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1.  Development and characterization of microsatellite loci for the pseudometallophyte Commelina communis (Commelinaceae)1 
Applications in Plant Sciences  2015;3(2):apps.1400098.
• Premise of the study: Microsatellite primers were developed for the pseudometallophyte Commelina communis (Commelinaceae), an important pioneer plant for phytoremediation of copper-contaminated soil. Two wild populations collected from metalliferous and nonmetalliferous sites were used to assess the polymorphism at each locus.
• Methods and Results: Based on the Fast Isolation by AFLP of Sequences COntaining repeats (FIASCO) method, a total of 34 pairs of simple sequence repeat (SSR) markers were designed. When 40 specimens from two populations were screened, 12 microsatellite loci were found to be highly polymorphic. The number of alleles per locus ranged from one to 11 and the observed and expected heterozygosity per locus ranged from 0.000 to 1.000 and from 0.195 to 0.941, respectively.
• Conclusions: These markers will be useful for examining genetic diversity, population structure, and gene flow in populations of C. communis under different edaphic conditions and guiding sustainable management plans for phytoremediation.
doi:10.3732/apps.1400098
PMCID: PMC4332143
Commelina communis; Commelinaceae; genetic diversity; microsatellites; pseudometallophyte
2.  Educational Inequality in Female Cancer Mortality in Korea 
We evaluated the influence of socioeconomic factors on female cancer mortality using death data from the Cause of Death Statistics and the Korean Population and Housing Census databases collected in 2001, 2006, and 2011. We estimated Relative Index of Inequality (RII) of female cancer mortality using Poisson regression analysis. RII greater than 1 indicates increased mortality risk for women at the lowest educational level compared with women at the highest educational level. The RII for cervical cancer mortality was persistently greater than 1 for the entire study period, with a gradual increase over time. Subgroup analysis stratified by age (25-44 and 45-64 yr) revealed that younger women had increased RIIs of mortality due to cervical cancer and ovarian cancer during the entire study period. Older women had higher RII only for cervical cancer mortality, but the value was much lower than that for younger women. The RII for breast cancer mortality was greater than 1 for younger women since 2006. In conclusion, socioeconomic inequality in female cancer mortality has persisted for the last decade in Korea, which was most evident for cervical cancer, and for younger women.
Graphical Abstract
doi:10.3346/jkms.2015.30.1.1
PMCID: PMC4278015  PMID: 25552877
Educational Status; Mortality; Neoplasms; Socioeconomic Factors; Women
3.  Stability of Gut Enterotypes in Korean Monozygotic Twins and Their Association with Biomarkers and Diet 
Scientific Reports  2014;4:7348.
Studies on the human gut microbiota have suggested that human individuals could be categorized into enterotypes based on the compositions of their gut microbial communities. Here, we report that the gut microbiota of healthy Koreans are clustered into two enterotypes, dominated by either Bacteroides (enterotype 1) or Prevotella (enterotype 2). More than 72% of the paired fecal samples from monozygotic twin pairs were assigned to the same enterotype. Our longitudinal analysis of these twins indicated that more than 80% of the individuals belonged to the same enterotype after about a 2-year interval. Microbial functions based on KEGG pathways were also divided into two clusters. For enterotype 2, 100% of the samples belonged to the same functional cluster, while for enterotype 1, approximately half of the samples belonged to each functional cluster. Enterotype 2 was significantly associated with long-term dietary habits that were high in dietary fiber, various vitamins, and minerals. Among anthropometrical and biochemical traits, the level of serum uric acid was associated with enterotype. These results suggest that host genetics as well as host properties such as long-term dietary patterns and a particular clinical biomarker could be important contributors to the enterotype of an individual.
doi:10.1038/srep07348
PMCID: PMC4258686  PMID: 25482875
4.  Pain and satisfaction during rigid cystoscopic ureteral stent removal: a preliminary study 
BMC Urology  2014;14(1):90.
Background
Cystoscopy evokes discomfort and pain, especially in males. The cystoscopic retrograde approach is standard in the removal of ureteral stents. However the satisfaction and degree of pain during the procedure according to the use of several pain controlling methods are unclear.
Methods
This is a cross-sectional survey of 60 patients who underwent cystoscopic ureteral stent removal under intravenous analgesics (group 1, n = 20), midazolam induction (group 2, n = 20), and propofol (group 3, n = 20). Procedural pain and post-procedure satisfaction were determined, and cost differences between the approaches were clarified.
Results
Group 2 and 3 showed significantly less pain than group 1 (P < 0.001) and significantly higher satisfaction rate than group 1 (P < 0.001). Comparison of groups 2 and 3 revealed showed significantly less pain and higher satisfaction rate in group 3 (P < 0.001 for both). In Group 1, 17 (85.0%) patients wanted other treatment modalities, compared to eight group 2 patients (40.0%) and no group 3 patients.
