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1.  Non-muscle tropomyosin (Tpm3) is crucial for asymmetric cell division and maintenance of cortical integrity in mouse oocytes 
Cell Cycle  2014;13(15):2359-2369.
Tropomyosins are actin-binding cytoskeletal proteins that play a pivotal role in regulating the function of actin filaments in muscle and non-muscle cells; however, the roles of non-muscle tropomyosins in mouse oocytes are unknown. This study investigated the expression and functions of non-muscle tropomyosin (Tpm3) during meiotic maturation of mouse oocytes. Tpm3 mRNA was detected at all developmental stages in mouse oocytes. Tpm3 protein was localized at the cortex during the germinal vesicle and germinal vesicle breakdown stages. However, the overall fluorescence intensity of Tpm3 immunostaining was markedly decreased in metaphase II oocytes. Knockdown of Tpm3 impaired asymmetric division of oocytes and spindle migration, considerably reduced the amount of cortical actin, and caused membrane blebbing during cytokinesis. Expression of a constitutively active cofilin mutant and Tpm3 overexpression confirmed that Tpm3 protects cortical actin from depolymerization by cofilin. The data indicate that Tpm3 plays crucial roles in maintaining cortical actin integrity and asymmetric cell division during oocyte maturation, and that dynamic regulation of cortical actin by Tpm3 is critical to ensure proper polar body protrusion.
doi:10.4161/cc.29333
PMCID: PMC4128881  PMID: 25483187
Tropomyosin; actin; oocyte polarization; asymmetric division; cofilin
2.  Prevention of Cytomegalovirus Transmission via Breast Milk in Extremely Low Birth Weight Infants 
Yonsei Medical Journal  2015;56(4):998-1006.
Purpose
Extremely low birth weight infants (ELBWIs) have a high risk of acquiring cytomegalovirus (CMV) infection via breast milk and consequently developing serious symptoms. We evaluated whether freeze-thawing or pasteurization could prevent postnatal CMV infection transmitted through breast milk in ELBWIs.
Materials and Methods
Medical records of 385 ELBWIs with whole milk feeding, and freeze-thawed or pasteurized breast milk feeding were reviewed retrospectively. Postnatally acquired CMV infection was defined as an initial negative and a subsequent positive on follow-up urine CMV DNA polymerase chain reaction screening tests. The incidence, clinical characteristics, symptoms, sequelae, and long-term outcome at corrected age [(CA): 2 years of CMV infection] were analyzed.
Results
While no infant developed CMV infection with whole milk (0/22) or pasteurized breast milk (0/62) feeding, postnatal CMV infection was diagnosed in 8% (27/301) of ELBWIs who were fed freeze-thawed breast milk. Gestational age in the CMV group was significantly lower than the control group. In 82% (22/27) of cases, CMV infection was symptomatic and was associated with increased ventilator days and ≥moderate bronchopulmonary dysplasia (BPD). Neurodevelopmental outcome and growth status at CA 2 years were not different between the study groups. Lower gestational age and freeze-thawed breast milk feeding >60% of total oral intake during the first 8 postnatal weeks were independent risk factors for acquiring postnatal CMV infection. BPD (≥moderate) was the only significant adverse outcome associated with this CMV infection.
Conclusion
Pasteurization but not freeze-thawing of breast milk eradicated the postnatal acquisition of CMV infection through breast milk.
doi:10.3349/ymj.2015.56.4.998
PMCID: PMC4479869  PMID: 26069123
Cytomegalovirus; infant, extremely low birth weight; milk, human; pasteurization; freezing
3.  Effect of Prophylactic Palivizumab on Admission Due to Respiratory Syncytial Virus Infection in Former Very Low Birth Weight Infants with Bronchopulmonary Dysplasia 
Journal of Korean Medical Science  2015;30(7):924-931.
