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1.  Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1 
Cell Research  2011;21(9):1305-1315.
Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by the transcription factors Oct4, Sox2, and Klf4 in combination with c-Myc. Recently, Sox2 plus Oct4 was shown to reprogram fibroblasts and Oct4 alone was able to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here, we report that Bmi1 leads to the transdifferentiation of mouse fibroblasts into NSC-like cells, and, in combination with Oct4, can replace Sox2, Klf4 and c-Myc during the reprogramming of fibroblasts into iPS cells. Furthermore, activation of sonic hedgehog signaling (by Shh, purmorphamine, or oxysterol) compensates for the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One- and two-factor iPS cells are similar to mouse embryonic stem cells in their global gene expression profile, epigenetic status, and in vitro and in vivo differentiation into all three germ layers, as well as teratoma formation and germline transmission in vivo. These data support that converting fibroblasts with Bmi1 or activation of the sonic hedgehog pathway to an intermediate cell type that expresses Sox2, Klf4, and N-Myc allows iPS generation via the addition of Oct4.
PMCID: PMC3193470  PMID: 21709693
reprogramming; transdifferentiation; neural stem cells; induced pluripotent stem cells; Bmi1; Oct4
2.  Long-Term Ultrasound Follow-Up of Thyroid Colloid Cysts 
Objective. This study aimed to assess the interval changes of thyroid colloid cysts (TCCs) by performing long-term ultrasound (US) follow-up examinations. Methods. From 2007 to 2008, 437 patients underwent a lobectomy for the treatment of papillary thyroid microcarcinoma. Among them, 268 patients underwent 4 or more postoperative US follow-ups after surgery. This study investigated the prevalence and interval changes of TCCs ≥3 mm by using US follow-ups. Results. Among 268 patients, 35 (13.1%) had TCCs ≥3 mm by a preoperative thyroid US, and 6 (2.2%) had newly detected TCCs at a US follow-up. Through long-term US follow-up, the interval changes for TCCs were classified as follows: no interval change (n = 8), gradual increase (n = 8), gradual decrease (n = 5), positive fluctuation (n = 3), negative fluctuation (n = 6), disappearance (n = 5), and new detection (n = 6). None of the TCC cases had a TCC that was ≥10 mm at its largest diameter, and no patient complained of any relevant symptoms pertaining to the TCCs. Conclusions. In this study, TCCs demonstrated various interval changes, but no abrupt increase was found or acute onset of symptoms occurred.
PMCID: PMC4016894  PMID: 24864139
3.  Clinical Evaluation of a Loop-Mediated Isothermal Amplification (LAMP) Assay for Rapid Detection of Neisseria meningitidis in Cerebrospinal Fluid 
PLoS ONE  2015;10(4):e0122922.
Neisseria meningitidis (Nm) is a leading causative agent of bacterial meningitis in humans. Traditionally, meningococcal meningitis has been diagnosed by bacterial culture. However, isolation of bacteria from patients’ cerebrospinal fluid (CSF) is time consuming and sometimes yields negative results. Recently, polymerase chain reaction (PCR)-based diagnostic methods of detecting Nm have been considered the gold standard because of their superior sensitivity and specificity compared with culture. In this study, we developed a loop-mediated isothermal amplification (LAMP) method and evaluated its ability to detect Nm in cerebrospinal fluid (CSF).
Methodology/Principal Findings
We developed a meningococcal LAMP assay (Nm LAMP) that targets the ctrA gene. The primer specificity was validated using 16 strains of N. meningitidis (serogroup A, B, C, D, 29-E, W-135, X, Y, and Z) and 19 non-N. meningitidis species. Within 60 min, the Nm LAMP detected down to ten copies per reaction with sensitivity 1000-fold more than that of conventional PCR. The LAMP assays were evaluated using a set of 1574 randomly selected CSF specimens from children with suspected meningitis collected between 1998 and 2002 in Vietnam, China, and Korea. The LAMP method was shown to be more sensitive than PCR methods for CSF samples (31 CSF samples were positive by LAMP vs. 25 by PCR). The detection rate of the LAMP method was substantially higher than that of the PCR method. In a comparative analysis of the PCR and LAMP assays, the clinical sensitivity, specificity, positive predictive value, and negative predictive value of the LAMP assay were 100%, 99.6%, 80.6%, and 100%, respectively.