Conclusions
Considering the potential pain and dissatisfaction of rigid cystoscopic ureteral stent removal, procedures utilizing moderate sedation with midazolam or general anesthesia using propofol without muscle relaxation should be considered.
Trial registration
KCT0001260.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2490-14-90) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2490-14-90
PMCID: PMC4242475  PMID: 25406892
Stent; Stent exchange; Stent removal; Cystscopy; Urolithiasis; Pain
5.  Novel Antidepressant-Like Activity of Caffeic Acid Phenethyl Ester Is Mediated by Enhanced Glucocorticoid Receptor Function in the Hippocampus 
Caffeic acid phenethyl ester (CAPE) is an active component of propolis that has a variety of potential pharmacological effects. Although we previously demonstrated that propolis has antidepressant-like activity, the effect of CAPE on this activity remains unknown. The present study assessed whether treatment with CAPE (5, 10, and 20 µmol/kg for 21 days) has an antidepressant-like effect in mice subjected to chronic unpredictable stress via tail suspension (TST) and forced swim (FST) tests. CAPE administration induced behaviors consistent with an antidepressant effect, evidenced by decreased immobility in the TST and FST independent of any effect on serum corticosterone secretion. Western blots, conducted subsequent to behavioral assessment, revealed that CAPE significantly decreased glucocorticoid receptor phosphorylation at S234 (pGR(S234)), resulting in an increased pGR(S220/S234) ratio. We also observed negative correlations between pGR(S220)/(S234) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation, which was decreased by CAPE treatment. These findings suggest that CAPE treatment exerts an antidepressant-like effect via downregulation of p38MAPK phosphorylation, thereby contributing to enhanced GR function.
doi:10.1155/2014/646039
PMCID: PMC4248557  PMID: 25477995
6.  Decoding coalescent hidden Markov models in linear time 
In many areas of computational biology, hidden Markov models (HMMs) have been used to model local genomic features. In particular, coalescent HMMs have been used to infer ancient population sizes, migration rates, divergence times, and other parameters such as mutation and recombination rates. As more loci, sequences, and hidden states are added to the model, however, the runtime of coalescent HMMs can quickly become prohibitive. Here we present a new algorithm for reducing the runtime of coalescent HMMs from quadratic in the number of hidden time states to linear, without making any additional approximations. Our algorithm can be incorporated into various coalescent HMMs, including the popular method PSMC for inferring variable effective population sizes. Here we implement this algorithm to speed up our demographic inference method diCal, which is equivalent to PSMC when applied to a sample of two haplotypes. We demonstrate that the linear-time method can reconstruct a population size change history more accurately than the quadratic-time method, given similar computation resources. We also apply the method to data from the 1000 Genomes project, inferring a high-resolution history of size changes in the European population.
doi:10.1007/978-3-319-05269-4_8
PMCID: PMC4203418  PMID: 25340178
7.  Spontaneous Brain Activity in Type 2 Diabetics Revealed by Amplitude of Low-Frequency Fluctuations and Its Association with Diabetic Vascular Disease: A Resting-State fMRI Study 
PLoS ONE  2014;9(10):e108883.
Purpose
To investigate correlations between altered spontaneous brain activity, diabetic vascular disease, and cognitive function for patients with type 2 diabetes mellitus (T2DM) using resting-state functional magnetic resonance imaging (rs-fMRI).
Methods
Rs-fMRI was performed for T2DM patients (n = 26) and age-, gender-, and education-matched non-diabetic control subjects (n = 26). Amplitude of low frequency fluctuations (ALFF) were computed from fMRI signals to measure spontaneous neuronal activity. Differences in the ALFF patterns between patients and controls, as well as their correlations with clinical variables, were evaluated.
Results
Compared with healthy controls, T2DM patients exhibited significantly decreased ALFF values mainly in the frontal and parietal lobes, the bilateral thalumi, the posterior lobe of the cerebellum, and increased ALFF values mainly in the visual cortices. Furthermore, lower ALFF values in the left subcallosal gyrus correlated with lower ankle-brachial index values (r = 0.481, p = 0.020), while lower ALFF values in the bilateral medial prefrontal gyri correlated with higher urinary albumin-creatinine ratio (r = −0.418, p = 0.047). In addition, most of the regions with increased ALFF values in the visual cortices were found to negatively correlate with MoCA scores.
Conclusions
These results confirm that ALFF are altered in many brain regions in T2DM patients, and this is associated with the presence of diabetic vascular disease and poor cognitive performance. These findings may provide additional insight into the neurophysiological mechanisms that mediate T2DM-related cognitive dysfunction, and may also serve as a reference for future research.
doi:10.1371/journal.pone.0108883
PMCID: PMC4182760  PMID: 25272033
8.  Factors Associated with Hemorrhoids in Korean Adults: Korean National Health and Nutrition Examination Survey 
Korean Journal of Family Medicine  2014;35(5):227-236.
