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1.  Physical properties and biological/odontogenic effects of an experimentally developed fast-setting α-tricalcium phosphate-based pulp capping material 
BMC Oral Health  2014;14:87.
Recently, fast-setting α-tricalcium-phosphate (TCP) cement was developed for use in the pulp capping process. The aim of this study was to investigate the physical properties and biological effects of α-TCP cement in comparison with mineral trioxide aggregate (MTA).
We measured the setting time, pH values, compressive strength, and solubility of the two materials. We evaluated biocompatibility on the basis of cell morphology and a viability test using human dental pulp cells (hDPCs). Chemical composition of each material was analyzed by energy dispersive x-ray spectroscopic (EDS) analysis. The expression of odontogenic-related genes was evaluated by Western blotting and immunofluorescence. The calcified nodule formation was measured by Alizarin red staining. We performed the pulp capping procedure on rat teeth for histological investigation. The data were analyzed by an independent t-test for physical properties, one-way ANOVA for biological effects, and the Mann-Whitney U test for tertiary dentin formation. A P value of less than 0.05 was considered statistically significant for all tests.
The setting time, pH values, and compressive strength of α-TCP was lower than that of MTA (P < 0.05); however, the solubility of α-TCP was higher than that of MTA (P < 0.05). The resultant cell viability observed with the two materials was similar (P > 0.05). Scanning electron microscopy (SEM) revealed that cells attached to both materials were flat and had cytoplasmic extensions. The expression of odontogenic-related markers and mineralized nodule formation were higher in the two experimental groups compared to the control group (P < 0.05). Continuous tertiary dentin was formed underneath the capping materials in all samples of the tested groups.
Our study demonstrated that the α-TCP exhibited biocompatibility and odontogenicity comparable to MTA, whereas it had a quicker setting time.
PMCID: PMC4105101  PMID: 25015173
Calcium phosphate; Fast-setting; Mineral trioxide aggregate; Odontogenic; Pulp capping; Tertiary dentin
2.  Optimal Proteinuria Target for Renoprotection in Patients with IgA Nephropathy 
PLoS ONE  2014;9(7):e101935.
Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.
We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.
During a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m2/year, P = 0.03).
In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.
PMCID: PMC4086982  PMID: 25003873
3.  Protective Effect of Pinus koraiensis Needle Water Extract Against Oxidative Stress in HepG2 Cells and Obese Mice 
Journal of Medicinal Food  2013;16(7):569-576.
Needles of pine species are rich in polyphenols, which may exert beneficial effects on human health. The present study was conducted to evaluate the in vitro and in vivo antioxidant effects of Pinus koraiensis needle water extracts (PKW). HepG2 cells were pretreated with various concentrations of PKW (from 10−3 to 1 mg/mL) and oxidative stress was induced by tert-butyl hydroperoxide (t-BOOH). In the animal model, male ICR mice were fed a high-fat diet for 6 weeks to induce obesity, and then mice were continually fed a high-fat diet with or without orally administered PKW (400 mg/kg body weight) for 5 weeks. Pretreatment with PKW prevented significant increases in cytotoxicity and catalase activity induced by t-BOOH in HepG2 cells. Similarly, the catalase protein expression levels elevated by t-BOOH were abrogated in cells pretreated with PKW. In mice fed a high-fat diet, PKW significantly increased hepatic activities of catalase and glutathione reductase and lower lipid peroxidation levels were observed in the liver and kidney of mice with PKW supplementation. The present study demonstrates that PKW protects against oxidative stress in HepG2 cells treated with t-BOOH and in mice fed a high-fat diet.
PMCID: PMC3719463  PMID: 23822143
functional food; HepG2 cells; obesity; oxidative stress; Pinus koraiensis needle
4.  Efficacy of Hemocontrol Biofeedback System in Intradialytic Hypotension-Prone Hemodialysis Patients 
Journal of Korean Medical Science  2014;29(6):805-810.
