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1.  Reducible chimeric polypeptide consisting of octa-d-arginine and tetra-l-histidine peptides as an efficient gene delivery vector 
Cationic oligopeptide as a nonviral gene delivery vector has aroused much research interest recently, but its further application is limited by its low transfection efficiency. In the present study, we have created a high-efficiency gene vector by using octa-d-arginine and tetra-l-histidine to form a disulfide cross-linked chimeric polypeptide and used this vector to deliver the therapeutic gene tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) to see whether the gene could be transferred and could exert antitumor effects in vitro and in vivo. The result showed that the newly designed vector was able to condense DNA into nanosized polyplexes effectively, thus facilitating its transmembrane transport, promoting its endosomal escape, and finally enabling degradation within the cell. Our study has demonstrated that this chimeric polypeptide is an effective gene carrier in cancer therapy.
doi:10.2147/IJN.S83507
PMCID: PMC4516254
reducible polypeptide; disulfide bond; octa-d-arginine; tetra-l-histidine; TRAIL
2.  Hyperphosphatemia as an independent risk factor for coronary artery calcification progression in peritoneal dialysis patients 
BMC Nephrology  2015;16:107.
Background
Coronary artery calcification (CAC) is associated with cardiovascular mortality in end-stage renal disease (ESRD) patients. The present study aimed to identify modifiable risk factors for CAC progression in peritoneal dialysis (PD) patients.
Methods
Adult patients who received regular PD for more than 6 months and underwent a series of coronary artery calcification score (CaCS) measurements by multislice spiral computed tomography (MSCT) with an interval of ≥ 6 months were included in this observational cohort study. The demographic characteristics and clinical data, including laboratory data and adequacy of PD, were collected. Curve estimation was used to fit the straight line and obtain the slope. Binary logistic regression was performed to identify the independent risk factors for CAC progression in the PD patients, and multivariate linear regression was conducted to identify factors associated with hyperphosphatemia.
Results
A total of 207 adult patients on PD (116 men, 56.0 %) with a mean age of 59.8 ± 15.9 years were recruited to this study, and 157 of them (75.8 %) received three or more CaCS assessments. The patients were divided into a slow group (n = 137) and a rapid group (n = 70) according to the linear regression slope or the average speed of development. The follow-up time was 33.0 ± 18.8 months. Multivariate logistic regression revealed that age and serum phosphate level were independent risk factors for CAC progression after adjustments. Multivariate linear regression revealed that hyperphosphatemia was associated with elevations in the transferrin and serum albumin levels and normalized protein catabolic rate (nPCR) and reductions in the hemoglobin level, residual Ccr, and PD Ccr.
Conclusions
Hyperphosphatemia is an independent risk factor for CAC progression, and the serum phosphate level may be associated with protein intake and PD adequacy. These results provide important information for the clinical management of ESRD patients.
doi:10.1186/s12882-015-0103-8
PMCID: PMC4506628  PMID: 26187601
Coronary artery calcification; Peritoneal dialysis; Hyperphosphatemia; ESRD
3.  Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A 
Angiogenesis  2013;17(3):553-562.
Hypoxia-inducible factor-1 (HIF-1) plays an important role in retinal and subretinal neovascularization (NV). Increased levels of HIF-1 cause increased expression of vascular endothelial growth factor (VEGF-A) and current therapies for ocular NV focus on neutralizing VEGF-A, but there is mounting evidence that other HIF-1-responsive gene products may also participate. In this study, we tested the effect of a designed ankyrin repeat protein (DARPin) that selectively binds and antagonizes the hypoxia-regulated gene product PDGF-BB in three models of subretinal NV (relevant to neovascular age-related macular degeneration) and compared its effects to a DARPin that selectively antagonizes VEGF-A. Daily intraperitoneal injections of 10 mg/kg of the anti-PDGF-BB DARPin or 1 mg/kg of the anti-VEGF DARPin significantly suppressed subretinal NV from laser-induced rupture of Bruch's membrane. Injections of 1 mg/kg/day of the anti-PDGF-BB DARPin had no significant effect, but when combined with 1 mg/kg/day of the anti-VEGF-A DARPin there was greater suppression than injection of the anti-VEGF-A DARPin alone. In Vldlr−/− mice which spontaneously develop subretinal NV, intraocular injection of 1.85 μg of anti-PDGF-BB or anti-VEGF-A DARPin caused significant suppression of NV and when combined there was greater suppression than with either alone. The two DARPins also showed an additive effect in Tet/opsin/VEGF double transgenic mice, a particularly severe model of subretinal NV and exudative retinal detachment. In addition, intraocular injection of 1.85 μg of anti-PDGF-BB DARPin strongly suppressed ischemia-induced retinal NV, which is relevant to proliferative diabetic retinopathy and retinopathy of prematurity. These data demonstrate that PDGF-BB is another hypoxia-regulated gene product that along with VEGF-A contributes to ocular NV and suppression of both provides an additive effect.