Compared to PCR, LAMP detected Nm with higher analytical and clinical sensitivity. This sensitive and specific LAMP method offers significant advantages for screening patients on a population basis and for diagnosis in clinical settings.
PMCID: PMC4390149  PMID: 25853422
4.  Terminalia chebula Fructus Inhibits Migration and Proliferation of Vascular Smooth Muscle Cells and Production of Inflammatory Mediators in RAW 264.7 
Pathogenesis of atherosclerosis and neointima formation after angioplasty involves vascular smooth muscle cells (VSMCs) migration and proliferation followed by inflammatory responses mediated by recruited macrophages in the neointima. Terminalia chebula is widely used traditional medicine in Asia for its beneficial effects against cancer, diabetes, and bacterial infection. The study was designed to determine whether Terminalia chebula fructus water extract (TFW) suppresses VSMC migration and proliferation and inflammatory mediators production in macrophage (RAW 264.7). Our results showed that TFW possessed strong antioxidative effects in 1,1-diphenyl-2-picryl hydrazyl (DPPH) scavenging and lipid peroxidation assays. In addition, TFW reduced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression in RAW 264.7 cells. Also, TFW inhibited platelet-derived growth factor (PDGF-BB) induced VSMC migration as determined by wound healing and Boyden chamber assays. The antimigratory effect of TFW was due to its inhibitory effect on metalloproteinase-9 (MMP-9) expression, focal adhesion kinase (FAK) activation, and Rho-family of small GTPases (Cdc42 and RhoA) expression in VSMCs. Furthermore, TFW suppressed PDGF-BB induced VSMC proliferation by downregulation of mitogen activated protein kinases (MAPKs) signaling molecules. These results suggest that TFW could be a beneficial resource in the prevention of atherosclerosis.
PMCID: PMC4345257  PMID: 25784946
6.  Computed Tomography Features of Incidentally Detected Diffuse Thyroid Disease 
Objective. This study aimed to evaluate the CT features of incidentally detected DTD in the patients who underwent thyroidectomy and to assess the diagnostic accuracy of CT diagnosis. Methods. We enrolled 209 consecutive patients who received preoperative neck CT and subsequent thyroid surgery. Neck CT in each case was retrospectively investigated by a single radiologist. We evaluated the diagnostic accuracy of individual CT features and the cut-off CT criteria for detecting DTD by comparing the CT features with histopathological results. Results. Histopathological examination of the 209 cases revealed normal thyroid (n = 157), Hashimoto thyroiditis (n = 17), non-Hashimoto lymphocytic thyroiditis (n = 34), and diffuse hyperplasia (n = 1). The CT features suggestive of DTD included low attenuation, inhomogeneous attenuation, increased glandular size, lobulated margin, and inhomogeneous enhancement. ROC curve analysis revealed that CT diagnosis of DTD based on the CT classification of “3 or more” abnormal CT features was superior. When the “3 or more” CT classification was selected, the sensitivity, specificity, positive and negative predictive values, and accuracy of CT diagnosis for DTD were 55.8%, 95.5%, 80.6%, 86.7%, and 85.6%, respectively. Conclusion. Neck CT may be helpful for the detection of incidental DTD.
PMCID: PMC4274648  PMID: 25548565
7.  Papillary thyroid microcarcinoma in a thyroid pyramidal lobe 
Ultrasonography  2014;33(4):303-306.
We report an extremely rare case of papillary thyroid microcarcinoma (PTMC) in the thyroid Epub ahead of print pyramidal lobe (TPL). A 48-year-old woman underwent ultrasound-guided fine-needle aspiration for a small thyroid nodule in the right lobe in local clinic, and it revealed a malignant cytology. On preoperative ultrasonography for tumor staging in our hospital, another small suspiciously malignant hypoechoic nodule was detected in the left TPL. Total thyroidectomy and central nodal dissection were performed. Histopathology confirmed PTMCs in the left TPL and both thyroid lobes. Ultrasonography for TPL should be required for complete evaluation of possible multifocality of thyroid malignancy.
PMCID: PMC4176109  PMID: 25116459
Thyroid nodule; Pyramidal lobe; Papillary thyroid microcarcinoma; Ultrasonography
8.  Insulinoma Presenting as Medically Intractable Temporal Lobe Epilepsy 
Journal of Epilepsy Research  2014;4(1):21-23.
