: 1.02, 1.74, p = 0.03). However the results showed that early BP lowering had no evident effect on early neurological deterioration, early death within 7 days, long-term death, early and long-term dependency, early and long-term combination of death or dependency, long-term stroke recurrence, long-term myocardial infarction and long-term CVE.
Conclusions
The new results lend no support to early BP lowering after acute stroke. Early BP lowering may increase death within 30 days after acute stroke.
doi:10.1371/journal.pone.0097917
PMCID: PMC4031127  PMID: 24853087
20.  Novel Scaffolds Fabricated Using Oleuropein for Bone Tissue Engineering 
BioMed Research International  2014;2014:652432.
We investigated the feasibility of oleuropein as a cross-linking agent for fabricating three-dimensional (3D) porous composite scaffolds for bone tissue engineering. Human-like collagen (HLC) and nanohydroxyapatite (n-HAp) were used to fabricate the composite scaffold by way of cross-linking. The mechanical tests revealed superior properties for the cross-linked scaffolds compared to the uncross-linked scaffolds. The as-obtained composite scaffold had a 3D porous structure with pores ranging from 120 to 300 μm and a porosity of 73.6 ± 2.3%. The cross-linked scaffolds were seeded with MC3T3-E1 Subclone 14 mouse osteoblasts. Fluorescence staining, the Cell Counting Kit-8 (CCK-8) assay, and scanning electron microscopy (SEM) indicated that the scaffolds enhanced cell adhesion and proliferation. Our results indicate the potential of these scaffolds for bone tissue engineering.
doi:10.1155/2014/652432
PMCID: PMC4052823  PMID: 24959582
21.  The adaptation of a CTN-1 rabies virus strain to high-titered growth in chick embryo cells for vaccine development 
Virology Journal  2014;11:85.
Background
Rabies virus is the causative agent of rabies, a central nervous system disease that is almost invariably fatal. Currently vaccination is the most effective strategy for preventing rabies, and vaccines are most commonly produced from cultured cells. Although the vaccine strains employed in China include CTN, aG, PM and PV, there are no reports of strains that are adapted to primary chick embryo cells for use in human rabies prevention in China.
Results
Rabies virus strain CTN-1 V was adapted to chick embryo cells by serial passage to obtain the CTNCEC25 strain. A virus growth curve demonstrated that the CTNCEC25 strain achieved high titers in chick embryo cells and was nonpathogenic to adult mice by intracerebral inoculation. A comparison of the structural protein genes of the CTNCEC25 strain and the CTN-1 V strain identified eight amino acid changes in the mature M, G and L proteins. The immunogenicity of the CTNCEC25 strain increased with the adaptation process in chick embryo cells and conferred high protective efficacy. The inactivated vaccine induced high antibody responses and provided full protection from an intramuscular challenge in adult mice.
Conclusions
This is the first description of a CTNCEC25 strain that was highly adapted to chick embryo cells, and both its in vitro and in vivo biological properties were characterized. Given the high immunogenicity and good propagation characteristics of the CTNCEC25 strain, it has excellent potential to be a candidate for development into a human rabies vaccine with high safety and quality characteristics for controlling rabies in China.
doi:10.1186/1743-422X-11-85
PMCID: PMC4023167  PMID: 24885666
Rabies virus; CTN-1 V; Chick embryo cells; Adaptation; Vaccine
22.  Analysis of differentially expressed genes in cold-exposed mice to investigate the potential causes of cold-induced hypertension 
Cold exposure is considered to be an important contributing factor to the high morbidity of hypertension. In order to elucidate the cause and mechanism of cold-induced hypertension (CIH), gene expression analysis was performed on microarray data for two groups of cold-exposed mice (4°C for 1 week and 4°C for 5 weeks, three replicates per group) and their respective control groups maintained at 30°C. Analysis results indicated that the differentially expressed genes with the most significance were associated with adaptive thermogenesis, fatty acid metabolism and energy metabolism. The expected marked increase in metabolism during cold exposure caused tissue hypoxia. Genes involved in the hypoxia-inducible factor signaling pathway were activated. In addition, genes associated with oxidative stress were significantly upregulated, including superoxide dismutase 2 (SOD2) and epoxide hydrolase 2 (EPHX2). The majority of genes involved in inflammation-associated pathways were shown to be downregulated in the 4°C 5-week group. Therefore, the results of the present study indicate that tissue hypoxia and increased oxidative stress may play important roles in the process of CIH.
doi:10.3892/etm.2014.1703
PMCID: PMC4061198  PMID: 24944607
cold exposure; hypoxia; oxidative stress; hypertension; gene expression; protein-protein interaction network
23.  A preparation approach of exploring cluster ion implantation: from ultra-thin carbon film to graphene 
Nanoscale Research Letters  2014;9(1):205.