We conducted a study to determine whether the hemocontrol biofeedback system (HBS) can improve intradialytic hypotension (IDH) in hypotension-prone hemodialysis (HD) patients compared with conventional HD. In this multicenter prospective crossover study, 60 hypotension-prone patients were serially treated by conventional HD for 8 weeks (period A), by HD with hemoscan blood volume monitoring for 2 weeks (period B0), and by HBS HD for 8 weeks (period B1). The number of sessions complicated by symptomatic IDH during 24 HD sessions (14.9±5.8 sessions, 62.1% in period A vs 9.2±7.2 sessions, 38.4% in period B1, P<0.001) and the number of IDH-related nursing interventions in a session (0.96±0.66 in period A vs 0.56±0.54 in period B1, P<0.001) significantly decreased in period B1 than in period A. Recovery time from fatigue after dialysis was significantly shorter in period B1 than in period A. The patients with higher post-dialysis blood pressure, lower difference between pre- and post-dialysis blood pressure, less frequent IDH, and higher pre- and post-dialysis body weight in period A responded better to HBS in period B1 in regard to the reduction of IDH. In conclusion, HBS may improve the patient tolerability to HD by reducing the IDH frequency and promoting faster recovery from fatigue after dialysis.
Graphical Abstract
PMCID: PMC4055814  PMID: 24932082
Hypotension; Renal Dialysis; Clinical Trial; Dialysis Volume
5.  Compensation for Occupational Injuries and Diseases in Special Populations: Farmers and Soldiers 
Journal of Korean Medical Science  2014;29(Suppl):S24-S31.
Some types of workers such as farmers and soldiers are at a higher risk of work-related injury and illness than workers from other occupations. Despite this fact, they are not covered under the Industrial Safety Health (ISH) Act or the Industrial Accident Compensation Insurance (IACI) Act. The Safety Aid System for Farmers (SASF) is a voluntary insurance scheme, and it is the only public compensation plan for self-employed farmers. Fifty percent of SASF premiums are subsidized by the Korean government. Soldiers are compensated by the Veterans' Pension (VP) Act. The approval standard of and procedure for the VP Act are provided in the Decree of VP Act, and the Council for VP Benefits determines work-relatedness in the claimed cases. Meanwhile, SASF applies the insurance clause automatically without any expert advice or additional procedures. Furthermore, compared with IACI, these programs pay fewer benefits to workers. Thus, a stronger institutional strategy is needed to maintain a safe work environment, to protect workers' health in unavoidably hazardous environments, and to compensate for work-related injuries and diseases.
Graphical Abstract
PMCID: PMC4085171  PMID: 25006320
Compensation; Occupational Diseases; Farmers; Soldiers
6.  The Administrative Process for Recognition and Compensation for Occupational Diseases in Korea 
Journal of Korean Medical Science  2014;29(Suppl):S3-S11.
In the Workers' Compensation Insurance (WCI) system in Korea, occupational diseases (ODs) are approved through deliberation meetings of the Committee on Occupational Disease Judgment (CODJ) after disease investigations when workers or medical institutions requested the Korea Workers' Compensation and Welfare Service (COMWEL) for medical care benefits. Insufficient data presented by employers or workers or lack of objective evidence may increase the possibility of disapproval. The expertise of accident investigation staff members should be reinforced and employers' and related institutions' obligations to cooperate and submit data should be specified under the law. The deliberation meetings of the CODJ are held separately for musculoskeletal, cerebro-cardiovascular, and medical diseases, and the judgments of ODs are made by the chairperson of COMWEL and six committee members by majority vote by issue. To reinforce the expertise of the members of the CODJ, periodic education and a system to accredit the committee members after appropriate education should be introduced. To fairly and quickly compensate for diseases that occur in workers, the criteria for the recognition of occupational diseases should be continuously amended and the systems for disease investigations and judgments should be continuously improved.
Graphical Abstract
PMCID: PMC4085172  PMID: 25006321
Occupational Diseases; Workers' Compensation; Korea
7.  Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis 
BMC Plant Biology  2014;14:136.
The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level.
We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5′ splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD.
Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress adaptation in plants. It is also envisioned that alternative splicing of the clock genes plays more complex roles than previously expected.
PMCID: PMC4035800  PMID: 24885185
Arabidopsis thaliana; Circadian clock; Transcription factor; Alternative splicing; Nonsense-mediated decay (NMD); Environmental stress
8.  Gender Differences and Socioeconomic Status in Relation to Overweight among Older Korean People 
PLoS ONE  2014;9(5):e97990.
The ever-increasing older population and its association with serious overweight problems have garnered much attention. The correlation between being overweight and socioeconomic status factors could be helpful for understanding the inequalities among the overweight population. We examined the correlation between being overweight and some key variables, such as demographics, socioeconomic status, general health status, and health behavior in a large sample of older individuals, by each gender.