We describe a female insulinoma patient who presented with recurrent attacks of abnormal behavior, confusion, and seizure. Her interictal EEG showed epileptiform discharges on the left temporal area, therefore she was initially misdiagnosed as temporal lobe epilepsy. In the video-EEG monitoring, hypoglycemic state was detected during the seizure attack, so the right diagnosis was made after the endocrinologic investigations. After surgical removal of the tumor, the patient became seizure-free, and no abnormality was found in the follow-up EEG after six months. Since insulinoma shares some common clinical and EEG features with complex partial seizure of temporal lobe origin, insulioma should be included in the differential diagnosis for medically intractable temporal lobe epilepsy.
PMCID: PMC4066620  PMID: 24977127
Insulinoma; Hypoglycemia; EEG; Temporal lobe epilepsy
9.  Identification of Nasal Bone Fractures on Conventional Radiography and Facial CT: Comparison of the Diagnostic Accuracy in Different Imaging Modalities and Analysis of Interobserver Reliability 
Iranian Journal of Radiology  2013;10(3):140-147.
There has been no study to compare the diagnostic accuracy of an experienced radiologist with a trainee in nasal bone fracture.
To compare the diagnostic accuracy between conventional radiography and computed tomography (CT) for the identification of nasal bone fractures and to evaluate the interobserver reliability between a staff radiologist and a trainee.
Patients and Methods
A total of 108 patients who underwent conventional radiography and CT after acute nasal trauma were included in this retrospective study. Two readers, a staff radiologist and a second-year resident, independently assessed the results of the imaging studies.
Of the 108 patients, the presence of a nasal bone fracture was confirmed in 88 (81.5%) patients. The number of non-depressed fractures was higher than the number of depressed fractures. In nine (10.2%) patients, nasal bone fractures were only identified on conventional radiography, including three depressed and six non-depressed fractures. CT was more accurate as compared to conventional radiography for the identification of nasal bone fractures as determined by both readers (P <0.05), all diagnostic indices of an experienced radiologist were similar to or higher than those of a trainee, and κ statistics showed moderate agreement between the two diagnostic tools for both readers. There was no statistical difference in the assessment of interobserver reliability for both imaging modalities in the identification of nasal bone fractures.
For the identification of nasal bone fractures, CT was significantly superior to conventional radiography. Although a staff radiologist showed better values in the identification of nasal bone fracture and differentiation between depressed and non-depressed fractures than a trainee, there was no statistically significant difference in the interpretation of conventional radiography and CT between a radiologist and a trainee.
PMCID: PMC3857976  PMID: 24348599
Nasal Bone, Fractures, Bone; Radiography
10.  Anticonvulsant Effects of β-Hydroxybutyrate in Mice 
Journal of Epilepsy Research  2012;2(2):29-32.
Background and Purpose:
The ketogenic diet was formulated to mimic the biochemical changes seen upon fasting, specifically the formation of ketone bodies. Recent research data suggest that the anticonvulsant efficacy of the KD may be due in part to the direct actions of ketone bodies. This study was designed to investigate the anticonvulsant effects of β-hydroxybutyrate (BHB) on pilocarpine-induced seizures in mature mice.
Eighty-two male ICR mice at postnatal day 49 were used. All mice were pretreated with scopolamine methylbromide prior to pilocarpine injection. Experimental mice (n=42) were injected intraperitoneally with BHB (20 mmol/kg) 15 min prior to pilocarpine administration, while control animals (n=40) with normal saline. Pilocarpine (300 mg/kg) was administered intraperitoneally and mice were monitored for 2 h after pilocarpine injection.
All mice developed typical seizure behaviors. The mean (±SD) latency to the onset of seizures was significantly prolonged in the BHB-treated mice compared with controls (4.83±1.95 min vs. 3.67±1.90 min, p<0.01).
This study demonstrates that treatment with BHB prolongs the latency to the onset of seizures induced by pilocarpine in mature mice and suggests that BHB, one of the ketone bodies, may have direct anticonvulsant effects.
PMCID: PMC3952323  PMID: 24649459
Ketone body; 3-hydroxybutyric acid; Pilocarpine; Mice; Seizure
11.  Melatonin combined with exercise cannot alleviate cerebral injury in a rat model of focal cerebral ischemia/reperfusion injury 
Neural Regeneration Research  2012;7(13):993-999.