Based on the extensive application of 2 × 1.7MV Tandetron accelerator, a low-energy cluster chamber has been built to explore for synthesizing graphene. Raman spectrum and atomic force microscopy (AFM) show that an amorphous carbon film in nanometer was deposited on the silicon by C4 cluster implantation. And we replaced the substrate with Ni/SiO2/Si and measured the thickness of Ni film by Rutherford backscattering spectrometry (RBS). Combined with suitable anneal conditions, these samples implanted by various small carbon clusters were made to grow graphene. Results from Raman spectrum reveal that few-layer graphene were obtained and discuss whether IG/I2D can contribute to explain the relationship between the number of graphene layers and cluster implantation dosage.
doi:10.1186/1556-276X-9-205
PMCID: PMC4029969  PMID: 24910570
Carbon cluster; Low-energy implantation; Graphene; Raman spectra; 29.20.-c; 29.25.Ni; 81.05.-t
24.  MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers 
Cell Cycle  2013;12(9):1385-1394.
Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-143 (miR-143) has been observed in CRC tissues. Here in this study, we found that miR-143 expression was downregulated both in CRC patients’ blood samples and tumor specimens. MiR-143 expression levels were strongly correlated with clinical stages and lymph node metastasis. Furthermore, insulin-like growth factor-I receptor (IGF-IR), a known oncogene, was a novel direct target of miR-143, whose expression levels were inversely correlated with miR-143 expression in human CRC specimens. Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner. Taken together, these results revealed that miR-143 levels in human blood and tumor tissues are associated with CRC cancer occurrence, metastasis and drug resistance, and miR-143 levels may be used as a new diagnostic marker and therapeutic target for CRC in the future.
doi:10.4161/cc.24477
PMCID: PMC3674066  PMID: 23574723
microRNA-143; tumorigenesis; angiogenesis; IGF-IR; chemotherapy
25.  BRG1 variant rs1122608 on chromosome 19p13.2 confers protection against stroke and regulates expression of pre-mRNA-splicing factor SFRS3 
Human genetics  2013;133(5):499-508.
A single nucleotide polymorphism (SNP) rs1122608 on chromosome 19p13.2 and in the BRG1/SMARCA4 gene was previously associated with coronary artery disease (CAD). CAD and ischemic stroke are both associated with atherosclerosis. Thus, we tested the hypothesis that rs1122608 is associated with ischemic stroke. Further studies were used to identify the most likely mechanism by which rs1122608 regulates atherosclerosis. For case–control association studies, two independent Chinese Han GeneID cohorts were used, including a Central cohort with 1,075 cases and 2,685 controls and the Northern cohort with 1,208 cases and 824 controls. eQTL and real-time RT-PCR analyses were used to identify the potential candidate gene(s) affected by rs1122608. The minor allele T of SNP rs1122608 showed significant association with a decreased risk of ischemic stroke in the Central GeneID cohort (adjusted Padj = 2.1 × 10−4, OR 0.61). The association was replicated in an independent Northern GeneID cohort (Padj = 6.00 × 10−3, OR 0.69). The association became more significant in the combined population (Padj = 7.86 × 10−5, OR 0.73). Allele T of SNP rs1122608 also showed significant association with a decreased total cholesterol level (Padj = 0.013). Allele T of rs1122608 was associated with an increased expression level of SFRS3 encoding an mRNA splicing regulator, but not with the expression of BRG1/SMARCA4 or LDLR (located 36 kb from rs1122608). Increased expression of SFSR3 may decrease IL-1β expression and secretion, resulting in reduced risk of atherosclerosis and stroke. This is the first study that demonstrates that rs1122608 confers protection against ischemic stroke and implicates splicing factor SFSR3 in the disease process.
doi:10.1007/s00439-013-1389-x
PMCID: PMC3988217  PMID: 24190014

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