doi:10.1007/s10456-013-9402-5
PMCID: PMC3999311  PMID: 24154861
Age-related macular degeneration; Diabetic retinopathy; HIF-1; DARPin
4.  Synthesis of novel spin-labeled derivatives of 5-FU as potential antineoplastic agents 
Chemotherapy is a general treatment option for various cancers, including lung cancer. In order to find compounds with superior bioactivity and less toxicity against lung cancer, novel spin-labeled 5-fluorouracil (5-FU) derivatives (3a–f) were synthesized and evaluated against four human tumor cell lines (A-549, DU-145, KB, and KBvin). Two promising compounds 3d and 3f exhibited IC50 values of 2.76 and 2.38 μM, respectively, against non-small cell lung carcinoma cell line A-549. These compounds were twofold more cytotoxic than 5-FU and less toxic against other tested cell lines. Compound 3f exhibited seven times more selective cytotoxicity against A-549 than 5-FU. Our results suggest that compounds 3d and 3f merit further investigation for development into clinical trial candidates for non-small cell lung cancer.
doi:10.1007/s00044-013-0906-8
PMCID: PMC4337784  PMID: 25722628
5-Fluorouracil; Spin-labeled; Nitroxide; Cytotoxicity
5.  Trends in the Levels of Serum Lipids and Lipoproteins and the Prevalence of Dyslipidemia in Adults with Newly Diagnosed Type 2 Diabetes in the Southwest Chinese Han Population during 2003–2012 
Objective. To determine the trends of serum lipid levels and dyslipidemia in adults newly diagnosed with type 2 diabetes mellitus during 2003–2012 in Southwest China. Methods. Serum lipid measurements of 994 adults were obtained from 5 independent, cross-sectional studies (2003-2004, 2005-2006, 2007-2008, 2009-2010, and 2011-2012). The main outcome measures were mean serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; body mass index; hemoglobin A1C level; and the percentages of patients with dyslipidemia, hypertension, coronary heart disease, and cerebrovascular disease. Results. The mean total cholesterol and low-density lipoprotein cholesterol levels increased from 4.92 ± 1.15 to 5.30 ± 1.17 mmol/L (P = 0.039) and 2.72 ± 0.83 to 3.11 ± 1.09 mmol/L (P = 0.004), respectively, and the mean HDL cholesterol level declined from 1.22 ± 0.30 to 1.06 ± 0.24 mmol/L (P < 0.001). The percentages of patients with dyslipidemia increased gradually. The incidence of coronary heart and cerebrovascular diseases increased from 8.2% to 19.1% and 6.6% to 15.3%, respectively (P < 0.05). Conclusion. Unfavorable upward trends were observed in serum lipid levels and the prevalence of dyslipidemia, coronary heart disease, and cerebrovascular disease in adults newly diagnosed with type 2 diabetes mellitus in Southwest China during 2003–2012.
doi:10.1155/2015/818075
PMCID: PMC4451154  PMID: 26089896
6.  Reduction-responsive cross-linked stearyl peptide for effective delivery of plasmid DNA 
Low efficiency and significant toxicity are the main obstacles to successful gene delivery. We have developed a cationic reduction-responsive vector based on a disulfide cross-linked stearylated polyarginine peptide modified with histidine (C-SHR) for DNA delivery. The structure of the C-SHR was characterized, and the in vitro and in vivo transfection efficiency and cytotoxicity of C-SHR/plasmid DNA complexes were examined. Compared with non-cross-linked stearylated polyarginine peptide (SHR), C-SHR increased the intracellular uptake and dissociation behavior of the complexes. In addition, the gene transfection efficiency of C-SHR/plasmid DNA complexes in HEK293 and HeLa cells was improved and was comparable with that of bPEI-25K/plasmid DNA complexes, and the cytotoxicity of C-SHR was significantly less than that of bPEI-25K. Importantly, the in vivo gene transfection efficiency of C-SHR/plasmid DNA complexes was five fold higher than that of SHR/plasmid DNA complexes, suggesting that C-SHR is an efficient non-viral vector for DNA delivery.
doi:10.2147/IJN.S82413
PMCID: PMC4431505  PMID: 26056440
polyarginine; histidine; stearyl; reduction-responsive; peptide; DNA delivery
7.  The ‘Positive Effect’ Is Present in Older Chinese Adults: Evidence from an Eye Tracking Study 
PLoS ONE  2015;10(4):e0121372.
The 'Positive Effect' is defined as the phenomenon of preferential cognitive processing of positive affective information, and avoidance or dismissal of negative affective information in the social environment. The ‘Positive Effect’ is found for older people compared with younger people in western societies and is believed to reflect a preference for positive emotional regulation in older adults. It is not known whether such an effect is Universal, and in East Asian cultures, there is a highly controversial debate concerning this question. In the current experiment we explored whether Chinese older participants showed a 'Positive Effect' when they inspected picture pairs that were either a positive or a negative picture presented with a neutral picture, or a positive and negative picture paired together. The results indicated that both groups of participants showed an attentional bias to both pleasant (more processing of) and unpleasant pictures (initial orienting to) when these were paired with neutral pictures. When pleasant and unpleasant pictures were paired together both groups showed an initial orientation bias for the pleasant picture, but the older participants showed this bias for initial orienting and increased processing measures, providing evidence of a ‘Positive Effect’ in older Chinese adults.