Background
Although hemorrhoids are one of the most common anal diseases among Koreans, risk factors for hemorrhoids have not been well identified.
Methods
We analyzed the data from the 4th Korean National Health and Nutrition Examination Survey (KNHANES) between 2007 and 2009. Study subjects were 17,228 participants of KNHANES who were aged 19 years or older. Logistic regression analysis was conducted to evaluate associations between hemorrhoids and probable risk factors.
Results
Overall prevalence of hemorrhoids among study subjects was 14.4%, being more prevalent among women (15.7%) than among men (13.0%). Obesity and abdominal obesity were associated with a higher risk of hemorrhoids with odds ratio (OR) (95% confidence intervals, 95% CI) of 1.13 (1.01 to 1.26) and 1.16 (1.04 to 1.30), respectively. Both self-reported depression (OR, 1.83; 95% CI, 1.62 to 2.08) and physician diagnosed depression (OR, 1.71; 95% CI, 1.35 to 2.17) were associated with significantly higher risk of hemorrhoids. No regular walking (OR, 1.11; 95% CI, 1.00 to 1.23) and experience of pregnancy (OR, 1.62; 95% CI, 1.17 to 2.25) for women were also associated with higher risk of hemorrhoids. However, educational level, alcohol consumption, physical activities, diabetes mellitus, hypertension, fiber, fat intake, and energy intake were not associated with a risk of hemorrhoids. Low quality of life assessed with EuroQol-5 Dimension and EuroQol-Visual Analogue Scale was significantly associated with hemorrhoids.
Conclusion
This nationwide cross-sectional study of Korean adults suggests that obesity, abdominal obesity, depression, and past pregnancy may be risk factors for hemorrhoids and hemorrhoids affect quality of life negatively.
doi:10.4082/kjfm.2014.35.5.227
PMCID: PMC4192796  PMID: 25309703
Hemorrhoids; Koreans; Risk Factors; Quality of Life; Obesity; Depression
9.  Traumatic Penile Injury: From Circumcision Injury to Penile Amputation 
BioMed Research International  2014;2014:375285.
The treatment of external genitalia trauma is diverse according to the nature of trauma and injured anatomic site. The classification of trauma is important to establish a strategy of treatment; however, to date there has been less effort to make a classification for trauma of external genitalia. The classification of external trauma in male could be established by the nature of injury mechanism or anatomic site: accidental versus self-mutilation injury and penis versus penis plus scrotum or perineum. Accidental injury covers large portion of external genitalia trauma because of high prevalence and severity of this disease. The aim of this study is to summarize the mechanism and treatment of the traumatic injury of penis. This study is the first review describing the issue.
doi:10.1155/2014/375285
PMCID: PMC4164514  PMID: 25250318
10.  Diagnostic Accuracy of Intracellular Mycobacterium tuberculosis Detection for Tuberculous Meningitis 
Rationale: Early diagnosis and treatment of tuberculous meningitis saves lives, but current laboratory diagnostic tests lack sensitivity.
Objectives: We investigated whether the detection of intracellular bacteria by a modified Ziehl-Neelsen stain and early secretory antigen target (ESAT)-6 in cerebrospinal fluid leukocytes improves tuberculous meningitis diagnosis.
Methods: Cerebrospinal fluid specimens from patients with suspected tuberculous meningitis were stained by conventional Ziehl-Neelsen stain, a modified Ziehl-Neelsen stain involving cytospin slides with Triton processing, and an ESAT-6 immunocytochemical stain. Acid-fast bacteria and ESAT-6–expressing leukocytes were detected by microscopy. All tests were performed prospectively in a central laboratory by experienced technicians masked to the patients’ final diagnosis.
Measurements and Main Results: Two hundred and eighty patients with suspected tuberculous meningitis were enrolled. Thirty-seven had Mycobacterium tuberculosis cultured from cerebrospinal fluid; 40 had a microbiologically confirmed alternative diagnosis; the rest had probable or possible tuberculous meningitis according to published criteria. Against a clinical diagnostic gold standard the sensitivity of conventional Ziehl-Neelsen stain was 3.3% (95% confidence interval, 1.6–6.7%), compared with 82.9% (95% confidence interval, 77.4–87.3%) for modified Ziehl-Neelsen stain and 75.1% (95% confidence interval, 68.8–80.6%) for ESAT-6 immunostain. Intracellular bacteria were seen in 87.8% of the slides positive by the modified Ziehl-Neelsen stain. The specificity of modified Ziehl-Neelsen and ESAT-6 stain was 85.0% (95% confidence interval, 69.4–93.8%) and 90.0% (95% confidence interval, 75.4–96.7%), respectively.
