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1.  Reproducibility of SD-OCT–Based Ganglion Cell–Layer Thickness in Glaucoma Using Two Different Segmentation Algorithms 
Purpose.
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.
Methods.
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.
Results.
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.
Conclusions.
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.
doi:10.1167/iovs.13-12131
PMCID: PMC3809946  PMID: 24045993
ganglion cell layer; glaucoma; image segmentation; reproducibility
2.  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.
doi:10.1128/JVI.00984-13
PMCID: PMC3753990  PMID: 23843642
3.  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.
doi:10.1155/2014/538382
PMCID: PMC3933405  PMID: 24653856
4.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.3109/02713683.2012.754047
PMCID: PMC3700396  PMID: 23286385
Glaucoma; tandem affinity purification; TKB1
5.  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.
doi:10.3390/nu6020517
PMCID: PMC3942714  PMID: 24473234
Panax ginseng; influenza A virus; epithelial cells; oxidative stress; interferon
6.  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.
doi:10.1007/s10059-013-2281-1
PMCID: PMC3887854  PMID: 23269432
development; NZFP; SUMO; TATA binding protein; Xenopus
7.  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.
doi:10.1371/journal.pone.0085940
PMCID: PMC3904841  PMID: 24489681
8.  Adjustment of the Retinal Angle in SD-OCT of Glaucomatous Eyes Provides Better Intervisit Reproducibility of Peripapillary RNFL Thickness 
Purpose.
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.
Methods.
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 5.1.0.96).
Results.
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.
Conclusions.
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.
doi:10.1167/iovs.13-12211
PMCID: PMC3720146  PMID: 23788372
spectral-domain coherence tomography (SD-OCT); retinal angle adjustment; peripapillary retinal nerve fiber layer (RNFL) thickness
9.  Effect of Peritoneal Dialysis Modality on the 1-Year Rate of Decline of Residual Renal Function 
Yonsei Medical Journal  2013;55(1):141-148.
Purpose
The effect of different peritoneal dialysis (PD) modalities on the decline in residual renal function (RRF) is unclear due to inconsistencies among studies. In particular, the effect of automated peritoneal dialysis (APD) modalities [continuous cyclic peritoneal dialysis (CCPD) and nightly intermittent peritoneal dialysis (NIPD)] on RRF has not been examined in a large cohort.
Materials and Methods
We conducted a single-center retrospective study to investigate the association between PD modalities and decline in RRF in 142 incident PD patients [34 on CCPD, 36 on NIPD, and 72 on continuous ambulatory peritoneal dialysis (CAPD)]. RRF was measured within 2 months from PD start and at 1 year after PD initiation.
Results
The RRF at 1 year after PD initiation was 1.98±2.20 mL/min/1.73 m2 in CCPD patients and 3.63±3.67 mL/min/1.73 m2 in NIPD patients, which were moderately lower than 4.23±3.51 mL/min/1.73 m2 in CAPD patients (p=0.064). Moreover, there was no significant difference in the 1-year rate of decline of RRF between CCPD and NIPD patients, although APD patients had a faster 1-year RRF decline rate than CAPD patients (CCPD and NIPD vs. CAPD: -45.68 and -36.69 vs. 1.17%/year, p=0.045). APD was associated with a more rapid decline in RRF in patients with end-stage renal disease undergoing PD, although multivariate analysis attenuated the significance of this finding (β=-31.50; 95% CI, -63.61 to 0.62; p=0.052).