We used data from the 2008 Korean Longitudinal Study of Aging and it included 8,157 participants who were 45 years or older. To understand the relationship between the overweight participants in accordance to demographic and socioeconomic characteristics, health status, and health behaviors, a weighted chi-square test and logistic regression analysis were conducted by separating variables related to overweight, according to the genders.
The number of people in the normal group was 6,347 (77.8%), while the people who were considered overweight were 1,810 (22.2%). Women (n = 4,583) constituted 52.7% of the subject, 24.9% of whom were classified as overweight. Meanwhile, 20.6% of the 47.3% (n = 3,574) of the sample who were men were classified as overweight. Participants between the ages of 45 and 64 with chronic diseases were more likely to be overweight. Men in the 4th quartile of household income were more likely to be overweight than those who were in the 1st quartile, in contrast, while unemployed women with lower education levels and urban residents were at greater risk for being overweight.
Among the men, health status and health behavior appeared to show a correlation with being overweight; however, among women, socioeconomic status factors were strongly related to being overweight. These findings appear to support the association of gender-specifics with the prevalence of being overweight.
PMCID: PMC4024045  PMID: 24836697
9.  Transgene-mediated co-suppression of DNA topoisomerase-1 gene in Caenorhabditis elegans  
Ectopic expression of multi-transgenic copies can result in reduced expression of the transgene and can induce silence of endogenous gene; this process is called as co-suppression. Using a transgene-mediated co-suppression technique, we demonstrated the biological function of DNA topoisomerase-1 (top-1) in C. elegans development. Introduction of full-length top-1 transgene sufficiently induced the co-suppression of endogenous top-1 gene, causing embryonic lethality and abnormal germline development. We also found that the co-suppression of top-1 gene affected morphogenesis, lifespan and larval growth that were not observed in top-1 (RNAi) animals. Strikingly, co-suppression effects were significantly reduced by the elimination of top-1 introns, suggesting that efficient co-suppression may require intron(s) in C. elegans. Sequence analysis revealed that the introns 1 and 2 of top-1 gene possess consensus binding sites for several transcription factors, including MAB-3, LIN-14, TTX-3/CEH-10, CEH-1, and CEH-22. Among them, we examined a genetic link between ceh-22 and top-1. The ceh-22 is partially required for the specification of distal tip cells (DTC), which functions as a stem cell niche in the C. elegans gonad. Intriguingly, top-1 (RNAi) significantly enhanced DTC loss in ceh-22 mutant gonads, indicating that top-1 may play an important role in CEH-22-mediated DTC fate specification. Therefore, our findings suggest that transgene-mediated co-suppression facilitates the silencing of the specific genes and the study of gene function in vivo.
PMCID: PMC4058960  PMID: 24955284
DNA topoisomerase I; co-suppression; Caenorhabditis elegans; morphogenesis; distal tip cells (DTCs); lifespan
10.  The Hippo Signaling Pathway Interactome 
Science (New York, N.Y.)  2013;342(6159):737-740.
The Hippo pathway controls metazoan organ growth by regulating cell proliferation and apoptosis. Many components have been identified, but our knowledge of the composition and structure of this pathway is still incomplete. Using existing pathway components as baits, we generated by mass spectrometry a high-confidence Drosophila Hippo protein-protein interaction network (Hippo-PPIN) consisting of 153 proteins and 204 interactions. Depletion of 67% of the proteins by RNA interference regulated the transcriptional coactivator Yorkie (Yki) either positively or negatively. We selected for further characterization a new member of the alpha-arrestin family, Leash, and show that it promotes degradation of Yki through the lysosomal pathway. Given the importance of the Hippo pathway in tumor development, the Hippo-PPIN will contribute to our understanding of this network in both normal growth and cancer.
PMCID: PMC3951131  PMID: 24114784
11.  Impact of Parental Socioeconomic Status on Childhood and Adolescent Overweight and Underweight in Korea 
Journal of Epidemiology  2014;24(3):221-229.
The prevalence of overweight and underweight is steadily increasing among children and adolescents. To explore the relationship between parental socioeconomic status and body mass index, we examined levels of overweight and underweight among representative samples of children and adolescents in South Korea.