doi:10.1371/journal.pone.0121372
PMCID: PMC4400038  PMID: 25880585
8.  Vitamin D/VDR signaling pathway ameliorates 2,4,6-trinitrobenzene sulfonic acid-induced colitis by inhibiting intestinal epithelial apoptosis 
Increasing epidemiological data have suggested a link between vitamin D deficiency and the incidence of inflammatory bowel disease (IBD). In the present study, we confirmed that vitamin D deficiency, as well as the decreased local expression of vitamin D receptor (VDR), was prevalent in an IBD cohort. The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD. Based on the established inhibitory effects of the vitamin D/VDR pathway on IEC apoptosis, we treated mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with paricalcitol, a vitamin D analog, in order to investigate the mechanisms responsible for the inhibitory effects of the vitamin D/VDR pathway. We observed that following treatment with vitamin D, the mice presented with only minor bodyweight loss, and the mice also showed improved histological scores and decreased intestinal epithelial permeability compared with the vehicle-treated group. The colonic mRNA expression of inflammatory cytokines and chemokines was markedly suppressed, indicating less severe colitis in the vitamin D-treated mice. Subsequently, we investigated p53 upregulated modulator of apoptosis (PUMA) and p53, two major independent pathways of apoptosis, as well as caspase-3. We found that the vitamin D-treated mice had lower expression levels of caspase-3 than the vehicle-treated mice. PUMA expression showed the same tendency; however, the p53 protein level was not altered. The present study indicates that vitamin D attenuates the development of TNBS-induced colitis by inhibiting the apoptosis of IECs. The mechanisms involved include the downregulation of PUMA expression. Our data provide experimental support for the clinical trials of vitamin D intervention in patients with IBD.
doi:10.3892/ijmm.2015.2150
PMCID: PMC4380119  PMID: 25813397
vitamin D; vitamin D receptor; 2; 4; 6-trinitrobenzene sulfonic acid; inflammatory bowel disease; p53 upregulated modulator of apoptosis; apoptosis
9.  High prevalence of maternal vitamin D deficiency in preterm births in northeast China, Shenyang 
Introduction: Maternal vitamin D deficiency has been associated with a number of fetal and neonatal health problems. Preterm birth is one of the most detrimental, and the role of maternal vitamin D deficiency in preterm births has not been universally acknowledged. There had been limited epidemiological studies of vitamin D deficiency on the Chinese population. Subjects and methods: 1103 women delivered in Shengjing Hospital, China Medical University from January 1st, 2012 to January 1st, 2013. Finally, 821 mother-newborn pairs which contained 143 mother-newborn pairs who were preterm delivery were recruited for analysis. Results: There was significant difference between spring and summer (P<0.0001) as well as spring and autumn (P<0.01). Compared to those in summer and autumn, the 25 (OH) D level was significantly lower in winter (summer vs winter P<0.0001, autumn vs winter P<0.0001). Maternal vitamin D level showed obvious variation with months and seasons, with higher level in summer months and lower level in winter months. There were significant difference between the vitamin D level of the very preterm group and the mildly preterm groups (P<0.01), as well as the very preterm group and the in-term groups (P<0.001). Prevalence of Vitamin D deficiency occurred in 63.04% of pregnant women in very preterm group, compared with 36.61% in in-term group. Conclusion: Vitamin D nutritional status of pregnant women and their newborns in Shenyang were relatively good compared to cities in similar latitudes. Vitamin D deficiency was most severe in late spring and least in summer. Severe preterm births before 31 weeks of gestation was associated with maternal vitamin D deficiency.
PMCID: PMC4396334  PMID: 25973031
Serum 25-hydroxyvitamin D; vitamin D deficiency; pregnancy; season; preterm
10.  Design, Synthesis and Cytotoxic Activity of Novel Sulfonylurea Derivatives of Podophyllotoxin 
Bioorganic & medicinal chemistry  2013;22(1):204-210.
Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41–1.76 μM) and 14e (IC50: 1.72–2.01 μM) showed superior cytotoxic activity compared with etoposide (IC50: 2.03– >20μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4′-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin’s 4β position can significantly improve cytotoxic activity.
doi:10.1016/j.bmc.2013.11.035
PMCID: PMC3902999  PMID: 24332656
podophyllotoxin; sulfonylurea; synthesis; cytotoxic activity
11.  A switch from CD44+ cell to EMT cell drives the metastasis of prostate cancer 
Oncotarget  2014;6(2):1202-1216.
Epithelial–mesenchymal transition (EMT) has been linked to cancer stem-like (CD44+) cell in the prostate cancer (PCa) metastasis. However, the molecular mechanism remains elusive. Here, we found EMT contributed to metastasis in PCa patients failed in androgen deprivation therapy (ADT). Castration TRAMP model also proved PCa treated with ADT promoted EMT with increased CD44+ stem-like cells. Switched CD44+ cell to EMT cell is a key step for luminal PCa cell metastasis. Our results also suggested ADT might go through promoting TGFβ1-CD44 signaling to enhance swift to EMT. Targeting CD44 with salinomycin and siRNA could inhibit cell transition and decrease PCa invasion. Together, cancer stem-like (CD44+) cells could be the initiator cells of EMT modulated by TGFβ1-CD44 signaling. Combined therapy of ADT with anti-CD44 may become a new potential therapeutic approach to battle later stage PCa.