The aim of this study was to observe the effects of prophylactic palivizumab on hospitalization secondary to respiratory syncytial virus (RSV) infection (RSVhospitalization) in former very low birth weight infants (VLBWI) with bronchopulmonary dysplasia (BPD). This study also sought to identify the risk factors of RSVhospitalizationin this particular infant population. A prospective observational study was conducted between September 2007 and April 2008 in seven Korean hospitals. Children with a history of very low birth weight, a diagnosis of BPD and who were <2 yr old at the onset of the RSV season were included in this study. Palivizumab injections were administered monthly for a maximum of five months during the RSV season. RSVhospitalization rates were reviewed, and RSVhospitalization rates between subgroups were categorized by gestational age, birth weight, and duration of ventilator care. A total of 90 subjects completed the follow-up interviews. The mean gestational age at birth was 26.1±1.7 weeks, and the mean birth weight was 889.4±222.2 g. The incidence of RSVhospitalization in the study population was 8.9% (8/90), and the mean hospital stay was 11.0±5.5 days, including one death. There were no statistically significant differences in the patients' demographic characteristics or risk factors for RSV hospitalization. When subgroup analyses were conducted, there were still no statistically significant differences. The administration of palivizumab prophylaxis during the entire RSV season is important in VLBWI with BPD, regardless of their gestational age and birth weight, or previous ventilator dependency.
Graphical Abstract
doi:10.3346/jkms.2015.30.7.924
PMCID: PMC4479947  PMID: 26130956
Respiratory Syncytial Viruses; Palivizumab; Hospitalization; Bronchopulmonary Dysplasia; Preterm; Infant
4.  Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of AMPK-dependent autophagy 
British Journal of Pharmacology  2014;171(13):3146-3157.
BACKGROUND AND PURPOSE
Recent clinical trials report that metformin, an activator of AMP-activated protein kinase (AMPK) used to treat type 2 diabetes, significantly reduces the risk of stroke by actions that are independent of its glucose-lowering effects. However, the underlying molecular mechanisms are not known. Here, we tested the possibility that acute metformin preconditioning confers neuroprotection by pre-activation of AMPK-dependent autophagy in a rat model of permanent middle cerebral artery occlusion (pMCAO).
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were pretreated with either vehicle, an AMPK inhibitor, Compound C, or an autophagy inhibitor, 3-methyladenine, and were injected with a single dose of metformin (10 mg kg−1, i.p.). Then, AMPK activity and autophagy biomarkers in the brain were assessed. At 24 h after metformin treatment, rats were subjected to pMCAO; infarct volume, neurological deficits and cell apoptosis were evaluated 24 and 96 h later.
KEY RESULTS
A single dose of metformin significantly activated AMPK and induced autophagy in the brain. The enhanced autophagic activity was inhibited by Compound C pretreatment. Furthermore, acute metformin preconditioning significantly reduced infarct volume, neurological deficits and cell apoptosis during a subsequent focal cerebral ischaemia. The neuroprotection mediated by metformin preconditioning was fully abolished by Compound C and partially inhibited by 3-methyladenine.
CONCLUSIONS AND IMPLICATIONS
These results provide the first evidence that acute metformin preconditioning induces autophagy by activation of brain AMPK, which confers neuroprotection against subsequent cerebral ischaemia. This suggests that metformin, a well-known hypoglycaemic drug, may have a practical clinical use for stroke prevention.
doi:10.1111/bph.12655
PMCID: PMC4080970  PMID: 24611741
metformin; autophagy; stroke; preconditioning; AMPK; neuroprotection
5.  Simulation Analysis on Photoelectric Conversion Characteristics of Silicon Nanowire Array Photoelectrodes 
Semiconductor nanowire photoelectrochemical cells have attracted extensive attention in the light-conversion field owing to the low-cost preparation, excellent optical absorption, and short distance of carrier collection. Although there are numbers of experimental investigations to improve the device performance, the understanding of the detailed process of photoelectric conversion needs to be further improved. In this work, a thorough optoelectronic simulation is employed to figure out how the nanowire diameter, doping concentration, and illumination wavelength affect the photoelectric conversion characteristics of the silicon nanowire array photoelectrodes. We find that two balances should be carefully weighted between optical absorption and photogenerated-carrier collection, along with between short-circuit photocurrent density and open-circuit voltage. For the small-diameter nanowire array photoelectrodes, the overall absorption is higher than that of the larger-diameter ones with the most contribution from the nanowires. However, the substrate shows increasing absorption with increasing illumination wavelength. Higher doping density leads to a larger open-circuit voltage; while lower doping density can guarantee a relatively higher short-circuit photocurrent. To obtain high-light-conversion-efficiency photoelectrodes, the doping density should be carefully chosen with considerations of illumination wavelength and surface recombination. Suppressing the surface recombination velocity can effectively enhance the short-circuit photocurrent (open-circuit voltage) for the lightly (heavily) doped nanowire array photoelectrodes. Our systematical results provide a theoretical guidance for the photoelectrochemical devices based on semiconductor nanostructures.