Conclusion
Our results suggest that CAPD might be more helpful than APD for preserving RRF during the first year of dialysis therapy, although there was no significant difference in the 1-year rate of decline of RRF between the two APD modalities.
doi:10.3349/ymj.2014.55.1.141
PMCID: PMC3874913  PMID: 24339299
Continuous ambulatory peritoneal dialysis; end-stage kidney disease; glomerular filtration rate; peritoneal dialysis
10.  New vaccines against influenza virus 
Vaccination is one of the most effective and cost-benefit interventions that prevent the mortality and reduce morbidity from infectious pathogens. However, the licensed influenza vaccine induces strain-specific immunity and must be updated annually based on predicted strains that will circulate in the upcoming season. Influenza virus still causes significant health problems worldwide due to the low vaccine efficacy from unexpected outbreaks of next epidemic strains or the emergence of pandemic viruses. Current influenza vaccines are based on immunity to the hemagglutinin antigen that is highly variable among different influenza viruses circulating in humans and animals. Several scientific advances have been endeavored to develop universal vaccines that will induce broad protection. Universal vaccines have been focused on regions of viral proteins that are highly conserved across different virus subtypes. The strategies of universal vaccines include the matrix 2 protein, the hemagglutinin HA2 stalk domain, and T cell-based multivalent antigens. Supplemented and/or adjuvanted vaccination in combination with universal target antigenic vaccines would have much promise. This review summarizes encouraging scientific advances in the field with a focus on novel vaccine designs.
doi:10.7774/cevr.2014.3.1.12
PMCID: PMC3890446  PMID: 24427759
Universal vaccines; M2 protein; Stalk domain; T cell immunity; Supplemented vaccination
11.  Epileptic Nystagmus and Vertigo Associated with Bilateral Temporal and Frontal Lobe Epilepsy 
Epileptic nystagmus is defined as a quick, repetitive jerky movement of the eyeball associated with seizure activity. In cases of epileptic nystagmus associated with ictal discharge from multiple brain areas, localization of the exact epileptogenic zone could be extremely difficult. In a nine-year-old patient with epileptic nystagmus and vertigo associated with bilateral temporal and frontal lobe epilepsy, we could infer the epileptic focus by interpreting the patient's clinical picture, characteristics of nystagmus, and findings of electroencephalography.
doi:10.3342/ceo.2013.6.4.259
PMCID: PMC3863677  PMID: 24353868
Epilepsy; Pathologic nystagmus; Vertigo; Electroencephalography
12.  Genome Sequence of the Extreme Obligate Alkaliphile Bacillus marmarensis Strain DSM 21297 
Genome Announcements  2013;1(6):e00967-13.
Bacillus marmarensis strain DSM 21297 is an extreme obligate alkaliphile able to grow in medium up to pH 12.5. A whole-shotgun strategy and de novo assembly led to the generation of a 4-Mbp genome of this strain. The genome features alkaliphilic adaptations and pathways for n-butanol and poly(3-hydroxybutyrate) synthesis.
doi:10.1128/genomeA.00967-13
PMCID: PMC3869328  PMID: 24285666
13.  PPIRank - an advanced method for ranking protein-protein interations in TAP/MS data 
Proteome Science  2013;11(Suppl 1):S16.
Background
Tandem affinity purification coupled with mass-spectrometry (TAP/MS) analysis is a popular method for the identification of novel endogenous protein-protein interactions (PPIs) in large-scale. Computational analysis of TAP/MS data is a critical step, particularly for high-throughput datasets, yet it remains challenging due to the noisy nature of TAP/MS data.
Results
We investigated several major TAP/MS data analysis methods for identifying PPIs, and developed an advanced method, which incorporates an improved statistical method to filter out false positives from the negative controls. Our method is named PPIRank that stands for PPI ranking in TAP/MS data. We compared PPIRank with several other existing methods in analyzing two pathway-specific TAP/MS PPI datasets from Drosophila.
Conclusion
Experimental results show that PPIRank is more capable than other approaches in terms of identifying known interactions collected in the BioGRID PPI database. Specifically, PPIRank is able to capture more true interactions and simultaneously less false positives in both Insulin and Hippo pathways of Drosophila Melanogaster.
doi:10.1186/1477-5956-11-S1-S16
PMCID: PMC3908380  PMID: 24565074
Protein-Protein Interaction; TAP/MS; Spectral Counts
14.  Downregulation of ERK signaling impairs U2OS osteosarcoma cell migration in collagen matrix by suppressing MMP9 production 
Oncology Letters  2013;7(1):215-218.
