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1.  Bumblebee Venom Serine Protease Increases Fungal Insecticidal Virulence by Inducing Insect Melanization 
PLoS ONE  2013;8(4):e62555.
Insect-killing (entomopathogenic) fungi have high potential for controlling agriculturally harmful pests. However, their pathogenicity is slow, and this is one reason for their poor acceptance as a fungal insecticide. The expression of bumblebee, Bombus ignitus, venom serine protease (VSP) by Beauveria bassiana (ERL1170) induced melanization of yellow spotted longicorn beetles (Psacothea hilaris) as an over-reactive immune response, and caused substantially earlier mortality in beet armyworm (Spodopetra exigua) larvae when compared to the wild type. No fungal outgrowth or sporulation was observed on the melanized insects, thus suggesting a self-restriction of the dispersal of the genetically modified fungus in the environment. The research is the first use of a multi-functional bumblebee VSP to significantly increase the speed of fungal pathogenicity, while minimizing the dispersal of the fungal transformant in the environment.
PMCID: PMC3633896  PMID: 23626832
2.  Genetic and Epigenetic Regulation in Age-related Macular Degeneration 
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the older population worldwide. While strong genetic risk factors have been associated with AMD etiology, environmental influences through epigenetic regulation are also likely to play a role. Recent advances in epigenetic studies have resulted in the development of numerous epigenetic drugs for the treatment of cancer and inflammation. Here, we review the current literature on the genetic and epigenetic mechanisms of AMD and suggest that understanding the cooperation of epigenetic and genetic mechanisms will greatly advance the clinical management of AMD.
PMCID: PMC3755470  PMID: 23997991
3.  Are glucocorticoid-induced osteoporosis recommendations sufficient to determine antiosteoporotic treatment for patients with rheumatoid arthritis? 
We investigated differences in identifying candidates for antiosteoporotic treatment in rheumatoid arthritis (RA) patients according to two available clinical guidelines.
We prospectively enrolled 100 female patients aged 50 years or older with RA who visited Hanyang University Hospital for periodic examinations between April 2011 and August 2011. We applied the glucocorticoid-induced osteoporosis (GIOP) recommendations and the National Osteoporosis Foundation (NOF) guidelines to RA patients and examined agreement between the guidelines for identifying candidates for antiosteoporotic treatment. We also analyzed the impact of screening vertebral fractures (VFs) in determining the treatment of osteoporosis in RA patients.
The 57 patients taking glucocorticoids were classified into high-risk (n = 23), medium-risk (n = 16), and low-risk (n = 18) groups according to the GIOP recommendations. Based on the NOF guidelines, 36 of 57 patients were candidates for antiosteoporotic treatment and the agreement between two guidelines was high (κ = 0.76). Two of the 18 patients in the low-risk group and 19 of 43 patients not eligible per the GIOP recommendations were classified as candidates for antiosteoporotic treatment by the NOF guidelines.
In determining antiosteoporotic treatment for RA patients, using only the GIOP recommendations is insufficient. Application of the NOF guidelines in patients not eligible for or classified into the low-risk group per the GIOP recommendations and screening for VFs may be helpful in deciding on antiosteoporotic treatment in RA patients.
PMCID: PMC4101598  PMID: 25045299
Glucocorticoids; Osteoporosis; Arthritis, rheumatoid; Guideline
4.  The Influence of Vertebral Fracture on the Functional Disability of Patients with Rheumatoid Arthritis 
Journal of Korean Medical Science  2014;29(6):859-863.
The aim of the present study was to identify the influence of vertebral fracture (VF) on the functional disability in patients with rheumatoid arthritis (RA). This study consecutively enrolled 100 female patients aged 50 yr or older with RA. All participants underwent lateral imaging of the thoracolumbar spine by simple radiography to identify any VFs. They also completed questionnaires via interview regarding demographics, medical history, and disease outcomes including functional disability. We used univariate analysis to evaluate associations between functional disability and VF, and made multivariate logistic regression models to test independent effect of the presence of VF, the number of VFs, and the severity of VF on functional disability. Among the 100 RA patients, 47 had at least one VF, but 34 of them were asymptomatic that they had experienced a fracture. The multiple VFs ≥ 3 (OR, 8.95; 95% CI, 1.77-44.15, P = 0.01) and moderate or severe VF (OR, 3.38; 95% CI, 1.26-9.04, P = 0.02) were related to disability in univariate analysis. The multiple VFs ≥ 3 (OR, 6.13; 95% CI, 1.02-36.94, P = 0.048) was associated with functional disability of RA patients after adjusting various confounders and it was mainly in walking and arising. The VF might be an important factor which affects functional disability in RA patients.