doi:10.1186/s11671-015-0985-1
PMCID: PMC4485660  PMID: 26123274
Si nanowire; Photoelectrode; Simulation; Conversion efficiency
6.  Emergency Department Overcrowding and Ambulance Turnaround Time 
PLoS ONE  2015;10(6):e0130758.
Objective
The aims of this study were to describe overcrowding in regional emergency departments in Seoul, Korea and evaluate the effect of crowdedness on ambulance turnaround time.
Methods
This study was conducted between January 2010 and December 2010. Patients who were transported by 119-responding ambulances to 28 emergency centers within Seoul were eligible for enrollment. Overcrowding was defined as the average occupancy rate, which was equal to the average number of patients staying in an emergency department (ED) for 4 hours divided by the number of beds in the ED. After selecting groups for final analysis, multi-level regression modeling (MLM) was performed with random-effects for EDs, to evaluate associations between occupancy rate and turnaround time.
Results
Between January 2010 and December 2010, 163,659 patients transported to 28 EDs were enrolled. The median occupancy rate was 0.42 (range: 0.10-1.94; interquartile range (IQR): 0.20-0.76). Overcrowded EDs were more likely to have older patients, those with normal mentality, and non-trauma patients. Overcrowded EDs were more likely to have longer turnaround intervals and traveling distances. The MLM analysis showed that an increase of 1% in occupancy rate was associated with 0.02-minute decrease in turnaround interval (95% CI: 0.01 to 0.03). In subgroup analyses limited to EDs with occupancy rates over 100%, we also observed a 0.03 minute decrease in turnaround interval per 1% increase in occupancy rate (95% CI: 0.01 to 0.05).
Conclusions
In this study, we found wide variation in emergency department crowding in a metropolitan Korean city. Our data indicate that ED overcrowding is negatively associated with turnaround interval with very small practical significance.
doi:10.1371/journal.pone.0130758
PMCID: PMC4482653  PMID: 26115183
7.  Clinicians’ Tendencies to Under-Rate Parkinsonian Tremors in the Less Affected Hand 
PLoS ONE  2015;10(6):e0131703.
The standard assessment method for tremor severity in Parkinson’s disease is visual observation by neurologists using clinical rating scales. This is, therefore, a subjective rating that is dependent on clinical expertise. The objective of this study was to report clinicians’ tendencies to under-rate Parkinsonian tremors in the less affected hand. This was observed through objective tremor measurement with accelerometers. Tremor amplitudes were measured objectively using tri-axis-accelerometers for both hands simultaneously in 53 patients with Parkinson’s disease during resting and postural tremors. The videotaped tremor was rated by neurologists using clinical rating scales. The tremor measured by accelerometer was compared with clinical ratings. Neurologists tended to under-rate the less affected hand in resting tremor when the contralateral hand had severe tremor in Session I. The participating neurologists corrected this tendency in Session II after being informed of it. The under-rating tendency was then repeated by other uninformed neurologists in Session III. Kappa statistics showed high inter-rater agreements and high agreements between estimated scores derived from the accelerometer signals and the mean Clinical Tremor Rating Scale evaluated in every session. Therefore, clinicians need to be aware of this under-rating tendency in visual inspection of the less affected hand in order to make accurate tremor severity assessments.