The present study investigated the role of extracellular signal-regulated kinase (ERK) activation in the migratory phenotype of human U2OS osteosarcoma (OS) cells in a collagen matrix. The activation of ERK was inhibited by PD98059, a specific inhibitor of ERK kinase. Additionally, no significant differences were observed in the adhesion and proliferation of the cells with or without PD98059 treatment in collagen-coated dishes. The migratory capacity of the U2OS cells was then examined in non-coated and collagen-coated dishes, and the results depicted that collagen I enhanced the migration of the U2OS cells, the effect of which was significantly blocked by the treatment of the cells with PD98059. Furthermore, enhanced gene and protein expression of matrix metalloproteinase 9 (MMP9), but not MMP2, was observed to be involved in the enhanced migratory phenotype of the U20S cells in the collagen-coated plates. This effect was partially abolished by the treatment of the cells in the collagen-coated dishes with ERK inhibitor. Collectively, the data demonstrate that ERK signaling is important for the migration of U2OS cells through the extracellular matrix (ECM), which is comprised mostly of collagen, by enhancing MMP9 production. These results may contribute to the regulation of MMP9 production in metastatic OS.
doi:10.3892/ol.2013.1655
PMCID: PMC3861606  PMID: 24348851
U2OS; osteosarcoma; extracellular signal-regulated kinase; matrix metalloproteinase 9; PD98059
15.  Effects of Visual Biofeedback Training for Fall Prevention in the Elderly 
Journal of Physical Therapy Science  2013;25(11):1393-1395.
[Purpose] The purpose of this study was to investigate the effects of six weeks of visual biofeedback training for prevention of falling in the elderly. The Tetrax system was used for visual biofeedback training. [Subjects and Methods] Thirty elderly persons (experimental group=15, control group=15) who were above 70 and under 80 years of age participated in biofeedback training. They were trained for 15 minutes a day, three times per week. We measured the weight distribution index, stability index, and fall index in the subjects using the Tetrax system, and paired t-tests were used to evaluate the changes before and after intervention. The difference between the groups was compared using an independent t-test. [Results] The experimental group showed significant differences in weight distribution index, stability index, and fall index. The control group showed no significant differences. According to the comparison of training effects between the two groups, the variables of stability index and fall index revealed a statistically significant difference. [Conclusion] The method of visual biofeedback training used in this study should be considered a therapeutic method for the elderly to improve weight distribution, stability, and effectiveness in preventing falls.
doi:10.1589/jpts.25.1393
PMCID: PMC3881463  PMID: 24396196
Biofeedback; Elderly; Fall prevention
16.  A combined machine-learning and graph-based framework for the segmentation of retinal surfaces in SD-OCT volumes 
Biomedical Optics Express  2013;4(12):2712-2728.
Optical coherence tomography is routinely used clinically for the detection and management of ocular diseases as well as in research where the studies may involve animals. This routine use requires that the developed automated segmentation methods not only be accurate and reliable, but also be adaptable to meet new requirements. We have previously proposed the use of a graph-theoretic approach for the automated 3-D segmentation of multiple retinal surfaces in volumetric human SD-OCT scans. The method ensures the global optimality of the set of surfaces with respect to a cost function. Cost functions have thus far been typically designed by hand by domain experts. This difficult and time-consuming task significantly impacts the adaptability of these methods to new models. Here, we describe a framework for the automated machine-learning based design of the cost function utilized by this graph-theoretic method. The impact of the learned components on the final segmentation accuracy are statistically assessed in order to tailor the method to specific applications. This adaptability is demonstrated by utilizing the method to segment seven, ten and five retinal surfaces from SD-OCT scans obtained from humans, mice and canines, respectively. The overall unsigned border position errors observed when using the recommended configuration of the graph-theoretic method was 6.45 ± 1.87 μm, 3.35 ± 0.62 μm and 9.75 ± 3.18 μm for the human, mouse and canine set of images, respectively.
doi:10.1364/BOE.4.002712
PMCID: PMC3862166  PMID: 24409375
(100.0100) Image processing; (100.2000) Digital image processing; (100.4994) Pattern recognition, image transforms; (100.6890) Three-dimensional image processing; (110.4500) Optical coherence tomography
17.  Analysis of ASB10 variants in open angle glaucoma 
Human Molecular Genetics  2012;21(20):4543-4548.