Graphical Abstract
PMCID: PMC4055822  PMID: 24932090
Arthritis, Rheumatoid; Spinal Fractures; Health Assessment Questionaire
5.  Notch Intracellular Domain Expression in Various Skin Fibroproliferative Diseases 
Annals of Dermatology  2014;26(3):332-337.
The effects of the Notch signaling pathway in fibroproliferative skin diseases have not been fully elucidated.
The aim of this study was to investigate the expression of activated Notch signaling molecules in various skin fibroproliferative diseases.
Immunohistochemical analysis of Notch intracellular domain (NICD) expression in keloid, hypertrophic scar, morphea, dermatofibroma, and normal control skin specimens was performed, and the clinical characteristics of patients with various skin fibroproliferative diseases were analyzed.
NICD was highly expressed in fibroblasts of keloids and moderately to highly expressed in hypertrophic scars and dermatofibromas, whereas low or no expression was detected in the fibroblasts of normal skin specimens and morpheas. NICD was constitutively expressed in keratinocytes, endothelial cells, and immune cells in normal skin specimens.
NICD was significantly expressed in human fibroproliferative skin disorders, especially keloids, suggesting that an activated Notch signaling pathway is involved in the pathogenesis of skin fibrosis.
PMCID: PMC4069643  PMID: 24966632
Benign fibrous histiocytoma; Hypertrophic cicatrix; Keloid; Localized scleroderma; Notch receptors
6.  The Autographa californica Multiple Nucleopolyhedrovirus ORF78 Is Essential for Budded Virus Production and General Occlusion Body Formation 
Journal of Virology  2013;87(15):8441-8450.
ORF78 (ac78) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a baculovirus core gene of unknown function. To determine the role of ac78 in the baculovirus life cycle, an AcMNPV mutant with ac78 deleted, Ac78KO, was constructed. Quantitative PCR analysis revealed that ac78 is a late gene in the viral life cycle. After transfection into Spodoptera frugiperda cells, Ac78KO produced a single-cell infection phenotype, indicating that no infectious budded viruses (BVs) were produced. The defect in BV production was also confirmed by both viral titration and Western blotting. However, viral DNA replication was unaffected, and occlusion bodies were formed. An analysis of BVs and occlusion-derived viruses (ODVs) revealed that AC78 is associated with both forms of the virions and is an envelope structural protein. Electron microscopy revealed that AC78 also plays an important role in the embedding of ODV into the occlusion body. The results of this study demonstrate that AC78 is a late virion-associated protein and is essential for the viral life cycle.
PMCID: PMC3719795  PMID: 23698311
7.  Poor agreement between QuantiFERON-TB Gold test and tuberculin skin test results for the diagnosis of latent tuberculosis infection in rheumatoid arthritis patients and healthy controls 
We investigated the agreement between the QuantiFERON-TB Gold (QFT-Gold) test and the tuberculin skin test (TST) in the diagnosis of latent tuberculosis infection in patients with rheumatoid arthritis (RA), compared with healthy controls, in Korea.
We recruited 64 patients with RA and 79 healthy controls at two university hospitals in South Korea. The participants underwent both the QFT-Gold test and the TST simultaneously between August 2006 and February 2009. All patients were diagnosed using the classification criteria for RA revised in 1987 by the American College of Rheumatology. Bacillus Calmette-Guérin vaccination status and current medications were evaluated, and disease activities were assessed using the Disease Activity Score in 28 joints. Eleven patients with RA produced indeterminate QFT-Gold test results and were thus excluded from the kappa analysis.