PMCID: PMC4359227  PMID: 25483103
androgen deprivation therapy; epithelial-mesenchymal transition; TGFβ1; cancer stem cell; CD44; prostate cancer
12.  Association between GDF5 rs143383 polymorphism and knee osteoarthritis: an updated meta-analysis based on 23,995 subjects 
Background
Previous studies investigating the association between GDF5 rs143383 polymorphism and knee osteoarthritis (OA) have suggested stronger associations in Asians than Caucasians, but limitations on the amount of available data have meant that a definitive assessment has not been possible. Given the availability of more recent data, the aim of this meta-analysis was to determine the overall association between GDF5 rs143383 polymorphism and knee OA and whether the association varies by ethnicity.
Methods
Searches of Medline, Embase, and ISI Web of Science were conducted up to July 2013. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of association between the GDF5 polymorphism and knee OA risk.
Results
A total of 20 studies with 23,995 individuals were included. There were weak but significant associations present between the GDF5 polymorphism and knee OA at the allele level (C vs. T: OR =0.85, 95% CI = 0.80-0.90) and genotype level (CC vs. TT: OR = 0.73; CT vs. TT: OR = 0.84; CC/CT vs. TT: OR = 0.81; CC vs. CT/TT: OR = 0.81) in the overall population. In the subgroup analysis by ethnicity, we observed a strong significant association (OR = 0.60 to 0.80, all P <0.05) in Asian population and weaker associations (OR =0.78 to 0.87, all P <0.05) in Caucasian population; however marked heterogeneity was detected in all models except for CC vs. TT (I2 = 12.9%) and CC vs. CT + TT (I2 = 0.0%) in Asians.
Conclusions
These results strongly suggest that the C allele and CC genotype of the GDF5 gene are protective for knee OA susceptibility across different populations.
doi:10.1186/1471-2474-15-404
PMCID: PMC4265459  PMID: 25467786
GDF5; Polymorphism; Knee; Osteoarthritis; Meta-analysis
13.  Effects of cyclooxygenase-2 gene silencing on the biological behavior of SKOV3 ovarian cancer cells 
Molecular Medicine Reports  2014;11(1):59-66.
The aim of the present study was to investigate the effects of plasmid-mediated RNA interference targeting of cyclooxygenase-2 (COX-2) on the biological behaviors of SKOV3 human ovarian cancer cells and to analyze the function of COX-2 in carcinogenesis and development of ovarian cancer. A COX-2 small hairpin (sh)RNA sequence was designed and synthesized and pGPU6-COX-2-shRNA plasmids were constructed. The recombinant vector plasmids were stably transfected into SKOV3 cells. The mRNA and protein expression of COX-2 was subsequently analyzed by quantitative polymerase chain reaction and western blot analysis, respectively. MTT and colony formation assays were used to detect the cellular proliferation ability and flow cytometry was performed to detect phase changes in the cell cycle. Finally, a Transwell assay was used to detect cell invasion. The SKOV3 cells, transfected with recombinant vector plasmids, and control cells, were injected into nude mice and the tumor emergence time, volume and weight were measured. The impact of COX-2 gene silencing on the growth of xenograft tumors in nude mice was analyzed. Following transfection of the pGPU6-COX-2-shRNA plasmid, in vitro analyses indicated that the shRNA efficiently suppressed the mRNA and protein expression of COX-2. COX-2 gene silencing significantly inhibited the proliferation and invasion ability of SKOV3 cells, leading to cell cycle arrest in G1. The tumor formation time in the interference group was significantly prolonged, and the tumor volume and weight were significantly decreased, as compared with the control group. Plasmid-mediated shRNA was shown to effectively silence COX-2 expression in SKOV3 ovarian cancer cells. It was identified that COX-2 functioned in regulating proliferation, cell cycle and invasion of ovarian cancer cells. These findings provided a theoretical basis for determining the function of COX-2 in the development of ovarian cancer and suggested that COX-2 may be an effective target for gene therapy and clinical applications.
doi:10.3892/mmr.2014.2732
PMCID: PMC4237092  PMID: 25335121
ovarian cancer; cyclooxygenase-2; RNA interference; proliferation; invasion; gene therapy
14.  A high-concentrate diet induced colonic epithelial barrier disruption is associated with the activating of cell apoptosis in lactating goats 
BMC Veterinary Research  2014;10:235.
Background
In ruminants, lower ruminal pH causes massive disruption of ruminal epithelial structure during periods of feeding high-concentrate diets. However, the influence of excessive organic fatty acids in the lumen of hindgut on the epithelial structure is unclear. In this study, twelve mid-lactating goats were randomly assigned to either a HC diet group (65% concentrate of dry matter; n = 6) or a LC diet group (35% concentrate of dry matter; n = 6) for 10 weeks. The colonic epithelial structure was detected by HE staining and transmission electron microscopy (TEM), and the apoptotic status of epithelial cells was estimated by TUNEL method and caspase activities.