Glaucoma is a common cause of visual disability and affects ∼1.6% of individuals over 40 years of age ( 1). Non-synonymous coding sequence variations in the ankyrin repeat and SOCS box containing gene 10 (ASB10) were recently associated with 6.0% of cases of primary open angle glaucoma (POAG) in patients from Oregon and Germany. We tested a cohort of POAG patients (n= 158) and normal control subjects (n= 82), both from Iowa, for ASB10 mutations. Our study had 80% power to detect a 4.9% mutation frequency in POAG patients. A total of 11 non-synonymous coding sequence mutations were detected in the cohort, but no association with POAG was detected when analyzed individually or as a group (P > 0.05). Furthermore, a survey of the National Heart, Lung, and Blood Institute's (NHLBI's) Exome Sequencing Project revealed that non-synonymous ASB10 mutations are present in the general population at a far higher frequency than the prevalence of POAG. These data suggest that non-synonymous mutations in ASB10 do not cause Mendelian forms of POAG.
doi:10.1093/hmg/dds288
PMCID: PMC3459468  PMID: 22798626
18.  Rational syntheses of core-shell Fex@Pt nanoparticles for the study of electrocatalytic oxygen reduction reaction 
Scientific Reports  2013;3:2872.
We report on the syntheses of core-shell Fex@Pt (x = 0.4–1.2) nanoparticles (NPs) with Pt-shell thickness systematically controlled while the overall particle size is constant. The syntheses were achieved via one-pot ultrasound-assisted polyol synthesis (UPS) reactions. Fe1.2@Pt showed a record-breaking high core-element content (55 at%) of core-shell NPs. Based on observations from a series of control experiments, we propose a mechanism of the NPs' formation that enables control of shell thickness in UPS reactions. Fex@Pt NPs showed drastic enhancements in mass and specific activity for oxygen reduction reaction (ORR) and significantly enhanced durability compared to commercial Pt NPs. Fex@Pt with a 1 (monolayer) ML Pt shell showed the highest activity. The ab initio density functional theory calculations on the binding energies of oxygen species on the surfaces of Fex@Pt NPs showed that the 1 ML case is most favourable for the ORR, and in good agreement with the experimental results.
doi:10.1038/srep02872
PMCID: PMC3791448  PMID: 24096587
19.  Lactobacillus plantarum DK119 as a Probiotic Confers Protection against Influenza Virus by Modulating Innate Immunity 
PLoS ONE  2013;8(10):e75368.
Lactobacillus plantarum DK119 (DK119) isolated from the fermented Korean cabbage food was used as a probiotic to determine its antiviral effects on influenza virus. DK119 intranasal or oral administration conferred 100% protection against subsequent lethal infection with influenza A viruses, prevented significant weight loss, and lowered lung viral loads in a mouse model. The antiviral protective efficacy was observed in a dose and route dependent manner of DK119 administration. Mice that were treated with DK119 showed high levels of cytokines IL-12 and IFN-γ in bronchoalveolar lavage fluids, and a low degree of inflammation upon infection with influenza virus. Depletion of alveolar macrophage cells in lungs and bronchoalveolar lavages completely abrogated the DK119-mediated protection. Modulating host innate immunity of dendritic and macrophage cells, and cytokine production pattern appeared to be possible mechanisms by which DK119 exhibited antiviral effects on influenza virus infection. These results indicate that DK119 can be developed as a beneficial antiviral probiotic microorganism.
doi:10.1371/journal.pone.0075368
PMCID: PMC3790790  PMID: 24124485
20.  Distinct roles of DKK1 and DKK2 in tumor angiogenesis 
Angiogenesis  2013;17:221-234.