Conclusions: Enhanced bacterial detection by simple modification of the Ziehl-Neelsen stain and an ESAT-6 intracellular stain improve the laboratory diagnosis of tuberculous meningitis.
doi:10.1164/rccm.201309-1686OC
PMCID: PMC3977721  PMID: 24450377
tuberculosis; central nervous system; cerebrospinal fluid; diagnosis
11.  Measuring the improvement in health-related quality of life using King’s health questionnaire in non-obese and obese patients with lower urinary tract symptoms after alpha-adrenergic medication: a preliminary study 
BMC Urology  2014;14:60.
Background
The efficacy of medical treatment among obese men with lower urinary tract symptoms (LUTS) has been less clear, especially regarding the improvement of QoL. We aimed to investigate the difference in efficacy and consequent satisfaction of life quality after medical treatment of male LUTS according to obesity.
Methods
An 8-week prospective study was performed for a total of 140 patients >50 years old with International Prostate Symptom Scores (IPSS) > 12 points and prostate volume > 20 mL. Obesity was determined by either body mass index (BMI) or waist circumference (WC). Patients were divided into 2 groups according to BMI or WC. Patients received tamsulosin at a dose of 0.4 mg daily for 8 weeks. The changes from baseline in the IPSS, maximal urinary flow rate (Qmax), post-void residual volume, questionnaire of quality of life (QoL), and King’s Health Questionnaire (KHQ) were analyzed.
Results
Of the 150 enrolled patients, 96 completed the study. Seventy-five patients (78.1%) had BMI ≥ 23 kg/m2, and 24 (25.0%) had WC > 90 cm. Overall, the IPSS, IPSS QoL, and total KHQ showed significant improvement. Obese (BMI ≥ 23 kg/m2) and non-obese (BMI < 23 kg/m2) both showed improvement of the IPSS and IPSS QoL scores, but only the obese (BMI ≥ 23 kg/m2) group showed improvement of the total KHQ score (P < 0.001 vs. P = 0.55). Only the obese (WC > 90 cm) group showed improvement of the IPSS and total KHQ scores (P < 0.001).
Conclusions
Our preliminary study showed the different efficacy of an alpha-blocker for improvement of LUTS and life quality according to obesity. Obese patients, defined by BMI or WC, showed the tendency toward a more favorable improvement of LUTS and life quality.
Trial registration
Current Controlled Trials 2010–058. Registered 2 September 2010 in Soonchunhyang Univeristy Hospital
doi:10.1186/1471-2490-14-60
PMCID: PMC4126641  PMID: 25099073
Alpha-blocker; Prostatic hyperplasia; Body mass index; Waist circumference
12.  A sequentially Markov conditional sampling distribution for structured populations with migration and recombination 
Conditional sampling distributions (CSDs), sometimes referred to as copying models, underlie numerous practical tools in population genomic analyses. Though an important application that has received much attention is the inference of population structure, the explicit exchange of migrants at specified rates has not hitherto been incorporated into the CSD in a principled framework. Recently, in the case of a single panmictic population, a sequentially Markov CSD has been developed as an accurate, efficient approximation to a principled CSD derived from the diffusion process dual to the coalescent with recombination. In this paper, the sequentially Markov CSD framework is extended to incorporate subdivided population structure, thus providing an efficiently computable CSD that admits a genealogical interpretation related to the structured coalescent with migration and recombination. As a concrete application, it is demonstrated empirically that the CSD developed here can be employed to yield accurate estimation of a wide range of migration rates.
doi:10.1016/j.tpb.2012.08.004
PMCID: PMC3532580  PMID: 23010245
structured coalescent; recombination; migration; conditional sampling distribution; hidden Markov model; sequentially Markov coalescent
13.  Stem Cell Based Gene Therapy in Prostate Cancer 
BioMed Research International  2014;2014:549136.
Current prostate cancer treatment, especially hormone refractory cancer, may create profound iatrogenic outcomes because of the adverse effects of cytotoxic agents. Suicide gene therapy has been investigated for the substitute modality for current chemotherapy because it enables the treatment targeting the cancer cells. However the classic suicide gene therapy has several profound side effects, including immune-compromised due to viral vector. Recently, stem cells have been regarded as a new upgraded cellular vehicle or vector because of its homing effects. Suicide gene therapy using genetically engineered mesenchymal stem cells or neural stem cells has the advantage of being safe, because prodrug administration not only eliminates tumor cells but consequently kills the more resistant therapeutic stem cells as well. The attractiveness of prodrug cancer gene therapy by stem cells targeted to tumors lies in activating the prodrug directly within the tumor mass, thus avoiding systemic toxicity. Therapeutic achievements using stem cells in prostate cancer include the cytosine deaminase/5-fluorocytosine prodrug system, herpes simplex virus thymidine kinase/ganciclovir, carboxyl esterase/CPT11, and interferon-beta. The aim of this study is to review the stem cell therapy in prostate cancer including its proven mechanisms and also limitations.
doi:10.1155/2014/549136
PMCID: PMC4120795  PMID: 25121103
14.  Dietary Restraint Is Non-Genetically Associated with Change in Body Mass Index: The Healthy Twin Study 
Yonsei Medical Journal  2014;55(4):1138-1144.