Results
HC goats showed higher level of free lipopolysaccharide (LPS) in rumen fluid (p < 0.01) but not in colonic digesta (p > 0.05), and higher total volatile fatty acid (VFA) concentrations in rumen fluid (p < 0.05) and in colonic digesta (p < 0.01), and higher content of starch in colonic digesta (p < 0.05) compared to LC goats. HC goats demonstrated profound alterations in the colonic epithelial structure and tight junctions (TJ), apparently due to damage of the epithelium with widened TJs space and nuclear breakdown and mitochondrial swelling. HC goats showed higher level of apoptosis in the colonic epithelium with higher proportion of TUNEL-positive apoptotic cells and increases of caspase-3 and −3/7 activities, as well as the lower ratio of bcl-2/bax mRNA expression in the colonic mucosa (p < 0.05). However, β-defense mRNA was significantly down-regulated in the colonic mucosa of HC goats compared to LC (p < 0.05). HC goats showed higher level of TJ proteins including claudin-1 and claudin-4 in the colonic mucosa than LC (p < 0.05). Neither free LPS content in the colonic digesta nor NF-κ B protein expression in tissues showed significant difference between HC and LC goats (p > 0.05).
Conclusions
Our results reveal that long-term feeding HC diet to lactating goats causes severe damages to the colonic mucosa barrier associated with activating cells apoptosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12917-014-0235-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12917-014-0235-2
PMCID: PMC4180839  PMID: 25256013
LPS; Apoptosis; Tight junctions; Colonic mucosa; HC diet; Goat
15.  Integrative Genomic Analysis Identifies That SERPINA6-rs1998056 Regulated by FOXA/ERα Is Associated with Female Hepatocellular Carcinoma 
PLoS ONE  2014;9(9):e107246.
The human forkhead box A1 (FOXA1) and A2 (FOXA2) transcription factors have been found to control estrogen and androgen signaling through co-regulating target genes with sex hormone receptors. Here we used an integrative strategy to examine the hypothesis that genetic variants at FOXA1/2 binding elements may be associated with sexual dimorphism of hepatocellular carcinoma (HCC) risk. Firstly we extracted chromatin immunoprecipitation-sequencing (ChIP-seq) data of FOXA1, FOXA2 and estrogen receptor 1(ERα) from ENCODE database to obtain dual target regions of FOXA/ERα, and further intersected these regions with genes’ promoters. Then we used MATCH program to predict FOXA binding elements, in which genetic variants were retrieved by dbSNP database (NCBI, build 134). A total of 15 candidate variants were identified in this stage. Secondly we performed a case-control study with 1,081 HCC patients and 2,008 matched controls and found a significant association of SERPINA6-rs1998056 with female HCC risk under common genetic models (e.g. GG versus CC: OR = 2.03, 95% CI = 1.26–3.27, P = 0.004). Moreover, results from our real-time quantitative polymerase chain reaction (qPCR) using 72 normal liver tissues adjacent to the tumors showed that SERPINA6 expression was significantly different among different genotypes of this variant (GG versus CC: P = 0.032; Group test: P = 0.060). In summary, our study suggested that SERPINA6-rs1998056 regulated by FOXA/ERα might be associated with female HCC risk.
doi:10.1371/journal.pone.0107246
PMCID: PMC4157870  PMID: 25198130
16.  Revisiting corrective saccades: role of visual feedback 
Vision research  2013;89:54-64.
To clarify the role of visual feedback in the generation of corrective movements after inaccurate primary saccades, we used a visually-triggered saccade task in which we varied how long the target was visible. The target was on for only 100 ms (OFF100ms), on until the start of the primary saccade (OFFonset) or on for 2 s (ON). We found that the tolerance for the post-saccadic error was small (− 2%) with a visual signal (ON) but greater (−6%) without visual feedback (OFF100ms). Saccades with an error of −10%, however, were likely to be followed by corrective saccades regardless of whether or not visual feedback was present. Corrective saccades were generally generated earlier when visual error information was available; their latency was related to the size of the error. The LATER (Linear Approach to Threshold with Ergodic Rate) model analysis also showed a comparable small population of short latency corrective saccades irrespective of the target visibility. Finally, we found, in the absence of visual feedback, the accuracy of corrective saccades across subjects was related to the latency of the primary saccade. Our findings provide new insights into the mechanisms underlying the programming of corrective saccades: 1) the preparation of corrective saccades begins along with the preparation of the primary saccades, 2) the accuracy of corrective saccades depends on the reaction time of the primary saccades and 3) if visual feedback is available after the initiation of the primary saccade, the prepared correction can be updated.
doi:10.1016/j.visres.2013.07.012
PMCID: PMC3784029  PMID: 23891705
Primary saccade; Corrective saccade; Visual feedback; LATER model; Forward control
17.  Hyperglycemia is Associated with the Incidence of Frailty and Lower Extremity Mobility Limitations in Older Women 
Objectives
To determine the degree to which hyperglycemia predicts the development of frailty and/or lower extremity mobility limitations.
Design
Secondary data analysis of longitudinal data collected in a prospective cohort study.
Setting
Baltimore, Maryland
Participants
We examined 329 women from the Women’s Health and Aging Studies II aged 70–79 years at baseline who had all variables needed for analysis.