doi:10.1371/journal.pone.0131703
PMCID: PMC4482425  PMID: 26110768
8.  Ligand-Enabled Triple C–H Activation Reactions: One-Pot Synthesis of Diverse 4-Aryl-2-quinolinones from Propionamides** 
Diverse 4-aryl-2-quinolinones are prepared from propionamides in one pot via ligand-promoted triple sequential C–H activation reactions and a stereospecific Heck reaction. In these cascade reactions, three new C–C bonds and one C–N bond are formed to rapidly build molecular complexity from propionic acid
doi:10.1002/anie.201403878
PMCID: PMC4114037  PMID: 24828691
C–H activation; arylation; dehydrogenation; amidation; quinolinone
9.  Enhanced Healing of Rat Calvarial Bone Defects with Hypoxic Conditioned Medium from Mesenchymal Stem Cells through Increased Endogenous Stem Cell Migration via Regulation of ICAM-1 Targeted-microRNA-221 
Molecules and Cells  2015;38(7):643-650.
The use of conditioned medium from mesenchymal stem cells may be a feasible approach for regeneration of bone defects through secretion of various components of mesenchymal stem cells such as cytokines, chemokines, and growth factors. Mesenchymal stem cells secrete and accumulate multiple factors in conditioned medium under specific physiological conditions. In this study, we investigated whether the conditioned medium collected under hypoxic condition could effectively influence bone regeneration through enhanced migration and adhesion of endogenous mesenchymal stem cells. Cell migration and adhesion abilities were increased through overexpression of intercellular adhesion molecule-1 in hypoxic conditioned medium treated group. Intercellular adhesion molecule-1 was upregulated by microRNA-221 in mesenchymal stem cells because microRNAs are key regulators of various biological functions via gene expression. To investigate the effects in vivo, evaluation of bone regeneration by computed tomography and histological assays revealed that osteogenesis was enhanced in the hypoxic conditioned medium group relative to the other groups. These results suggest that behavioral changes of endogenous mesenchymal stem cells through microRNA-221 targeted-intercellular adhesion molecule-1 expression under hypoxic conditions may be a potential treatment for patients with bone defects.
doi:10.14348/molcells.2015.0050
PMCID: PMC4507031  PMID: 26062554
bone regeneration; calvarial defect model; hypoxic conditioned medium; intercellular adhesion molecule-1; mesenchymal stem cells; microRNA-221
10.  Draft Genome Sequence of the Bacterium Lysobacter capsici X2-3, with a Broad Spectrum of Antimicrobial Activity against Multiple Plant-Pathogenic Microbes 
Genome Announcements  2015;3(3):e00589-15.
Lysobacter capsici strain X2-3 was isolated from the wheat rhizosphere in China and exhibits a remarkable capacity to inhibit the growth of multiple pathogens. Here, we report the draft genome sequence of L. capsici strain X2-3 in China.
doi:10.1128/genomeA.00589-15
PMCID: PMC4457069  PMID: 26044432
11.  A Smartphone Application Significantly Improved Diabetes Self-Care Activities with High User Satisfaction 
Diabetes & Metabolism Journal  2015;39(3):207-217.
Background
We developed for the first time a smartphone application designed for diabetes self-management in Korea and registered a patent for the relevant algorithm. We also investigated the user satisfaction with the application and the change in diabetes related self-care activities after using the application.
Methods
We conducted a questionnaire survey on volunteers with diabetes who were using the application. Ninety subjects responded to the questionnaire between June 2012 and March 2013. A modified version of the Summary of Diabetes Self-Care Activities (SDSCA) was used in this study.
Results
The survey results exhibited a mean subject age of 44.0 years old, and males accounted for 78.9% of the subjects. Fifty percent of the subjects had diabetes for less than 3 years. The majority of respondents experienced positive changes in their clinical course after using the application (83.1%) and were satisfied with the structure and completeness of the application (86.7%). Additionally, the respondents' answers indicated that the application was easy to use (96.7%) and recommendable to others (97.7%) and that they would continue using the application to manage their diabetes (96.7%). After using the Diabetes Notepad application, diabetes related self-care activities assessed by SDSCA displayed statistically significant improvements (P<0.05), except for the number of days of drinking.