We analyzed data from the 2009 Korean Survey on the Obesity of Youth and Children, conducted by the National Youth Policy Institute. The sample response rate for this survey was 93.9%. After excluding 745 subjects who had missing information on age, height, or weight, 9411 subjects were included. To measure parental socioeconomic status, 4 categories were assessed by using a structured questionnaire: subjective economic status, parental education level, parental occupational status, and family structure. We used the chi-squared test in univariable analysis and multinomial logistic regression in multivariable analysis.
Multinomial logistic regression analysis identified sex, education level, parental interest in weight management, and parental body shapes as statistically significant characteristics affecting overweight in children, and sex, place of residence, parental interest in weight management, and paternal and maternal body shapes as statistically significant characteristics affecting underweight (P < 0.05).
Underweight and overweight coexist among adolescent Korean males of low socioeconomic status, which indicates that these conditions can coexist in developed countries. Appropriate interventions to address both overweight and underweight in adolescents are required.
PMCID: PMC4000770  PMID: 24614915
childhood and adolescent overweight and underweight; Korea; parental factors; risk factor; socioeconomic status
13.  Association between Physical Activity and Health-Related Quality of Life in Korean: The Korea National Health and Nutrition Examination Survey IV 
Korean Journal of Family Medicine  2014;35(3):152-159.
Numerous studies have identified that physical activity (PA) has positive influences on quality of life. However, there has been little domestic research about the relation of PA to health-related quality of life (HRQoL) among the general population. The purpose of this study was to evaluate the effect of PA on HRQoL in Korean adults aged 40 years or over.
This cross-sectional study was based on data acquired from the Korean National Health and Nutrition Examination Survey IV. Final study subjects were 10,392 adults aged 40 years or over. According to the severity and frequency of PA, the subjects were divided into three PA groups as follows: high-activity, mid-activity, and low-activity group. We compared the HRQoL estimated by the EuroQoL 5-dimension (EQ-5D), the EQ visual analogue scale (EQ-VAS), and EQ-5D index between three PA groups.
The odds ratios for mid-activity group and high activity group compared with low activity group were significantly decreased in the dimension of mobility of EQ-5D (mid-activity group, 0.81 [0.69-0.94]; high activity group, 0.81 [0.67-0.99]). EQ-VAS was decreased as PA level was lowered from high activity group and mid-activity to low activity group. EQ-5D index was the highest in mid-activity group and the lowest in low activity group.
PA above mid-activity group showed better HRQoL compared than low activity group.
PMCID: PMC4040433  PMID: 24921034
Motor Activity; Quality of Life; Population; Health
14.  Effect of Long-Term Dietary Arginyl-Fructose (AF) on Hyperglycemia and HbA1c in Diabetic db/db Mice 
We have previously reported that Amadori compounds exert anti-diabetic effects by lowering sucrose-induced hyperglycemia in normal Sprague-Dawley rats. In the present study we extended our recent findings to evaluate whether α-glucosidase inhibitor arginyl-fructose (AF) lowers blood glucose level in diabetic db/db mice, a genetic model for type 2 diabetes. The db/db mice were randomly assigned to high-carbohydrate diets (66.1% corn starch) with and without AF (4% in the diet) for 6 weeks. Changes in body weight, blood glucose level, and food intake were measured daily for 42 days. Dietary supplementation of AF resulted in a significant decrease of blood glucose level (p < 0.001) and body weight (p < 0.001). The level of HbA1c, a better indicator of plasma glucose concentration over prolonged periods of time, was also significantly decreased for 6-week period (p < 0.001). Dietary treatment of acarbose® (0.04% in diet), a positive control, also significantly alleviated the level of blood glucose, HbA1c, and body weight. These results indicate that AF Maillard reaction product improves postprandial hyperglycemia by suppressing glucose absorption as well as decreasing HbA1c level.
PMCID: PMC4057735  PMID: 24823880
type 2 diabetes; pre-diabetes; blood glucose; α-glucosidase inhibition; arginyl-fructose (AF)
15.  Direct endothelial junction restoration results in significant tumor vascular normalization and metastasis inhibition in mice 
Oncotarget  2014;5(9):2761-2777.