Tumor angiogenesis is essential for tumor invasive growth and metastasis, and generates abnormal vascular structures unlike developmental neovessel formation. To reduce tumor vascular abnormalities such as leakage and perivascular cell coverage deficiency that limit cancer therapy effectiveness, novel therapeutic approaches focus on vessel normalization. We have previously shown that Dickkopf-1 (DKK1), a Wnt antagonist, inhibits and its homolog DKK2 enhances, angiogenesis in normal tissues. In the present study, we investigated the effects of DKK1 and DKK2 on tumor growth and angiogenesis. Treatment of B16F10 melanoma-bearing mice with adenovirus expressing DKK1 significantly reduced tumor growth but DKK2 increased growth compared with controls. Similar pattern of tumor growth was observed in endothelial-specific DKK1 and DKK2 transgenic mice. Interestingly, tumor vascular density and perfusion were significantly decreased by DKK1 but increased by DKK2. Moreover, coverage of blood vessels by pericytes was reduced by DKK1, while DKK2 increased it. We further observed that DKK1 diminished retinal vessel density and increased avascular area in an in vivo murine model of oxygen-induced retinopathy, whereas DKK2 showed opposite results. These findings demonstrate that DKK1 and DKK2 have differential roles in normalization and functionality of tumor blood vessels, in addition to angiogenesis.
Electronic supplementary material
The online version of this article (doi:10.1007/s10456-013-9390-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s10456-013-9390-5
PMCID: PMC3898121  PMID: 24091497
DKK1; DKK2; Tumor angiogenesis; Perivascular coverage; Vessel normalization
21.  Korean Red Ginseng protects endothelial cells from serum-deprived apoptosis by regulating Bcl-2 family protein dynamics and caspase S-nitrosylation 
Journal of Ginseng Research  2013;37(4):413-424.
Korean Red Ginseng extract (KRGE) is a traditional herbal medicine utilized to prevent endothelium dysfunction in the cardiovascular system; however, its underlying mechanism has not been clearly elucidated. We here examined the pharmacological effect and molecular mechanism of KRGE on apoptosis of human umbilical vein endothelial cells (HUVECs) in a serum-deprived apoptosis model. KRGE protected HUVECs from serum-deprived apoptosis by inhibiting mitochondrial cytochrome c release and caspase-9/-3 activation. This protective effect was significantly higher than that of American ginseng extract. KRGE treatment increased antiapoptotic Bcl-2 and Bcl-XL protein expression and Akt-dependent Bad phosphorylation. Moreover, KRGE prevented serum deprivation-induced subcellular redistribution of these proteins between the mitochondrion and the cytosol, resulting in suppression of mitochondrial cytochrome c release. In addition, KRGE increased nitric oxide (NO) production via Akt-dependent activation of endothelial NO synthase (eNOS), as well as inhibited caspase-9/-3 activities. These increases were reversed by co-treatment of cells with inhibitors of eNOS and phosphoinositide 3-kinase (PI3K) and pre-incubation of cell lysates in dithiothreitol, indicating KRGE induces NO-mediated caspase modification. Indeed, KRGE inhibited caspase-3 activity via S-nitrosylation. These findings suggest that KRGE prevents serum deprivation-induced HUVEC apoptosis via increased Bcl-2 and Bcl-XL protein expression, PI3K/Akt-dependent Bad phosphorylation, and eNOS/NO-mediated S-nitrosylation of caspases. The cytoprotective property of KRGE may be valuable for developing new pharmaceutical means that limit endothelial cell death induced during the pathogenesis of vascular diseases.
doi:10.5142/jgr.2013.37.413
PMCID: PMC3825856  PMID: 24233159
Panax ginseng; Endothelial cells; Apoptosis; Bcl-2 family; Nitric oxide
22.  The parallel growth of motoneuron axons with the dorsal aorta depends on Vegfc/Vegfr3 signaling in zebrafish 
Development (Cambridge, England)  2013;140(19):4081-4090.