Methods
Hemoglobin A1c [HbA1c] at baseline was the independent variable and categorized as: <5.5%, 5.5 to 5.9%, 6.0–6.4%, 6.5–7.9%, ≥8%. The incidence of frailty and lower extremity mobility limitations (based on self-reported walking difficulty, walking speed, and short performance physical battery [SPPB] score) was determined (follow-up≈9 years). Frailty was assessed using the Cardiovascular Health Study criteria. Covariates included demographics, body mass index, interleukin-6, and clinical history of comorbidities. Statistical analyses included Kaplan-Meier survival curves and Cox regression models adjusting for key covariates.
Results
In time-to-event analyses, HbA1c category was associated with incidence of walking difficulty (p=0.049) and low physical performance (p=0.001); association with incidence of frailty and low walking speed had a trend towards significance (both p=0.10). In demographics-adjusted regression models, HbA1c≥8% (versus<5.5%) was associated with an approximately three-times increased risk of incident frailty and three-to-five times increased risk of lower extremity mobility limitations (all p<0.05). In fully adjusted models, HbA1c≥8% (versus<5.5%) was associated with incident frailty (hazard ratio[HR]=3.33, 95% confidence interval=1.24–8.93), walking difficulty (HR=3.47,1.26–9.55), low walking speed (HR=2.82,1.19–6.71), and low physical performance (HR=3.60,1.52–8.53).
Conclusions
Hyperglycemia is associated with the development of frailty and lower extremity mobility limitations in older women; future studies should identify mediators of these relationships.
doi:10.1111/j.1532-5415.2012.04099.x
PMCID: PMC4144067  PMID: 22882211
Hyperglycemia; Elderly; Frailty; Mobility; Disability
18.  Is hyperglycemia associated with frailty status in older women? 
OBJECTIVES
To determine whether hyperglycemia is related to prevalent frailty status in older women.
DESIGN
Secondary data analysis of baseline data of a prospective cohort study.
SETTING
Baltimore, Maryland.
PARTICIPANTS
Five hundred forty-three women aged 70 to 79.
METHODS
Research used baseline data from 543 participants in the Women’s Health and Aging Studies I and II aged 70 to 79 who had all variables needed for analyses. The dependent variable was baseline frailty status (not frail, prefrail, frail), measured using an empirically derived model defining frailty according to weight loss, slow walking speed, weakness, exhaustion, and low activity (1–2 characteristics Present = prefrail, ≥3 = frail). Covariates included body mass index (BMI), interleukin-6 (IL-6), age, race, and several chronic diseases. Analyses included descriptive methods and multinomial logistic regression to adjust for key covariates.
RESULTS
A hemoglobin A1c (HbA1c) level of 6.5% or greater in older women was significantly associated with higher likelihood of prefrail and frail status (normal HbA1c <6.0% was reference). The association between HbA1C levels of 6.0% to 6.5% and frailty status was not different from that of normal HbA1c, but HbA1c levels of 6.5% to 6.9% had nearly twice the likelihood of frailty (odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.47–2.59) as normal HbA1c. A HbA1c level of 9.0% or greater was also strongly associated (OR = 2.57, 95% CI = 1.99,3.32). Significant associations were also seen between baseline prefrail and frail status and low (18.5–20.0 kg/m2) and high (.30.0 kg/m2) body mass index (BMI), interleukin-6, and all chronic diseases evaluated, but controlling for these covariates only minimally attenuated the independent association between HbA1c and frailty status.
CONCLUSION
Hyperglycemia is associated with greater prevalence of prefrail and frail status; BMI, inflammation, and comorbidities do not explain the association. Longitudinal research and study of alternative pathways are needed.
PMCID: PMC4120964  PMID: 19484839
hyperglycemia; frailty; older women
19.  Myotonia Congenita-Associated Mutations in Chloride Channel-1 Affect Zebrafish Body Wave Swimming Kinematics 
PLoS ONE  2014;9(8):e103445.
Myotonia congenita is a human muscle disorder caused by mutations in CLCN1, which encodes human chloride channel 1 (CLCN1). Zebrafish is becoming an increasingly useful model for human diseases, including muscle disorders. In this study, we generated transgenic zebrafish expressing, under the control of a muscle specific promoter, human CLCN1 carrying mutations that have been identified in human patients suffering from myotonia congenita. We developed video analytic tools that are able to provide precise quantitative measurements of movement abnormalities in order to analyse the effect of these CLCN1 mutations on adult transgenic zebrafish swimming. Two new parameters for body-wave kinematics of swimming reveal changes in body curvature and tail offset in transgenic zebrafish expressing the disease-associated CLCN1 mutants, presumably due to their effect on muscle function. The capability of the developed video analytic tool to distinguish wild-type from transgenic zebrafish could provide a useful asset to screen for compounds that reverse the disease phenotype, and may be applicable to other movement disorders besides myotonia congenita.
doi:10.1371/journal.pone.0103445
PMCID: PMC4118878  PMID: 25083883
20.  Androgen Receptor Enhances Kidney Stone-CaOx Crystal Formation via Modulation of Oxalate Biosynthesis & Oxidative Stress 
Molecular Endocrinology  2014;28(8):1291-1303.