Tumor blood vessels are leaky and immature, which causes inadequate blood supply to tumor tissues resulting in hypoxic microenvironment and promotes metastasis. Here we have explored tumor vessel modulating activity of Sac-1004, a recently developed molecule in our lab, which directly potentiates VE-cadherin-mediated endothelial cell junction. Sac-1004 could enhance vascular junction integrity in tumor vessels and thereby inhibit vascular leakage and enhance vascular perfusion. Improved perfusion enabled Sac-1004 to have synergistic anti-tumor effect on cisplatin-mediated apoptosis of tumor cells. Interestingly, characteristics of normalized blood vessels namely reduced hypoxia, improved pericyte coverage and decreased basement membrane thickness were readily observed in tumors treated with Sac-1004. Remarkably, Sac-1004 was also able to inhibit lung and lymph node metastasis in MMTV and B16BL6 tumor models. This was in correlation with a reduction in epithelial-to-mesenchymal transition of tumor cells with considerable diminution in expression of related transcription factors. Moreover, cancer stem cell population dropped substantially in Sac-1004 treated tumor tissues. Taken together, our results showed that direct restoration of vascular junction could be a significant strategy to induce normalization of tumor blood vessels and reduce metastasis.
PMCID: PMC4058043  PMID: 24811731
Vascular permeability; Hypoxia; Normalization; Epithelial-to-mesenchymal transition; Sac-1004
16.  Antiviral activity of ginseng extract against respiratory syncytial virus infection 
Panax ginseng has been known to have a number of immuno-modulatory effects. In this study, we investigated whether Panax Korean red ginseng extract (KRGE) has in vitro and in vivo antiviral effects on respiratory syncytial virus (RSV) infection. KRGE improved the survival of human lung epithelial cells against RSV infection and inhibited RSV replication. In addition, KRGE treatment suppressed the expression of RSV-induced inflammatory cytokine genes (IL-6 and IL-8) and the formation of reactive oxygen species in epithelial cell cultures. Oral administration of mice with KRGE resulted in lowering lung viral loads after RSV infection. Additionally, the in vivo effects of KRGE showed an enhanced level of interferon-γ (IFN-γ) producing dendritic cells subsequent to RSV infection. Taken together, these results suggested that KRGE has antiviral activity against RSV infection.
PMCID: PMC4072342  PMID: 24756136
Panax ginseng; respiratory syncytial virus; viral replication; interferon
17.  Multi-donor Analysis Reveals Structural Elements, Genetic Determinants, and Maturation Pathway for Effective HIV-1 Neutralization by VRCO1-class Antibodies 
Immunity  2013;39(2):245-258.
Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >1012 antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few—likely one—ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.
PMCID: PMC3985390  PMID: 23911655
18.  Reproducibility of SD-OCT–Based Ganglion Cell–Layer Thickness in Glaucoma Using Two Different Segmentation Algorithms 
To compare the reproducibility of spectral-domain optical coherence tomography (SD-OCT)–based ganglion cell–layer-plus-inner plexiform–layer (GCL+IPL) thickness measurements for glaucoma patients obtained using both a publicly available and a commercially available algorithm.
Macula SD-OCT volumes (200 × 200 × 1024 voxels, 6 × 6 × 2 mm3) were obtained prospectively from both eyes of patients with open-angle glaucoma or with suspected glaucoma on two separate visits within 4 months. The combined GCL+IPL thickness was computed for each SD-OCT volume within an elliptical annulus centered at the fovea, based on two algorithms: (1) a previously published graph-theoretical layer segmentation approach developed at the University of Iowa, and (2) a ganglion cell analysis module of version 6 of Cirrus software. The mean overall thickness of the elliptical annulus was computed as was the thickness within six sectors. For statistical analyses, eyes with an SD-OCT volume with low signal strength (<6), image acquisition errors, or errors in performing the commercial GCL+IPL analysis in at least one of the repeated acquisitions were excluded.
Using 104 eyes (from 56 patients) with repeated measurements, we found the intraclass correlation coefficient for the overall elliptical annular GCL+IPL thickness to be 0.98 (95% confidence interval [CI]: 0.97–0.99) with the Iowa algorithm and 0.95 (95% CI: 0.93–0.97) with the Cirrus algorithm; the intervisit SDs were 1.55 μm (Iowa) and 2.45 μm (Cirrus); and the coefficients of variation were 2.2% (Iowa) and 3.5% (Cirrus), P < 0.0001.
SD-OCT–based GCL+IPL thickness measurements in patients with early glaucoma are highly reproducible.