Previous studies have demonstrated that melatonin combined with exercise can alleviate secondary damage after spinal cord injury in rats. Therefore, it is hypothesized that melatonin combined with exercise can also alleviate ischemic brain damage. In this study, adult rats were subjected to right middle cerebral artery occlusion after receiving 10 mg/kg melatonin or vehicle subcutaneously twice daily for 14 days. Forced exercise using an animal treadmill was performed at 20 m/min for 30 minutes per day for 6 days prior to middle cerebral artery occlusion. After middle cerebral artery occlusion, each rat received melatonin combined with exercise, melatonin or exercise alone equally for 7 days until sacrifice. Interestingly, rats receiving melatonin combined with exercise exhibited more severe neurological deficits than those receiving melatonin or exercise alone. Hypoxia-inducible factor 1α mRNA in the brain tissue was upregulated in rats receiving melatonin combined with exercise. Similarly, microtubule associated protein-2 mRNA expression was significantly upregulated in rats receiving melatonin alone. Chondroitin sulfate proteoglycan 4 (NG2) mRNA expression was significantly decreased in rats receiving melatonin combined with exercise as well as in rats receiving exercise alone. Furthermore, neural cell loss in the primary motor cortex was significantly reduced in rats receiving melatonin or exercise alone, but the change was not observed in rats receiving melatonin combined with exercise. These findings suggest that excessive intervention with melatonin, exercise or their combination may lead to negative effects on ischemia/reperfusion-induced brain damage.
PMCID: PMC4341280  PMID: 25722687
focal cerebral ischemia/reperfusion; melatonin; exercise; neurological function; brain tissue loss; microtubule associated protein-2; chondroitin sulfate proteoglycan 4; NG2; hypoxia-inducible factor 1 alpha; neural regeneration
12.  Inhibitory Effect of Nelumbo nucifera (Gaertn.) on the Development of Atopic Dermatitis-Like Skin Lesions in NC/Nga Mice 
Atopic dermatitis (AD) is a chronic inflammatory skin disease which has a complex etiology that encompasses immunologic responses. The study was carried out to examine the effect of Nelumbo nucifera (Gaertn.) leaf (NL) on the AD-like skin lesion induced by repeated epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) on the dorsal skin of NC/Nga mice. Three different doses of NL (5, 25, and 50 mg/mice/day) were administered orally from the day of sensitization with DNCB for 4 weeks. The efficacy of NL was judged by histopathological examination, blood IgE level, measurement of transepidermal water loss (TEWL), scratching behavior, and skin severity score. NL resulted in the suppression of clinical severity score, TEWL, scratching behavior, and blood IgE level. Histopathologic analyses revealed that thickening of the epidermis and mast cell degranulation was significantly reduced in NL group. These results suggest that NL may be a useful natural resource for the management of AD.
PMCID: PMC3291163  PMID: 22454654
13.  Effects of imatinib mesylate on the pharmacokinetics of paracetamol (acetaminophen) in Korean patients with chronic myelogenous leukaemia 
The major objective of the present study was to investigate the effect of imatinib on the pharmacokinetics of paracetamol in patients with chronic myelogenous leukaemia (CML).
Patients (n= 12) received a single oral dose of acetaminophen 1000 mg on day 1 (control). On days 2–8, imatinib 400 mg was administered daily. On day 8 (treatment), another 1000 mg dose of paracetamol was administered 1 h after the morning dose of imatinib 400 mg. Blood and urine samples were collected for bioanalytical analyses.
The area under the plasma concentration–time curve (AUC) for paracetamol, paracetamol glucuronide and paracetamol sulphate under control conditions was similar to that after treatment with imatinib; the 90% confidence interval of the log AUC ratio was within 0.8 to 1.25. Urinary excretion of paracetamol, paracetamol glucuronide and paracetamol sulphate was also unaffected by imatinib. The pharmacokinetics of paracetamol and imatinib in Korean patients with CML were similar to previous pharmacokinetic results in white patients with CML. Co-administration of a single dose of paracetamol and multiple doses of imatinib was well tolerated and safety profiles were similar to those of either drug alone.
The pharmacokinetics of paracetamol and its major metabolites in the presence of imatinib were similar to those of the control conditions and the combination was well tolerated. These findings suggest that imatinib can be safely administered with paracetamol without dose adjustment of either drug.