Conclusion
This smartphone-based application can be a useful tool leading to positive changes in diabetes related self-care activities and increase user satisfaction.
doi:10.4093/dmj.2015.39.3.207
PMCID: PMC4483606  PMID: 26124991
Cell phones; Diabetes mellitus; Mobile applications; Self care
12.  Circulating Long Noncoding RNA as a Potential Target for Prostate Cancer 
Prostate cancer is considered the second most common visceral malignancy in men in Western countries. Its emergence is largely due to the coordination of a malignant network, and long noncoding RNA has been recently demonstrated to play a critical role in prostate carcinogenesis. The aberrant expression of long noncoding RNA in prostate cancer patients is strongly associated with diagnosis, risk stratification and carcinogenesis, information that provides new insight into the complicated intracellular milieu of prostate cancer. This review focuses mainly on literature evidence for the role of long noncoding RNA in prostate cancer, which may suggest novel strategies for its prognosis, diagnosis and clinical treatment.
doi:10.3390/ijms160613322
PMCID: PMC4490497  PMID: 26110379
long noncoding RNA; prostate cancer; biomarker; therapeutic target
13.  Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis 
Cancer Biology & Medicine  2015;12(2):126-139.
Objective
A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients.
Methods
Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated.
Results
Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.
Conclusion
K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.
doi:10.7497/j.issn.2095-3941.2015.0021
PMCID: PMC4493374  PMID: 26175928
Non-small cell lung cancer (NSCLC); tyrosine kinase inhibitor (TKI); targeted therapy; K-ras; PIK3CA; meta-analysis
14.  Anti-Amnesic Effect of Fermented Ganoderma lucidum Water Extracts by Lactic Acid Bacteria on Scopolamine-Induced Memory Impairment in Rats 
This study investigated the anti-amnesic effect of fermented Ganoderma lucidum water extracts (GW) on scopolamine-induced memory impairment in rats. GW were fermented by the lactic acid bacterium Bifidobacterium bifidum (FGWB), followed by Lactobacillus sakei LI033 (FGWBL). To induce amnesia, scopolamine (1 mg/kg) was intraperitoneally injected into rats 30 min before the behavioral tests. Step-through latencies of rats treated with primary fermented extracts (300 mg/kg, FGWB) and secondary fermented extracts (300 mg/kg, FGWBL) were significantly longer than those of rats treated with GW (300 mg/kg) in the retention trial of the multiple trial passive avoidance test. In the Morris water maze task, FGWBL significantly shortened escape latencies in training trials. Furthermore, swimming times within the target zone during the probe trial with FGWBL were significantly higher than the GW and FGWB treatments. In addition, acetylcholinesterase activities were lower in the brains of scopolamine-treated rats treated with FGWBL. These results suggest that FGWBL could be useful to enhance learning memory and cognitive function via cholinergic dysfunction.
doi:10.3746/pnf.2015.20.2.126
PMCID: PMC4500515  PMID: 26176000
Ganoderma lucidum; fermentation; scopolamine; passive avoidance test; Morris water maze test
15.  Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease 
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles. However, increasing evidences demonstrated that neuroinflammatory changes, including chronic microgliosis are key pathological components of AD. Microglia, the resident immune cells of the brain, is constantly survey the microenvironment under physiological conditions. In AD, deposition of β-amyliod (Aβ) peptide initiates a spectrum of cerebral neuroinflammation mediated by activating microglia. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Emerging studies have demonstrated that up-regulation of pro-inflammatory cytokines play multiple roles in both neurodegeneration and neuroprotection. Understanding the pro-inflammatory cytokines signaling pathways involved in the regulation of AD is crucial to the development of strategies for therapy. This review will discuss the mechanisms and important role of pro-inflammatory cytokines in the pathogenesis of AD, and the ongoing drug targeting pro-inflammatory cytokine for therapeutic modulation.
doi:10.3978/j.issn.2305-5839.2015.03.49
PMCID: PMC4486922  PMID: 26207229
Alzheimer’s disease (AD); microglia; pro-inflammatory cytokines; neurodegeneration; amyloid-β; therapy
16.  Inhibition of janus kinase 2 by compound AG490 suppresses the proliferation of MDA-MB-231 cells via up-regulating SARI (suppressor of AP-1, regulated by IFN) 
Objective(s):
The Janus kinase-signal transducers and activators of transcription signaling pathway (JAK/STAT pathway) play an important role in proliferation of breast cancer cells. Previous data showed that inhibition of STAT3 suppresses the growth of breast cancer cells, but the associated mechanisms are not well understood. This study aims to investigate the effect and associated mechanisms of JAK/STAT pathway inhibitor AG490 on proliferation and suppression of breast cancer cells.