SD-OCT–based ganglion cell–layer plus inner plexiform–layer thickness measurements for glaucoma patients, obtained with both a publicly available and a commercially available algorithm, are highly reproducible.
PMCID: PMC3809946  PMID: 24045993
ganglion cell layer; glaucoma; image segmentation; reproducibility
19.  Residue-Level Prediction of HIV-1 Antibody Epitopes Based on Neutralization of Diverse Viral Strains 
Journal of Virology  2013;87(18):10047-10058.
Delineation of antibody epitopes at the residue level is key to understanding antigen resistance mutations, designing epitope-specific probes for antibody isolation, and developing epitope-based vaccines. Ideally, epitope residues are determined in the context of the atomic-level structure of the antibody-antigen complex, though structure determination may in many cases be impractical. Here we describe an efficient computational method to predict antibody-specific HIV-1 envelope (Env) epitopes at the residue level, based on neutralization panels of diverse viral strains. The method primarily utilizes neutralization potency data over a set of diverse viral strains representing the antigen, and enhanced accuracy could be achieved by incorporating information from the unbound structure of the antigen. The method was evaluated on 19 HIV-1 Env antibodies with neutralization panels comprising 181 diverse viral strains and with available antibody-antigen complex structures. Prediction accuracy was shown to improve significantly over random selection, with an average of greater-than-8-fold enrichment of true positives at the 0.05 false-positive rate level. The method was used to prospectively predict epitope residues for two HIV-1 antibodies, 8ANC131 and 8ANC195, for which we experimentally validated the predictions. The method is inherently applicable to antigens that exhibit sequence diversity, and its accuracy was found to correlate inversely with sequence conservation of the epitope. Together the results show how knowledge inherent to a neutralization panel and unbound antigen structure can be utilized for residue-level prediction of antibody epitopes.
PMCID: PMC3753990  PMID: 23843642
20.  Robotic Assisted Laparoscopic Prostatectomy in Men with Proctocolectomy and Restorative Ileal Pouch-Anal Anastomosis 
Case Reports in Urology  2014;2014:538382.
We conducted a retrospective chart review of robotic prostatectomies done by a single surgeon between 2003 and 2012. During that time period, we identified two patients within the year 2012, with ileal pouch-anal anastomosis (IPPA) who also underwent robotic prostatectomies. The demographics and postoperative characteristics of the two patients were assessed. In both patients, prostatectomy, bilateral nerve sparing, and pelvic lymphadenectomy were successfully performed and the integrity of ileal pouch was maintained. There was a mean surgical time of 144.5 minutes, and an average estimated blood loss was 125 mL. Both patients were discharged on the second day postoperatively. In both patients there was a Gleason upgrade to 3 + 4, with negative margins, and preservation of fecal and urinary continence by their six-month followup. Owing to surgical modifications, these two surgeries represent the first successful robotic prostatectomies in patients with a J-pouch.
PMCID: PMC3933405  PMID: 24653856
21.  Identification of Proteins that Interact with TANK Binding Kinase 1 and Testing for Mutations Associated with Glaucoma 
Current eye research  2013;38(2):310-315.
Copy number variations (duplications) of TANK binding kinase 1 (TBK1) have been associated with normal tension glaucoma (NTG), a common cause of blindness worldwide. Mutations in other genes involved in autophagy (TLR4 and OPTN) have been associated with NTG. Here we report searching for additional proteins involved in autophagy that may also have roles in NTG.
Materials and methods
HEK-293T cells were transfected to produce synthetic TBK1 protein with FLAG and S tags. Proteins that associate with TBK1 were isolated from HEK-293T lysates using tandem affinity purification (TAP) and polyacrylamide gel electrophoresis (PAGE). Isolated proteins were identified with mass spectrometry. A cohort of 148 NTG patients and 77 controls from Iowa were tested for glaucoma-causing mutations in genes that encode identified proteins that interact with TBK1 using high resolution melt (HRM) analysis and DNA sequencing.
TAP studies show that three proteins expressed in HEK-293T cells (NAP1, TANK and TBKBP1) interact with TBK1. Testing cohorts of NTG and normal controls for disease-causing mutations in TANK, identified a total of nine unique variants including three non-synonymous changes, one synonymous changes and five intronic changes. When analyzed alone or as a group, the non-synonymous TBK1 coding sequence changes were not associated with either NTG or primary open angle glaucoma.