Purpose
We aimed to examine if past and more recent body mass index (BMI) changes are associated with eating behavior (EB) traits and whether these associations are due to non-genetic factors.
Materials and Methods
In 1321 Korean twins and family members, recent and past BMI change groups were defined using quartiles of BMI change between first and second visits over 2.4±0.9 years and BMI change between 20 years old and second visit, respectively. We applied linear mixed analysis for relationships of past or recent BMI change groups and each EB (restrained, external, and emotional EB using the Dutch Eating Behavior Questionnaire) assessed at second visit after adjusting for household effect and covariates (age, gender, education, medical history of diabetes, hypertension, and dyslipidemia, alcohol use, physical activity, smoking habit, and calorie intake). In monozygotic twin pairs, paired t-test for within-pair comparison and conditional logistic regression analysis were conducted regarding EB.
Results
Greater past BMI change was associated with higher restrained eating scores (P for trend=0.031), whereas greater recent BMI change was associated with higher external eating scores (P for trend=0.046). In co-twin-control analysis, twins with greater past BMI change were more likely to have higher restrained eating scores as compared with their co-twins with lower past BMI change (odds ratio 1.80; 95% confidence interval 1.13-2.87), whereas there were no associations between recent BMI change and external eating scores.
Conclusion
Greater BMI change since 20 years old is associated with higher dietary restraint, and non-genetic factors explain this relationship.
doi:10.3349/ymj.2014.55.4.1138
PMCID: PMC4075378  PMID: 24954348
Dietary restraint; non-genetic factor; BMI change; twin
15.  Selective Estrogen Receptor Modulation by Larrea nitida on MCF-7 Cell Proliferation and Immature Rat Uterus 
Biomolecules & Therapeutics  2014;22(4):347-354.
Larrea nitida is a plant that belongs to the Zygophyllaceae family and is widely used in South America to treat inflammatory diseases, tumors and menstrual pain. However, its pharmacological activity remains unclear. In this study we evaluated the property of selective estrogen receptor modulator (SERM) of Larrea nitida extracts (LNE) as a phytoestrogen that can mimic, modulate or disrupt the actions of endogenous estrogens, depending on the tissue and relative amount of other SERMs. To investigate the property of SERM of LNE, we performed MCF-7 cell proliferation assays, estrogen response element (ERE)-luciferase reporter gene assay, human estrogen receptor (hER) binding assays and in vivo uterotrophic assay. To gain insight into the active principles, we performed a bioassay-guided analysis of LNE employing solvents of various polarities and using classical column chromatography, which yielded 16 fractions (LNs). LNE showed high binding affinities for hERα and hERβ with IC50 values of 1.20 ×10−7 g/ml and 1.00×10−7 g/ml, respectively. LNE induced 17β-estradiol (E2)-induced MCF-7 cell proliferation, however, it reduced the proliferation in the presence of E2. Furthermore, LNE had an atrophic effect in the uterus of immature rats through reducing the expression level of progesterone receptor (PR) proteins. LN08 and LN10 had more potent affinities for binding on hER α and β than other fractions. Our results indicate that LNE had higher binding affinities for hERβ than hERα, and showed SERM properties in MCF-7 breast cancer cells and the rat uterus. LNE may be useful for the treatment of estrogen-related conditions, such as female cancers and menopause.
doi:10.4062/biomolther.2014.050
PMCID: PMC4131523  PMID: 25143815
Larrea nitida; Lignan; Phytoestrogen; Estrogen receptor; MCF-7 cell; Uterus
16.  Gene expression analysis of potential genes and pathways involved in the pathogenic mechanisms of parvovirus B19 in human colorectal cancer 
Oncology Letters  2014;8(2):523-532.
In order to investigate the pathogenic mechanisms of parvovirus B19 in human colorectal cancer, plasmids containing the VP1 or VP2 viral capsid proteins or the NS1 non-structural proteins of parvovirus B19 were constructed and transfected into primary human colorectal epithelial cells and LoVo cells. Differential gene expression was detected using a human genome expression array. Functional gene annotation analyses were performed using Database for Annotation, Visualization and Integrated Discovery v6.7 software. Gene ontology (GO) analyses revealed that VP1-related functions included the immune response, immune system process, defense response and the response to stimulus, while NS1-associated functions were found to include organelle fission, nuclear division, mitosis, the M-phase of the mitotic cell cycle, the mitotic cell cycle, M-phase, cell cycle phase, cell cycle process and cell division. Pathway expression analysis revealed that VP1-associated pathways included cell adhesion molecules, antigen processing and presentation, cytokines and the inflammatory response. Moreover, NS1-associated pathways included the cell cycle, pathways in cancer, colorectal cancer, the wnt signaling pathway and focal adhesion. Among the differential genes detected in the present study, 12 genes were found to participate in general cancer pathways and six genes were observed to participate in colorectal cancer pathways. NS1 is a key molecule in the pathogenic mechanism of parvovirus B19 in colorectal cancer. Several GO categories, pathways and genes were selected and may be the key targets through which parvovirus B19 participates in colorectal cancer pathogenesis.
doi:10.3892/ol.2014.2151
PMCID: PMC4081382  PMID: 25013465
colorectal cancer; parvovirus B19; pathogenesis; microarray; human
17.  USP8 modulates ubiquitination of LRIG1 for Met degradation 
Scientific Reports  2014;4:4980.