Materials and Methods:
CCK-8 assay and trypan blue exclusion assay were used to investigate the cytotoxicity of AG490 to MDA-MB-231 cells. Real-time PCR was used to detect the mRNA level of SARI (suppressor of AP-1, regulated by IFN). Western blot was used to analyze the protein levels of SARI, phospho-STAT3 and total STAT3. Luciferase reporter assay was adopted to explore the mechanism of SARI mRNA upregulation.
Results:
AG490 suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner. AG490 significantly up-regulated the mRNA and protein levels of SARI in MDA-MB-231 cells. Knockdown of SARI obviously attenuated AG490-induced growth suppression effect in MDA-MB-231 cells. Furthermore, AG490 dramatically enhanced the transcription activity of SARI promoter. But the transcription activity of truncated SARI promoter, which does not contain STAT3 binding site, cannot be activated by AG490 treatment.
Conclusion:
We demonstrate in this study that AG490 suppresses the proliferation of MDA-MB-231 cells through transcriptional activation of SARI.
PMCID: PMC4509956  PMID: 26221484
AG490; MDA-MB-231; Proliferation; SARI; STAT3
17.  Nucleolar Dysfunction in Huntington’s Disease 
Biochimica et biophysica acta  2013;1842(6):785-790.
Huntington’s disease (HD) is a fatal genetic disorder characterized by triad clinical symptoms of chorea, emotional distress, and cognitive decline. Genetic mutation in HD is identified by an expansion of CAG repeats coding for glutamine (Q) in exon 1 of the huntingtin (htt) gene. The exact mechanism on how mutant htt leads to the selective loss of medium spiny neurons (MSNs) in the striatum is still unknown. Recent studies suggest that nucleolar stress and dysfunction is linked to the pathogenesis of HD. Alterations of the nucleolar activity and integrity contributes to deregulation of ribosomal DNA (rDNA) transcription in HD pathogenesis. Furthermore, epigenetic modifications in the nucleolus are associated with neuronal damage in HD. In this review, we discuss about how post-translational modifications of upstream binding factor (UBF) are affected by histone acetyltransferase and histone methyltransferase and involved in the transcriptional regulation of rDNA in HD. The understanding of epigenetic modulation of UBF-dependent rDNA transcription in the nucleolus may lead to the identification of novel pathological markers and new therapeutic targets to treat HD.
doi:10.1016/j.bbadis.2013.09.017
PMCID: PMC3972370  PMID: 24184605
Huntington’s disease; nucleolus; upstream binding factor (UBF); rDNA transcription; acetylation and methylation; epigenetics
18.  Bypassing the Limitations of Directed C–H Functionalizations of Heterocycles 
Nature  2014;515(7527):389-393.
In directed C–H activation reactions, nitrogen and sulfur atoms present in heterocyclic substrates coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery.1–5 Herein, we report a robust and synthetically useful reaction that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand to promote the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is inherently anchored in close proximity with the target C–H bond adjacent to CONHOMe group, thus avoiding the interference from various heterocycles. Remarkably, this reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulfur, and phosphorus. Thus, this operationally simple aerobic reaction demonstrates the feasibility of bypassing a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.
doi:10.1038/nature13885
PMCID: PMC4248606  PMID: 25383516
19.  Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy 
Scientific Reports  2015;5:10201.