TAP showed that NAP1, TANK and TBKBP1 interact with TBK1 and are good candidates for contributing to NTG. A mutation screen of TANK detected three non-synonymous variants. Although, it remains possible that one or more of these TANK mutations may have a role in NTG, the data in this report do not provide statistical support for an association between TANK variants and NTG.
PMCID: PMC3700396  PMID: 23286385
Glaucoma; tandem affinity purification; TKB1
22.  Immunomodulatory Activity of Red Ginseng against Influenza A Virus Infection 
Nutrients  2014;6(2):517-529.
Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-γ production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions.
PMCID: PMC3942714  PMID: 24473234
Panax ginseng; influenza A virus; epithelial cells; oxidative stress; interferon
23.  SUMO Modification of NZFP Mediates Transcriptional Repression through TBP Binding 
Molecules and Cells  2012;35(1):70-78.
The negatively regulating zinc finger protein (NZFP) is an essential transcription repressor required for early development during gastrulation in Xenopus laevis. In this study, we found that NZFP interacts with the small ubiquitin-like modifier (SUMO) conjugation E2 enzyme, Ubc9, and contains three putative SUMO conjugation sites. Studies with NZFP mutants containing mutations at the putative SUMO conjugation sites showed that these sites were able to be modified independently with SUMO. NZFP was found to be localized in the same nuclear bodies with SUMO-1. However, sumoylation of NZFP did not play a role either in the translocation of NZFP into the nucleus or on nuclear body formation. While wild type NZFP showed significant transcriptional repression, SUMO-conjugation site mutants manifested a decrease in transcriptional repression activity which is reversely proportional to the amount of sumoylation. The sumoylation defective mutant lost its TBP binding activity, while wild type NZFP interacted with TBP and inhibited transcription complex formation. These results strongly suggest that the sumoylation of NZFP facilitates NZFP to bind to TBP and the NZFP/TBP complex then represses the transcription of the target gene by inhibiting basal transcription complex formation.
PMCID: PMC3887854  PMID: 23269432
development; NZFP; SUMO; TATA binding protein; Xenopus
24.  Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site 
PLoS ONE  2014;9(1):e85940.
Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.
PMCID: PMC3904841  PMID: 24489681
25.  Adjustment of the Retinal Angle in SD-OCT of Glaucomatous Eyes Provides Better Intervisit Reproducibility of Peripapillary RNFL Thickness 
To report an automated method for adjustment of the retinal angle in spectral-domain optical coherence tomography (SD-OCT) and compare its intervisit reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thicknesses of glaucomatous eyes to that obtained by the Cirrus algorithm.
Fifty-six glaucoma and glaucoma suspect subjects were repeatedly imaged, and optic nerve head (ONH)–centered OCT image volumes (200 × 200 × 1024 voxels, 6 × 6 × 2 mm3, Cirrus HD-OCT machine) were acquired within a 4-month period from one eye of the 56 patients. Retinal angle correction in B-scans was accomplished by adjusting the angle using the voxel aspect ratio of the SD-OCT followed by straightening of rotated A-scans. The RNFL layer was automatically segmented using the Iowa Reference Algorithm. Reproducibility of the peripapillary RNFL thicknesses was determined by intraclass correlation coefficient (ICC), coefficient of variation (CV), repeatability coefficient (RC), and 95% tolerance limit (TL) for the Iowa Reference Algorithm without and with the retinal angle correction and for the Cirrus algorithm (Cirrus version
The angle corrected Iowa Reference Algorithm (ICC: 0.990, 95% confidence interval [CI]: 0.983–0.994) for peripapillary RNFL thicknesses showed significantly better reproducibility than the nonangle corrected algorithm (ICC: 0.964, 95% CI: 0.940–0.979) and the Cirrus algorithm (ICC: 0.960, 95% CI: 0.933–0.976) based on the 95% CIs for the ICCs.
Angle correction leads to more consistent peripapillary RNFL thicknesses. This may lead to improved management of patients with glaucoma.
We report an automated method for adjustment of the retinal angle in spectral-domain optical coherence tomography (SD-OCT) and compare its intervisit reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thicknesses of glaucomatous eyes to that obtained by the Cirrus algorithm.
PMCID: PMC3720146  PMID: 23788372
spectral-domain coherence tomography (SD-OCT); retinal angle adjustment; peripapillary retinal nerve fiber layer (RNFL) thickness

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