Based on an induration of 10 mm in diameter as the TST cutoff value, the QFT-Gold test and TST demonstrated 75.0% agreement (κ = 0.23) in patients with RA and 75.9% agreement (κ = 0.19) in healthy controls. Among the 56 patients with RA who had negative TST results, 11 patients (17.2%) also yielded indeterminate QFT-Gold results.
Our study showed poor agreement between the results of the QFT-Gold test and the TST in both RA patients and healthy controls. Based on these findings, we emphasize the importance of making clinical decisions in the diagnosis of latent tuberculosis in Koreans with or without RA.
PMCID: PMC3932398  PMID: 24574836
QuantiFERON-TB Gold test; Tuberculin skin test; Latent tuberculosis; Arthritis, rheumatoid
8.  Bimolecular Fluorescence Complementation; Lighting-Up Tau-Tau Interaction in Living Cells 
PLoS ONE  2013;8(12):e81682.
Abnormal tau aggregation is a pathological hallmark of many neurodegenerative disorders and it is becoming apparent that soluble tau aggregates play a key role in neurodegeneration and memory impairment. Despite this pathological importance, there is currently no single method that allows monitoring soluble tau species in living cells. In this regard, we developed a cell-based sensor that visualizes tau self-assembly. By introducing bimolecular fluorescence complementation (BiFC) technique to tau, we were able to achieve spatial and temporal resolution of tau-tau interactions in a range of states, from soluble dimers to large aggregates. Under basal conditions, tau-BiFC cells exhibited little fluorescence intensity, implying that the majority of tau molecules exist as monomers. Upon chemically induced tau hyperphosphorylation, BiFC fluorescence greatly increased, indicating an increased level of tau-tau interactions. As an indicator of tau assembly, our BiFC sensor would be a useful tool for investigating tau pathology.
PMCID: PMC3847076  PMID: 24312574
9.  Effect of quercetin on apoptosis of PANC-1 cells 
To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells.
Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin.
Treatment with quercetin resulted in the increased accumulation of intracellular Ca2+ ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction.
These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents.
PMCID: PMC3868676  PMID: 24368982
Quercetin; Drug therapy; Apoptosis; Pancreatic neoplasms
10.  Transcriptome Analysis of the Small Brown Planthopper, Laodelphax striatellus Carrying Rice stripe virus 
The Plant Pathology Journal  2013;29(3):330-337.
Rice stripe virus (RSV), the type member of the genus Tenuivirus, transmits by the feeding behavior of small brown planthopper (SBPH), Laodelphax striatellus. To investigate the interactions between the virus and vector insect, total RNA was extracted from RSV-viruliferous SBPH (RVLS) and non-viruliferous SBPH (NVLS) adults to construct expressed sequence tag databases for comparative transcriptome analysis. Over 30 million bases were sequenced by 454 pyrosequencing to construct 1,538 and 953 of isotigs from the mRNA of RVLS and NVLS, respectively. The gene ontology (GO) analysis demonstrated that both libraries have similar GO structures, however, the gene expression pattern analysis revealed that 17.8% and 16.8% of isotigs were up- and down-regulated significantly in the RVLS, respectively. These RSV-dependently regulated genes possibly have important roles in the physiology of SBPH, transmission of RSV, and RSV and SBPH interaction.
PMCID: PMC4174806  PMID: 25288960
Laodelphax striatellus; Rice stripe virus; small brown planthopper; tenuivirus; transcriptome
11.  Fine Mapping of Xq28: Both MECP2 and IRAK1 Contribute to Risk for Systemic Lupus Erythematosus in Multiple Ancestral Groups 
Annals of the rheumatic diseases  2012;72(3):437-444.
The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE.
We fine-mapped ≥136 SNPs in a ~227kb region on Xq28, containing IRAK1, MECP2 and 7 adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15,783 case-control subjects derived from 4 different ancestral groups.
Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at P<5×10−8 with consistent association in subjects with African ancestry. Of these, 6 SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all 4 ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest P value in trans-ancestral meta-analysis (Pmeta=1.3×10−27, OR=1.43), and thus was considered to be the most-likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (P=0.0012) and healthy controls (P=0.0064).