The Met receptor tyrosine kinase is an attractive target for cancer therapy as it promotes invasive tumor growth. SAIT301 is a novel anti-Met antibody, which induces LRIG1-mediated Met degradation and inhibits tumor growth. However, detailed downstream mechanism by which LRIG1 mediates target protein down-regulation is unknown. In the present study, we discovered that SAIT301 induces ubiquitination of LRIG1, which in turn promotes recruitment of Met and LRIG1 complex to the lysosome through its interaction with Hrs, resulting in concomitant degradation of both LRIG1 and Met. We also identified USP8 as a LRIG1-specific deubiquitinating enzyme, reporting the interaction between USP8 and LRIG1 for the first time. SAIT301 triggers degradation of LRIG1 by inhibiting the interaction of LRIG1 and USP8, which regulates ubiquitin modification and stability of LRIG1. In summary, SAIT301 employs ubiquitination of LRIG1 for its highly effective Met degradation. This unique feature of SAIT301 enables it to function as a fully antagonistic antibody without Met activation. We found that USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. The relation of Met, LRIG1 and USP8 strongly supports the potential clinical benefit of a combination treatment of a USP8 inhibitor and a Met inhibitor, such as SAIT301.
doi:10.1038/srep04980
PMCID: PMC4021411  PMID: 24828152
18.  Herbal Prescription, DSGOST, Prevents Cold-Induced RhoA Activation and Endothelin-1 Production in Endothelial Cells 
Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Saenggang-tang (DSGOST), has long been used to treat Raynaud's phenomenon (RP) in traditional Chinese medicine (TCM). However, a biological mechanism by which DSGOST ameliorates RP is yet deciphered. In this study, we demonstrate that DSGOST inhibits cold-induced activation of RhoA, in both vascular smooth muscle cells (VSMC) and endothelial cells (EC), and blocks endothelin-1-mediated paracrine path for cold response on vessels. While cold induced RhoA activity in both cell types, DSGOST pretreatment prevented cold-induced RhoA activation. DSGOST inhibition of cold-induced RhoA activation further blocked α2c-adrenoreceptor translocation to the plasma membrane in VSMC. In addition, DSGOST inhibited endothelin-1-mediated RhoA activation and α2c-adrenoreceptor translocation in VSMC. Meanwhile, DSGOST inhibited cold-induced or RhoA-dependent phosphorylation of FAK, SRC, and ERK. Consistently, DSGOST inhibited cold-induced endothelin-1 expression in EC. Therefore, DSGOST prevents cold-induced RhoA in EC and blocks endothelin-1-mediated paracrine path between EC and VSMC. In conclusion, our data suggest that DSGOST is beneficial for treating RP-like syndrome.
doi:10.1155/2014/549307
PMCID: PMC4009260  PMID: 24839453
19.  Treatment of Bladder Dysfunction Using Stem Cell or Tissue Engineering Technique 
Korean Journal of Urology  2014;55(4):228-238.
Tissue engineering and stem cell transplantation are two important options that may help overcome limitations in the current treatment strategy for bladder dysfunction. Stem cell therapy holds great promise for treating pathophysiology, as well as for urological tissue engineering and regeneration. To date, stem cell therapy in urology has mainly focused on oncology and erectile dysfunction. The therapeutic potency of stem cells (SCs) was originally thought to derive from their ability to differentiate into various cell types including smooth muscle. The main mechanisms of SCs in reconstituting or restoring bladder function are migration, differentiation, and paracrine effects. Nowadays, paracrine effects of stem cells are thought to be more prominent because of their stimulating effects on stem cells and adjacent cells. Studies of stem cell therapy for bladder dysfunction have been limited to experimental models and have been less focused on tissue engineering for bladder regeneration. Bladder outlet obstruction is a representative model. Adipose-derived stem cells, bone marrow stem cells (BMSCs), and skeletal muscle-derived stem cells or muscle precursor cells are used for transplantation to treat bladder dysfunction. The aim of this study is to review stem cell therapy and updated tissue regeneration as treatments for bladder dysfunction and to provide the current status of stem cell therapy and tissue engineering for bladder dysfunction including its mechanisms and limitations.
doi:10.4111/kju.2014.55.4.228
PMCID: PMC3988432  PMID: 24741410
Overactive urinary bladder; Stem cells; Urinary bladder; Urinary bladder neck obstruction
20.  Theory of Mind as a Mediator of Reasoning and Facial Emotion Recognition: Findings from 200 Healthy People 
Psychiatry Investigation  2013;11(2):105-111.