PMCID: PMC3040540  PMID: 21219400
acetaminophen; CML; imatinib; Korean; paracetamol; pharmacokinetics
14.  Differentiation between Benign and Malignant Solid Thyroid Nodules Using an US Classification System 
Korean Journal of Radiology  2011;12(5):559-567.
To evaluate the diagnostic accuracy of a new ultrasound (US) classification system for differentiating between benign and malignant solid thyroid nodules.
Materials and Methods
In this study, we enrolled 191 consecutive patients who received real-time US and subsequent US diagnoses for solid thyroid nodules, and underwent US-guided fine-needle aspiration. Each thyroid nodule was prospectively classified into 1 of 5 diagnostic categories by real-time US: "malignant," "suspicious for malignancy," "borderline," "probably benign," and "benign". We evaluated the diagnostic accuracy of thyroid US and the cut-off US criteria by comparing the US diagnoses of thyroid nodules with cytopathologic results.
Of the 191 solid nodules, 103 were subjected to thyroid surgery. US categories for these 191 nodules were malignant (n = 52), suspicious for malignancy (n = 16), borderline (n = 23), probably benign (n = 18), and benign (n = 82). A receiver-operating characteristic curve analysis revealed that the US diagnosis for solid thyroid nodules using the 5-category US classification system was very good. The sensitivity, specificity, positive and negative predictive values, and accuracy of US diagnosis were 86%, 95%, 91%, 92%, and 92%, respectively, when benign, probably benign, and borderline categories were collectively classified as benign (negative).
The diagnostic accuracy of thyroid US for solid thyroid nodules is high when the above-mentioned US classification system is applied.
PMCID: PMC3168797  PMID: 21927557
Thyroid nodule; Solid, Ultrasound; Fine-needle aspiration; Classification; Malignancy
15.  Ultrasound-Guided Fine-Needle Aspiration Biopsy of Thyroid Nodules Smaller Than 5 mm in the Maximum Diameter: Assessment of Efficacy and Pathological Findings 
Korean Journal of Radiology  2009;10(5):435-440.
The aim of this study was to determine the efficacy of the use of an ultrasound-guided fine-needle aspiration biopsy (US-FNAB) to diagnose thyroid nodules smaller than 5 mm in the maximum diameter and to evaluate pathological findings of small thyroid malignancies.
Materials and Methods
From May 2007 to April 2008, we evaluated the findings of US-FNABs of small thyroid nodules less than 5 mm in the maximum diameter. The cytopathological findings were retrospectively reviewed and the diagnostic performance of the use of an US-FNAB was examined in all patients.
Of 201 small thyroid nodules in 180 patients, there were 162 adequate specimens (81%). Among 180 patients, 75 patients underwent thyroid surgery and 50 malignant and 33 benign nodules were identified based on a pathological examination. All small malignant thyroid nodules were identified as papillary thyroid microcarcinomas (PTMCs). There were 34 (55%) true positive, 0 (0%) false positive, 23 (37%) true negative and five (8%) false negative results for malignancy after performing a first US-FNAB in 62 surgically confirmed nodules. The sensitivity (87%), specificity (100%), positive predictive value (100%), negative predictive value (82%), accuracy (92%), false positive rate (0%) and false negative rate (8%) for an US-FNAB were determined. In 23 patients with a primary PTMC, capsular invasion (9%, 2 of 23), a perithyroidal lymph node metastasis (30%, 7 of 23), the rate of multifocality (9%, 2 of 23) and bilaterality (4%, 1 of 23) were also determined.
An US-FNAB of thyroid nodules smaller than 5 mm in the maximum diameter is an effective diagnostic procedure.
PMCID: PMC2731860  PMID: 19721827
Thyroid, nodule; Fine-needle biopsies; Ultrasound (US); Microcarcinoma
16.  Multilocus sequence typing analysis of Shigella flexneri isolates collected in Asian countries 
Journal of medical microbiology  2007;56(Pt 11):1460-1466.
The multilocus sequence typing scheme used previously for phylogenetic analysis of Escherichia coli was applied to 107 clinical isolates of Shigella flexneri. DNA sequencing of 3423 bp throughout seven housekeeping genes identified eight new allele types and ten new sequence types among the isolates. S. flexneri serotypes 1-5, X and Y were clustered together in a group containing many allelic variants while serotype 6 formed a distinct group, as previously established.