Blood vessels and neurons grow often side by side. However, the molecular and cellular mechanisms underlying their parallel development remain unclear. Here, we report that a subpopulation of secondary motoneurons extends axons ventrally outside of the neural tubes and rostrocaudally as a fascicle beneath the dorsal aorta (DA) in zebrafish. We tried to clarify the mechanism by which these motoneuron axons grow beneath the DA and found that Vegfc in the DA and Vegfr3 in the motoneurons were essential for the axon growth. Forced expression of either Vegfc in arteries or Vegfr3 in motoneurons resulted in enhanced axon growth of motoneurons over the DA. Both vegfr3 morphants and vegfc morphants lost the alignment of motoneuron axons with DA. In addition, forced expression of two mutant forms of Vegfr3 in motoneurons, potentially trapping endogenous Vegfc, resulted in failure of growth of motoneuron axons beneath the DA. Finally, a vegfr3 mutant fish lacked the motoneuron axons beneath the DA. Collectively, Vegfc from the preformed DA guides the axon growth of secondary motoneurons.
doi:10.1242/dev.091702
PMCID: PMC3913045  PMID: 24046321
Vegfc; Vegfr3; Motoneuron; Wiring; Guidance
23.  Neuroprotective Effect of a New Synthetic Aspirin-decursinol Adduct in Experimental Animal Models of Ischemic Stroke 
PLoS ONE  2013;8(9):e74886.
Stroke is the second leading cause of death. Experimental animal models of cerebral ischemia are widely used for researching mechanisms of ischemic damage and developing new drugs for the prevention and treatment of stroke. The present study aimed to comparatively investigate neuroprotective effects of aspirin (ASA), decursinol (DA) and new synthetic aspirin-decursinol adduct (ASA-DA) against transient focal and global cerebral ischemic damage. We found that treatment with 20 mg/kg, not 10 mg/kg, ASA-DA protected against ischemia-induced neuronal death after transient focal and global ischemic damage, and its neuroprotective effect was much better than that of ASA or DA alone. In addition, 20 mg/kg ASA-DA treatment reduced the ischemia-induced gliosis and maintained antioxidants levels in the corresponding injury regions. In brief, ASA-DA, a new synthetic drug, dramatically protected neurons from ischemic damage, and neuroprotective effects of ASA-DA may be closely related to the attenuation of ischemia-induced gliosis and maintenance of antioxidants.
doi:10.1371/journal.pone.0074886
PMCID: PMC3779249  PMID: 24073226
24.  Liquid metal nanodroplet dynamics inside nanocontainers 
Scientific Reports  2013;3:2588.
Here we report direct observations of spatial movements of nanodroplets of Pb metal trapped inside sealed carbon nanocontainers. We find drastic changes in the mobility of the liquid droplets as the particle size increases from a few to a few ten nanometers. In open containers the droplet becomes immobile and readily evaporates to the vacuum environment. The particle mobility strongly depends on confinement, particle size, and wetting on the enclosed surface. The collisions between droplets increase mobility but the tendency is reversed if collisions lead to droplet coalescence. The dynamics of confined nanodroplets could provide new insights into the activity of nanostructures in spatially constrained geometries.
doi:10.1038/srep02588
PMCID: PMC3763249  PMID: 24005021
25.  An Infant with Prenatally Diagnosed Congenital Anaplastic Astrocytoma Who Remains Disease-Free after Proton Therapy 
Journal of Korean Medical Science  2013;28(9):1394-1398.
The authors present a rare of prenatally diagnosed congenital anaplastic astrocytoma. A 9-month-old boy had three recurrences despite two surgical resections and various chemotherapeutic regimens. He underwent the 3rd gross tumor removal at 11 months of age, followed by proton therapy, and now he remains disease-free for 3 yr without a significant neurocognitive dysfunction. This is the 1st case of a pediatric tumor treated by proton therapy in Korea, and proton therapy may be a treatment of choice for a congenital anaplastic astrocytoma in infants and young children, considering limitation of radiation therapy.
doi:10.3346/jkms.2013.28.9.1394
PMCID: PMC3763118  PMID: 24015049
Congenital Anaplastic Astrocytoma; Proton Therapy; Recurrence

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