Objective
It was proposed that the ability to recognize facial emotions is closely related to complex neurocognitive processes and/or skills related to theory of mind (ToM). This study examines whether ToM skills mediate the relationship between higher neurocognitive functions, such as reasoning ability, and facial emotion recognition.
Methods
A total of 200 healthy subjects (101 males, 99 females) were recruited. Facial emotion recognition was measured through the use of 64 facial emotional stimuli that were selected from photographs from the Korean Facial Expressions of Emotion (KOFEE). Participants were requested to complete the Theory of Mind Picture Stories task and Standard Progressive Matrices (SPM).
Results
Multiple regression analysis showed that the SPM score (t=3.19, p=0.002, β=0.22) and the overall ToM score (t=2.56, p=0.011, β=0.18) were primarily associated with a total hit rate (%) of the emotion recognition task. Hierarchical regression analysis through a three-step mediation model showed that ToM may partially mediate the relationship between SPM and performance on facial emotion recognition.
Conclusion
These findings imply that higher neurocognitive functioning, inclusive of reasoning, may not only directly contribute towards facial emotion recognition but also influence ToM, which in turn, influences facial emotion recognition. These findings are particularly true for healthy young people.
doi:10.4306/pi.2014.11.2.105
PMCID: PMC4023082  PMID: 24843363
Facial emotion; Theory of mind; Analogical reasoning; Neurocognition; Social cognition
21.  mAChRs activation induces epithelial-mesenchymal transition on lung epithelial cells 
Background
Epithelial-mesenchymal transition (EMT) has been proposed as a mechanism in the progression of airway diseases and cancer. Here, we explored the role of acetylcholine (ACh) and the pathway involved in the process of EMT, as well as the effects of mAChRs antagonist.
Methods
Human lung epithelial cells were stimulated with carbachol, an analogue of ACh, and epithelial and mesenchymal marker proteins were evaluated using western blot and immunofluorescence analyses.
Results
Decreased E-cadherin expression and increased vimentin and α-SMA expression induced by TGF-β1 in alveolar epithelial cell (A549) were significantly abrogated by the non-selective mAChR antagonist atropine and enhanced by the acetylcholinesterase inhibitor physostigmine. An EMT event also occurred in response to physostigmine alone. Furthermore, ChAT express and ACh release by A549 cells were enhanced by TGF-β1. Interestingly, ACh analogue carbachol also induced EMT in A549 cells as well as in bronchial epithelial cells (16HBE) in a time- and concentration-dependent manner, the induction of carbachol was abrogated by selective antagonist of M1 (pirenzepine) and M3 (4-DAMP) mAChRs, but not by M2 (methoctramine) antagonist. Moreover, carbachol induced TGF-β1 production from A549 cells concomitantly with the EMT process. Carbachol-induced EMT occurred through phosphorylation of Smad2/3 and ERK, which was inhibited by pirenzepine and 4-DAMP.
Conclusions
Our findings for the first time indicated that mAChR activation, perhaps via M1 and M3 mAChR, induced lung epithelial cells to undergo EMT and provided insights into novel therapeutic strategies for airway diseases in which lung remodeling occurs.
doi:10.1186/1471-2466-14-53
PMCID: PMC3975135  PMID: 24678619
Epithelial-mesenchymal transition (EMT); Lung epithelial cells; Non-neuronal cholinergic system; Signaling pathway
22.  APPROXIMATE SAMPLING FORMULAS FOR GENERAL FINITE-ALLELES MODELS OF MUTATION 
Advances in applied probability  2012;44(2):408-428.
Many applications in genetic analyses utilize sampling distributions, which describe the probability of observing a sample of DNA sequences randomly drawn from a population. In the one-locus case with special models of mutation such as the infinite-alleles model or the finite-alleles parent-independent mutation model, closed-form sampling distributions under the coalescent have been known for many decades. However, no exact formula is currently known for more general models of mutation that are of biological interest. In this paper, models with finitely-many alleles are considered, and an urn construction related to the coalescent is used to derive approximate closed-form sampling formulas for an arbitrary irreducible recurrent mutation model or for a reversible recurrent mutation model, depending on whether the number of distinct observed allele types is at most three or four, respectively. It is demonstrated empirically that the formulas derived here are highly accurate when the per-base mutation rate is low, which holds for many biological organisms.
doi:10.1239/aap/1339878718
PMCID: PMC3953561  PMID: 24634516
Sampling probability; coalescent theory; urn models; martingale
23.  Impact of Clinical Performance Examination on Incoming Interns' Clinical Competency in Differential Diagnosis of Headache 
Background
In Korea, clinical performance examination (CPX) has been included in license examination for medical doctors since 2009 in order to improve clinical performance of medical students. This study aimed to evaluate the contribution of CPX to medical education.