Males develop kidney stones far more frequently than females with a ratio of 2–3:1, suggesting that androgen receptor (AR) signaling might play a key role in the development of nephrolithiasis. Using the cre-loxP system to selectively knock out AR in glyoxylate-induced calcium oxalate (CaOx) crystal mouse models, we found that the mice lacking hepatic AR had less oxalate biosynthesis, which might lead to lower CaOx crystal formation, and that the mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation. We found that AR could directly up-regulate hepatic glycolate oxidase and kidney epithelial NADPH oxidase subunit p22-PHOX at the transcriptional level. This up-regulation might then increase oxalate biosynthesis and oxidative stress that resulted in induction of kidney tubular injury. Targeting AR with the AR degradation enhancer ASC-J9 led to suppression of CaOx crystal formation via modulation of oxalate biosynthesis and oxidative stress in both in vitro and in vivo studies. Taken together, these results established the roles of AR in CaOx crystal formation.
doi:10.1210/me.2014-1047
PMCID: PMC4116591  PMID: 24956378
21.  Direct Interaction between Selenoprotein P and Tubulin 
Selenium (Se), an essential trace element for human health, mainly exerts its biological function via selenoproteins. Among the 25 selenoproteins identified in human, selenoprotein P (SelP) is the only one that contains multiple selenocysteines (Sec) in the sequence, and has been suggested to function as a Se transporter. Upon feeding a selenium-deficient diet, mice lacking SelP develop severe neurological dysfunction and exhibit widespread brainstem neurodegeneration, indicating an important role of SelP in normal brain function. To further elucidate the function of SelP in the brain, SelP was screened by the yeast two-hybrid system from a human fetal brain cDNA library for interactive proteins. Our results demonstrated that SelP interacts with tubulin, alpha 1a (TUBA1A). The interaction between SelP and tubulin was verified by fluorescence resonance energy transfer (FRET) and co-immunoprecipitation (co-IP) assays. We further found that SelP interacts with the C-terminus of tubulin by its His-rich domain, as demonstrated by FRET and Isothermal Titration Calorimetry (ITC) assays. The implications of the interaction between SelP and tubulin in the brain and in Alzheimer’s disease are discussed.
doi:10.3390/ijms150610199
PMCID: PMC4100148  PMID: 24914767
selenoprotein P (SelP); tubulin; protein-protein interaction; yeast two-hybrid system; fluorescence resonance energy transfer (fret)
22.  The Ets transcription factor GABP is a novel component of the Hippo pathway essential for growth and antioxidant defense 
Cell reports  2013;3(5):10.1016/j.celrep.2013.04.020.
Summary
The transcriptional co-activator YAP plays an important role in organ size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced GSH depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects acetaminophen-induced liver injury. Similar to its effects on YAP, the Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP.
doi:10.1016/j.celrep.2013.04.020
PMCID: PMC3855275  PMID: 23684612
GABP; Hippo pathway; YAP; Glutathione depletion; Liver injury; liver cancer
23.  The sequence and de novo assembly of the giant panda genome 
Li, Ruiqiang | Fan, Wei | Tian, Geng | Zhu, Hongmei | He, Lin | Cai, Jing | Huang, Quanfei | Cai, Qingle | Li, Bo | Bai, Yinqi | Zhang, Zhihe | Zhang, Yaping | Wang, Wen | Li, Jun | Wei, Fuwen | Li, Heng | Jian, Min | Li, Jianwen | Zhang, Zhaolei | Nielsen, Rasmus | Li, Dawei | Gu, Wanjun | Yang, Zhentao | Xuan, Zhaoling | Ryder, Oliver A. | Leung, Frederick Chi-Ching | Zhou, Yan | Cao, Jianjun | Sun, Xiao | Fu, Yonggui | Fang, Xiaodong | Guo, Xiaosen | Wang, Bo | Hou, Rong | Shen, Fujun | Mu, Bo | Ni, Peixiang | Lin, Runmao | Qian, Wubin | Wang, Guodong | Yu, Chang | Nie, Wenhui | Wang, Jinhuan | Wu, Zhigang | Liang, Huiqing | Min, Jiumeng | Wu, Qi | Cheng, Shifeng | Ruan, Jue | Wang, Mingwei | Shi, Zhongbin | Wen, Ming | Liu, Binghang | Ren, Xiaoli | Zheng, Huisong | Dong, Dong | Cook, Kathleen | Shan, Gao | Zhang, Hao | Kosiol, Carolin | Xie, Xueying | Lu, Zuhong | Zheng, Hancheng | Li, Yingrui | Steiner, Cynthia C. | Lam, Tommy Tsan-Yuk | Lin, Siyuan | Zhang, Qinghui | Li, Guoqing | Tian, Jing | Gong, Timing | Liu, Hongde | Zhang, Dejin | Fang, Lin | Ye, Chen | Zhang, Juanbin | Hu, Wenbo | Xu, Anlong | Ren, Yuanyuan | Zhang, Guojie | Bruford, Michael W. | Li, Qibin | Ma, Lijia | Guo, Yiran | An, Na | Hu, Yujie | Zheng, Yang | Shi, Yongyong | Li, Zhiqiang | Liu, Qing | Chen, Yanling | Zhao, Jing | Qu, Ning | Zhao, Shancen | Tian, Feng | Wang, Xiaoling | Wang, Haiyin | Xu, Lizhi | Liu, Xiao | Vinar, Tomas | Wang, Yajun | Lam, Tak-Wah | Yiu, Siu-Ming | Liu, Shiping | Zhang, Hemin | Li, Desheng | Huang, Yan | Wang, Xia | Yang, Guohua | Jiang, Zhi | Wang, Junyi | Qin, Nan | Li, Li | Li, Jingxiang | Bolund, Lars | Kristiansen, Karsten | Wong, Gane Ka-Shu | Olson, Maynard | Zhang, Xiuqing | Li, Songgang | Yang, Huanming | Wang, Jian | Wang, Jun
Nature  2009;463(7279):311-317.
Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
doi:10.1038/nature08696
PMCID: PMC3951497  PMID: 20010809
24.  Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways 
PLoS ONE  2014;9(3):e91245.
We previously reported that calycosin, a natural phytoestrogen structurally similar to estrogen, successfully triggered apoptosis of estrogen receptor (ER)-positive breast cancer cell line, MCF-7. To better understand the antitumor activities of calycosin against breast cancer, besides MCF-7 cells, another ER-positive cell line T-47D was analyzed here, with ER-negative cell lines (MDA-231, MDA-435) as control. Notably, calycosin led to inhibited cell proliferation and apoptosis only in ER-positive cells, particularly in MCF-7 cells, whereas no such effect was observed in ER-negative cells. Then we investigated whether regulation of ERβ, a subtype of ER, contributed to calycosin-induced apoptosis in breast cancer cells. The results showed that incubation of calycosin resulted in enhanced expression ERβ in MCF-7 and T-47D cells, rather than MDA-231 and MDA-435 cells. Moreover, with the upregulation of ERβ, successive changes in downstream signaling pathways were found, including inactivation of insulin-like growth factor 1 receptor (IGF-1R), then stimulation of p38 MAPK and suppression of the serine/threonine kinase (Akt), and finally poly(ADP-ribose) polymerase 1 (PARP-1) cleavage. However, the other two members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were not consequently regulated by downregulated IGF-1R, indicating ERK 1/2 and JNK pathways were not necessary to allow proliferation inhibition by calycosin. Taken together, our results indicate that calycosin tends to inhibit growth and induce apoptosis in ER-positive breast cancer cells, which is mediated by ERβ-induced inhibition of IGF-1R, along with the selective regulation of MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.
doi:10.1371/journal.pone.0091245
PMCID: PMC3949755  PMID: 24618835
25.  A Comparison of Referral Criteria used by the PlusoptiX Photoscreener 
Strabismus  2013;21(3):10.3109/09273972.2013.811606.
Purpose
To evaluate the sensitivity, specificity, and predictive value of 7 different referral criteria used for the plusoptiX photoscreener on the same cohort of children.
Methods
Retrospective chart review of patients presenting to a pediatric ophthalmology clinic who underwent plusoptiX photoscreening as part of a comprehensive examination. We applied multiple referral criteria from previously published studies as well as the manufacturer’s criteria in order to calculate specificity, sensitivity, and predictive value differences between the various referral criteria. We compared all criteria to the results of a pediatric ophthalmology examination based upon the 2003 American Association for Pediatric Ophthalmology and Strabismus (AAPOS) criteria, as well as the newly accepted revision of the AAPOS referral criteria.
Results
109 children were examined with a thorough pediatric ophthalmic exam and with the plusoptiX photoscreener. Of these, 58 (53%) were confirmed to demonstrate amblyopia risk factors, according to 2003 AAPOS criteria. The plusoptiX referral criteria were adjusted to match 7 different published plusoptiX referral paradigms so that the differing referral paradigms could be analyzed for sensitivity and specificity. When comparing the differing plusoptiX referral paradigms to 2003 AAPOS criteria, the sensitivity/specificity of the 7 different paradigms were respectively: Matta/Silbert 98%/80%, Arthur (2) 67%/96%, Arnold 81%/96%, Arthur 81%/92%, PediaVision 80%/94%, plusoptiX 98%/41%, AAPOS 74%/86%. When comparing the 7 differing referral paradigms to the newly approved (2013) AAPOS criteria, the sensitivity/specificity were respectively: Matta/Silbert 98%/68%, Arthur (2) 73%/92%, Arnold 92%/90%, Arthur 86%/85%, PediaVision 90%/92%, plusoptiX 98%/35%, AAPOS 87%/87%.
Conclusion
There are multiple referral criteria available for the plusoptiX photoscreener. Screening programs need to evaluate their own requirements with respect to desired sensitivity and specificity and decide on the most appropriate referral criteria for their program. The “Arnold” criteria is the best at maximizing sensitivity and specificity utilizing the 2003 “AAPOS” criteria and the “Arnold” and “PediaVision” were best at maximizing sensitivity and specificity for the newly accepted AAPOS referral criteria. Screening programs will need to decide the level of sensitivity and specificity that they wish to obtain, but for most screening programs the “Arnold” criteria may be preferred.
doi:10.3109/09273972.2013.811606
PMCID: PMC3820012  PMID: 23978147
Amblyopia; pediatric; strabismus screening; vision screening; vision screening/diagnosis

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