PMCID: PMC2652033  PMID: 17965345
17.  Efficacy and safety of dasatinib versus imatinib in the East Asian subpopulation of the DASISION trial of newly diagnosed chronic myeloid leukemia in chronic phase 
Leukemia & Lymphoma  2013;55(9):2093-2100.
Asian patients with chronic myeloid leukemia (CML) tend to have different characteristics compared with patients from other regions, including younger age and smaller body size. The phase 3, open-label, randomized DASISION trial (NCT00481247), comparing dasatinib 100 mg once daily (QD) (n = 259) with imatinib 400 mg QD (n = 260) in newly diagnosed chronic phase CML (CML-CP), included a sizeable East Asian population (n = 60: dasatinib; n = 48: imatinib). In East Asian patients, dasatinib showed favorable 24-month rates of major molecular response (68% vs. 50% for imatinib) and complete cytogenetic response (92% vs. 88%), and more patients achieved BCR–ABL1 transcript levels ≤ 10% at 3 months with dasatinib (91% vs. 69%), similar to the overall population. Relative to non-East Asian patients, the incidence of rash, fluid-related events and grade 3/4 neutropenia and thrombocytopenia appeared to be higher in East Asians, regardless of treatment. Pharmacokinetic analysis revealed statistically non-significant increased dasatinib exposure among East Asian patients. Results support the use of dasatinib 100 mg QD as first-line CML treatment in both East Asian and non-East Asian patients.
PMCID: PMC4196520  PMID: 24289108
CML; dasatinib; imatinib; East Asian; first-line treatment
18.  Clinical significance of laryngopharyngeal reflux in patients with chronic obstructive pulmonary disease 
Although chronic obstructive pulmonary disease (COPD) is closely associated with gastroesophageal reflux disease (GERD), the clinical significance of laryngopharyngeal reflux (LPR) is not fully understood in COPD.
Prospective cohorts were established among 118 patients with COPD from March 2013 to July 2014. Thirty-two age-matched and sex-matched normal controls, who had routine health check-ups during the study period, were included. Laryngopharyngeal reflux finding scores (RFS) and reflux symptom index (RSI) for LPR were subjected to association analysis with severity and acute exacerbation of COPD during the 1-year follow-up.
The mean age of patients enrolled in the study was 69.2±8.8 years, with 93.2% being male. Positive RFS (>7) and RSI (>13) were observed in 51 (42.5%) and six patients (5.0%), respectively. RFS and RSI were significantly higher in patients with COPD than in normal, healthy patients (P<0.001). RFS was significantly correlated with residual volume/total lung capacity (%, P=0.048). Scores for diffuse laryngeal edema, erythema, and hyperemia were significantly higher in the high-risk group (Global Initiative for Chronic Obstructive Lung Disease classification C and D; P=0.025 and P=0.049, respectively), while RSI was significantly higher in the more symptomatic group (Global Initiative for Chronic Obstructive Lung Disease classification B and D; P=0.047). RSI and RFS were significant predictors for severe acute exacerbation of COPD (P=0.03 and P=0.047, respectively), while only RSI was associated with severity of dyspnea.
Laryngeal examination and evaluation of laryngeal reflux symptom could be a surrogate clinical indicator related to severe acute exacerbation of COPD. Further studies of LPR in COPD patients should be considered.
PMCID: PMC4507795  PMID: 26203240
COPD; acute exacerbation; laryngopharyngeal reflux; reflux symptom index; reflux finding score
19.  Fractal Nature of Metallic and Insulating Domain Configurations in a VO2 Thin Film Revealed by Kelvin Probe Force Microscopy 
Scientific Reports  2015;5:10417.
We investigated the surface work function (WS) and its spatial distribution for epitaxial VO2/TiO2 thin films using Kelvin probe force microscopy (KPFM). Nearly grain-boundary-free samples allowed observation of metallic and insulating domains with distinct WS values, throughout the metal–insulator transition. The metallic fraction, estimated from WS maps, describes the evolution of the resistance based on a two-dimensional percolation model. The KPFM measurements also revealed the fractal nature of the domain configuration.
PMCID: PMC4434847  PMID: 25982229
20.  A histone deacetylase inhibitor improves hypothyroidism caused by a TRα1 mutant 
Human Molecular Genetics  2013;23(10):2651-2664.