Methods
Clinical competency in the differential diagnosis of secondary headache was compared between the incoming interns in 2009 unexposed to CPX and the incoming interns in 2010 exposed to CPX, using the data of patients who visited the emergency department due to headache (181 patients seen by 60 CPX non-exposed interns and 150 patients seen by 50 CPX-exposed interns). We obtained the data by reviewing electronic medical records and nominal lists of doctors. Clinical competency was assessed by sensitivity and specificity between the diagnostic impression by interns and the final diagnosis. The association between CPX exposure and clinical competency in secondary headache diagnosis was evaluated using multiple logistic regression analysis.
Results
When we assessed clinical competency on the basis of all listed diagnostic impressions, sensitivity and specificity were 67.9% and 80.0%, respectively, for headaches seen by CPX-exposed interns, and 51.7%, and 71.7%, respectively, for headaches seen by CPX non-exposed interns. Multivariable adjusted logistic regression analysis showed exposure to CPX was not associated with increased competency for identifying secondary headache.
Conclusion
Exposure to CPX as a part of the medical license examination was not effective for the improvement of clinical competency of interns in identifying secondary headache.
doi:10.4082/kjfm.2014.35.2.56
PMCID: PMC3978186  PMID: 24724000
Competency-Based Education; Clinical Performance Examination; Headache; Internship and Residency; Medical Student
24.  Validation and Reliability of a Smartphone Application for the International Prostate Symptom Score Questionnaire: A Randomized Repeated Measures Crossover Study 
Background
Smartphone-based assessment may be a useful diagnostic and monitoring tool for patients. There have been many attempts to create a smartphone diagnostic tool for clinical use in various medical fields but few have demonstrated scientific validity.
Objective
The purpose of this study was to develop a smartphone application of the International Prostate Symptom Score (IPSS) and to demonstrate its validity and reliability.
Methods
From June 2012 to May 2013, a total of 1581 male participants (≥40 years old), with or without lower urinary tract symptoms (LUTS), visited our urology clinic via the health improvement center at Soonchunhyang University Hospital (Republic of Korea) and were enrolled in this study. A randomized repeated measures crossover design was employed using a smartphone application of the IPSS and the conventional paper form of the IPSS. Paired t test under a hypothesis of non-inferior trial was conducted. For the reliability test, the intraclass correlation coefficient (ICC) was measured.
Results
The total score of the IPSS (P=.289) and each item of the IPSS (P=.157-1.000) showed no differences between the paper version and the smartphone version of the IPSS. The mild, moderate, and severe LUTS groups showed no differences between the two versions of the IPSS. A significant correlation was noted in the total group (ICC=.935, P<.001). The mild, moderate, and severe LUTS groups also showed significant correlations (ICC=.616, .549, and .548 respectively, all P<.001).There was selection bias in this study, as only participants who had smartphones could participate.
Conclusions
The validity and reliability of the smartphone application version were comparable to the conventional paper version of the IPSS. The smartphone application of the IPSS could be an effective method for measuring lower urinary tract symptoms.
doi:10.2196/jmir.3042
PMCID: PMC3936272  PMID: 24513507
smartphone; International Prostate Symptom Score; lower urinary tract symptoms; health survey; questionnaires
25.  Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice 
Journal of neurochemistry  2012;124(4):523-535.
Oxidative stress after stroke is associated with the inflammatory system activation in the brain. The complement cascade, especially the degradation products of complement component 3, is a key inflammatory mediator of cerebral ischemia. We have shown that proinflammatory complement component 3 is increased by oxidative stress after ischemic stroke in mice using DNA array. In this study, we investigated whether up-regulation of complement component 3 is directly related to oxidative stress after transient focal cerebral ischemia in mice and oxygen-glucose deprivation in brain cells. Persistent up-regulation of complement component 3 expression was reduced in copper/zinc-superoxide dismutase transgenic mice, and manganese-superoxide dismutase knockout mice showed highly increased complement component 3 levels after transient focal cerebral ischemia. Antioxidant N-tert-butyl-α-phenylnitrone treatment suppressed complement component 3 expression after transient focal cerebral ischemia. Accumulation of complement component 3 in neurons and microglia was decreased by N-tert-butyl-α-phenylnitrone, which reduced infarct volume and impaired neurological deficiency after cerebral ischemia and reperfusion in mice. Small interfering RNA specific for complement component 3 transfection showed a significant increase in brain cells viability after oxygen-glucose deprivation. Our study suggests that the neuroprotective effect of antioxidants through complement component 3 suppression is a new strategy for potential therapeutic approaches in stroke.
doi:10.1111/jnc.12111
PMCID: PMC3557607  PMID: 23199288
antioxidant; complement component 3; focal cerebral ischemia; oxidative stress

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