These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.
PMCID: PMC3567234  PMID: 22904263
Systemic Lupus Erythematosus; Gene Polymorphism; Xq28; IRAK1; MECP2
12.  Association of PPP2CA polymorphisms with SLE susceptibility in multiple ethnic groups 
Arthritis and rheumatism  2011;63(9):2755-2763.
T cells from patients with SLE express increased amounts of PP2Ac which contribute to decreased production of IL-2. Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
We conducted a trans-ethnic study consisting of 8,695 SLE cases and 7,308 controls from four different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across the PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time PCR.
A 32-kb haplotype comprised of multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans (HA), European Americans (EA) and Asians but not in African-Americans (AA). Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, EA and HA populations (pmeta=3.8×10−7, OR=1.3[1.14–1.31]). In EA, the largest ethnic dataset, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-dsDNA and anti-RNP antibodies. PPP2CA expression was approximately 2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying GG genotype (p = 0.008).
Our data provide the first evidence for an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in EA, HA and Asians.
PMCID: PMC3163110  PMID: 21590681
13.  Analysis of Genes Expression of Spodoptera exigua Larvae upon AcMNPV Infection 
PLoS ONE  2012;7(7):e42462.
The impact of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) infection on host gene expression in Spodoptera exigua 4th instar larvae was investigated through the use of 454 sequencing-based RNA-seq of cDNA libraries developed from insects challenged with active AcMNPV or heat-inactivated AcMNPV.
Methodology/Principal Findings
By comparing the two cDNA libraries, we show that 201 host genes are significantly up-regulated and 234 genes are significantly down-regulated by active AcMNPV infection. Down-regulated host genes included genes encoding antimicrobial peptides, namely three gloverin isoforms and an attacin, indicating that the viral infection actively repressed the expression of a portion of the host immune gene repertoire. Another interesting group of down-regulated host genes included genes encoding two juvenile hormone binding proteins and a hexamerin, all of which are involved in juvenile hormone regulation. The expression of these genes was enhanced by the topical application of Juvenile Hormone III (JHIII) in the insects challenged with heat-inactivated AcMNPV. However, infection with the active virus strongly suppresses the expression of these three genes, regardless of the absence or presence of JHIII.
Using RNA-seq, we have identified groups of immune-regulated and juvenile hormone-regulated genes that are suppressed by infection with active AcMNPV. This information and further studies on the regulation of host gene expression by AcMNPV will provide the tools needed to enhance the utility of the virus as an effective protein expression system and as an insecticide.
PMCID: PMC3409162  PMID: 22860129
14.  Quantitative localization of impacted mesiodens using panoramic and periapical radiographs 
Imaging Science in Dentistry  2011;41(2):63-69.
The purpose of this study was to evaluate a new technique for localizing impacted mesiodens using its horizontal magnification ratio on panoramic radiographs.
Materials and Methods
Location-magnification equation of a panoramic equipment was obtained from horizontal magnification ratio of a metal ball which was located variable positions from the center of image layer at interval of 2 mm. Panoramic radiographs were obtained from a skull phantom with a metal ball which was a substitute for impacted mesiodens and was embedded 10mm(Group 1), 15mm(Group 2), and 20mm(Group 3) posterior to the central incisor. Each group obtained 7 panoramic radiographs at variable positions and one periapical radiograph. Three methods were used to estimate the actual width of the incisors and the balls which were used to calculate the magnification ratio. The methods included using the actual incisor width and the calculated ball width (Method 1), using the actual incisor width and the ball widths measured on periapical radiograph (Method 2), and using the incisor and the ball widths measured on periapical radiograph (Method 3). The location of the metal ball was calculated by using the location-magnification equation.
The smallest difference between the calculated and the actual distance was 0.1±0.7 mm in Group 1/Method 3. The largest difference was -4.2±1.6 mm in Group 3/Method 2. In all groups, method 3 was the most accurate.
Quantitative localization of impacted mesiodens is possible by using panoramic radiograph.
PMCID: PMC3174464  PMID: 21977477
Radiography, Dental; Radiography, Panoramic; Tooth, Supernumerary

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