Mutations of the thyroid hormone receptor α gene (THRA) cause hypothyroidism in patients with growth and developmental retardation, and skeletal dysplasia. Genetic evidence indicates that the dominant negative activity of TRα1 mutants underlies pathological manifestations. Using a mouse model of hypothyroidism caused by a dominant negative TRα1PV mutant and its derived mouse model harboring a mutated nuclear receptor corepressor (NCOR1ΔID) (Thra1PV/+Ncor1ΔID/ΔID mice), we recently showed that aberrant release of TRα1 mutants from the NCOR1 repressor complex mediates dominant negative actions of TRα1 mutants in vivo. We tested the hypothesis that deacetylation of nucleosomal histones associated with aberrant recruitment of corepressors by TRα1 mutants underlies pathological phenotypic expression. We treated Thra1PV/+and Thra1PV/+Ncor1ΔID/ΔID mice with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxyamic acid (SAHA). SAHA significantly ameliorated the impaired growth, bone development and adipogenesis of Thra1PV/+ mice. In Thra1PV/+Ncor1ΔID/ΔID mice, SAHA improved these abnormalities even further. We focused our molecular analyses on how SAHA improved the impaired adipogenesis leading to the lean phenotype. We found that SAHA reverted the impaired adipogenesis by de-repressing the expression of the two master regulators of adipogenesis, C/ebpα and Pparγ, as well as other adipogenic genes at both the mRNA and protein levels. Chromatin immunoprecipitation analyses indicated SAHA increased the extent of acetylation of nucleosomal H4K5 and H3 to re-activate adipogenic genes to reverting adipogenesis. Thus, HDAC confers in vivo aberrant actions of TRα1 mutants. Importantly, for the first time, the present studies show that HDAC inhibitors are clearly beneficial for hypothyroidism and could be therapeutics for treatment.
PMCID: PMC3990165  PMID: 24381310
21.  PSA-NCAM-Negative Neural Crest Cells Emerging during Neural Induction of Pluripotent Stem Cells Cause Mesodermal Tumors and Unwanted Grafts 
Stem Cell Reports  2015;4(5):821-834.
Tumorigenic potential of human pluripotent stem cells (hPSCs) is an important issue in clinical applications. Despite many efforts, PSC-derived neural precursor cells (NPCs) have repeatedly induced tumors in animal models even though pluripotent cells were not detected. We found that polysialic acid-neural cell adhesion molecule (PSA-NCAM)− cells among the early NPCs caused tumors, whereas PSA-NCAM+ cells were nontumorigenic. Molecular profiling, global gene analysis, and multilineage differentiation of PSA-NCAM− cells confirm that they are multipotent neural crest stem cells (NCSCs) that could differentiate into both ectodermal and mesodermal lineages. Transplantation of PSA-NCAM− cells in a gradient manner mixed with PSA-NCAM+ cells proportionally increased mesodermal tumor formation and unwanted grafts such as PERIPHERIN+ cells or pigmented cells in the rat brain. Therefore, we suggest that NCSCs are a critical target for tumor prevention in hPSC-derived NPCs, and removal of PSA-NCAM− cells eliminates the tumorigenic potential originating from NCSCs after transplantation.
Graphical Abstract
•PSA-NCAM− cells isolated from neural rosettes are classified as multipotent NCSCs•NCSCs are a potential target for tumor prevention in hPSC-derived-NPC-based therapy•Removal of PSA-NCAM− cells prevents the introduction of mesodermal tumor in the CNS•Removal of PSA-NCAM− cells prevents the introduction of unwanted grafts in the CNS
By PSA-NCAM-targeted cell sorting from hPSC-derived neural rosettes, D.-W. Kim, D.-S. Kim, and colleagues show that PSA-NCAM− cells are multipotent NCSCs with the capacity to differentiate into both ectodermal and mesodermal lineages. They also demonstrate that NCSCs are responsible for mesodermal tumor and unwanted graft formations in the CNS. These results suggest that removal of PSA-NCAM− cells eliminates the tumorigenic potential originating from NCSCs.
PMCID: PMC4437469  PMID: 25937368
22.  Mie resonance-mediated antireflection effects of Si nanocone arrays fabricated on 8-in. wafers using a nanoimprint technique 
We fabricated 8-in. Si nanocone (NC) arrays using a nanoimprint technique and investigated their optical characteristics. The NC arrays exhibited remarkable antireflection effects; the optical reflectance was less than 10% in the visible wavelength range. The photoluminescence intensity of the NC arrays was an order of magnitude larger than that of a planar wafer. Optical simulations and analyses suggested that the Mie resonance reduced effective refractive index, and multiple scattering in the NCs enabled the drastic decrease in reflection.
PACS: 88.40.H-;; 81.07.Gf
PMCID: PMC4395620  PMID: 25897308
Si; Nanocone array; Antireflection; Mie resonance; Nanoimprint
23.  Arabidopsis mutant plants with diverse defects in polyamine metabolism show unequal sensitivity to exogenous cadaverine probably based on their spermine content 
Arabidopsis plants do not synthesize the polyamine cadaverine, a five carbon-chain diamine and structural analog of putrescine. Mutants defective in polyamine metabolic genes were exposed to exogenous cadaverine. Spermine-deficient spms mutant grew well while a T-DNA insertion mutant (pao4-1) of polyamine oxidase (PAO) 4 was severely inhibited in root growth compared to wild type (WT) or other pao loss-of-function mutants. To understand the molecular basis of this phenomenon, polyamine contents of WT, spms and pao4-1 plants treated with cadaverine were analyzed. Putrescine contents increased in all the three plants, and spermidine contents decreased in WT and pao4-1 but not in spms. Spermine contents increased in WT and pao4-1. As there were good correlations between putrescine (or spermine) contents and the degree of root growth inhibition, effects of exogenously added putrescine and spermine were examined. Spermine mimicked the original phenomenon, whereas high levels of putrescine evenly inhibited root growth, suggesting that cadaverine-induced spermine accumulation may explain the phenomenon. We also tested growth response of cadaverine-treated WT and pao4-1 plants to NaCl and found that spermine-accumulated pao4-1 plant was not NaCl tolerant. Based on the results, the effect of cadaverine on Arabidopsis growth and the role of PAO during NaCl stress are discussed.
Electronic supplementary material
The online version of this article (doi:10.1007/s12298-014-0227-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3988325  PMID: 24757319
Arabidopsis; Cadaverine; NaCl response; Polyamine oxidase; Putrescine; Spermidine; Spermine
24.  Mesenchymal Stem Cell-Conditioned Medium Enhances Osteogenic and Chondrogenic Differentiation of Human Embryonic Stem Cells and Human Induced Pluripotent Stem Cells by Mesodermal Lineage Induction 
Tissue Engineering. Part A  2013;20(7-8):1306-1313.
Human mesenchymal stem cells (hMSCs) have the ability to differentiate into mesenchymal lineages. In this study, we hypothesized that treatment of embryoid bodies (EBs) composed of either human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) with a hMSC-conditioned medium (CM) can stimulate the induction of the mesodermal lineage and subsequent differentiation toward the osteogenic and chondrogenic lineage. Quantitative real-time reverse transcription–polymerase chain reaction (qRT-PCR) analysis indicated that the hMSC-CM treatment increased gene expression related to the mesodermal lineage and decreased gene expression related to the endodermal and ectodermal lineage in EBs. Fourteen days after culturing the mesodermal lineage-induced EBs in the osteogenic or chondrogenic differentiation medium, we observed enhanced osteogenic and chondrogenic differentiation compared with untreated EBs, as evaluated using qRT-PCR, cytochemistry, immunocytochemistry, and flow cytometry. This method may be useful for enhancing the osteogenic or chondrogenic differentiation of hESCs or hiPSCs.
PMCID: PMC3993069  PMID: 24224833
25.  Transparent conductor-embedding nanocones for selective emitters: optical and electrical improvements of Si solar cells 
Scientific Reports  2015;5:9256.
Periodical nanocone-arrays were employed in an emitter region for high efficient Si solar cells. Conventional wet-etching process was performed to form the nanocone-arrays for a large area, which spontaneously provides the graded doping features for a selective emitter. This enables to lower the electrical contact resistance and enhances the carrier collection due to the high electric field distribution through a nanocone. Optically, the convex-shaped nanocones efficiently reduce light-reflection and the incident light is effectively focused into Si via nanocone structure, resulting in an extremely improved the carrier collection performances. This nanocone-arrayed selective emitter simultaneously satisfies optical and electrical improvement. We report the record high efficiency of 16.3% for the periodically nanoscale patterned emitter Si solar cell.
PMCID: PMC4365400  PMID: 25787933

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