MicroRNAs (miRNAs) open up a new field for molecular diagnosis for cancer and other diseases based on their stability in serum. However, the role of circulating miRNAs in plasma/serum in epilepsy diagnosis is still unclear. The aim of this study was to evaluate whether miRNAs can be used as biomarkers for drug-resistant epilepsy. We measured the differences in serum miRNA levels between 30 drug-resistant patients and 30 drug-responsive epilepsy patients in discovery and training phases using Illumina HiSeq2000 sequencing followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays. The selected miRNAs were then validated in 77 drug-resistant epilepsy patients, 81 drug-responsive epilepsy patients and 85 healthy controls by qRT-PCR. We found that circulating miRNAs are differentially expressed between drug-resistant group and drug-responsive group. MiR-194-5p, -301a-3p, -30b-5p, -342-5p and -4446-3p were significantly deregulated in drug-resistant group compared to drug-responsive group and control group. Among these 5 miRNAs, miR-301a-3p had the best diagnostic value for drug-resistant epilepsy with 80.5% sensitivity and 81.2% specificity, and was negatively associated with seizure severity. These provide the rationale for further confirmation studies in larger prospective cohorts and in other ethnics.
doi:10.1038/srep10201
PMCID: PMC4435024  PMID: 25984652
20.  Palladium(II)-Catalyzed Enantioselective C(sp3)–H Activation Using a Chiral Hydroxamic Acid Ligand 
An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene β-C(sp3)–H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C(sp3)–H activation of acyclic amides.
doi:10.1021/ja504196j
PMCID: PMC4063184  PMID: 24815880
21.  Benefit of initial dual-therapy on stroke prevention in Chinese hypertensive patients: a real world cohort study 
Journal of Thoracic Disease  2015;7(5):881-889.
Aims
Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients.
Methods and Results
Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person-year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30-0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months.
Conclusions
Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention.
doi:10.3978/j.issn.2072-1439.2015.04.41
PMCID: PMC4454863  PMID: 26101644
Hypertension; stroke; mono-therapy; dual-therapy; combination-therapy
22.  Accuracy and precision of integumental linear dimensions in a three-dimensional facial imaging system 
Korean Journal of Orthodontics  2015;45(3):105-112.
Objective
A recently developed facial scanning method uses three-dimensional (3D) surface imaging with a light-emitting diode. Such scanning enables surface data to be captured in high-resolution color and at relatively fast speeds. The purpose of this study was to evaluate the accuracy and precision of 3D images obtained using the Morpheus 3D® scanner (Morpheus Co., Seoul, Korea).
Methods
The sample comprised 30 subjects aged 24-34 years (mean 29.0 ± 2.5 years). To test the correlation between direct and 3D image measurements, 21 landmarks were labeled on the face of each subject. Sixteen direct measurements were obtained twice using digital calipers; the same measurements were then made on two sets of 3D facial images. The mean values of measurements obtained from both methods were compared. To investigate the precision, a comparison was made between two sets of measurements taken with each method.
Results
When comparing the variables from both methods, five of the 16 possible anthropometric variables were found to be significantly different. However, in 12 of the 16 cases, the mean difference was under 1 mm. The average value of the differences for all variables was 0.75 mm. Precision was high in both methods, with error magnitudes under 0.5 mm.
Conclusions
3D scanning images have high levels of precision and fairly good congruence with traditional anthropometry methods, with mean differences of less than 1 mm. 3D surface imaging using the Morpheus 3D® scanner is therefore a clinically acceptable method of recording facial integumental data.
doi:10.4041/kjod.2015.45.3.105
PMCID: PMC4446371  PMID: 26023538
Three-dimensional scanner; Three-dimensional diagnosis and treatment planning; Structured light-based scanners
23.  Oxidative stress by layered double hydroxide nanoparticles via an SFK-JNK and p38-NF-κB signaling pathway mediates induction of interleukin-6 and interleukin-8 in human lung epithelial cells 
Anionic nanoclays are layered double hydroxide nanoparticles (LDH-NPs) that have been shown to exhibit toxicity by inducing reactive oxidative species and a proinflammatory mediator in human lung epithelial A549 cells. However, the molecular mechanism responsible for this LDH-NP-induced toxicity and the relationship between oxidative stress and inflammatory events remains unclear. In this study, we focused on intracellular signaling pathways and transcription factors induced in response to oxidative stress caused by exposure to LDH-NPs in A549 cells. Mitogen-activated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase, c-Jun-N-terminal kinase (JNK), and p38, were investigated as potential signaling mechanisms responsible for regulation of oxidative stress and cytokine release. Src family kinases (SFKs), which are known to mediate activation of MAPK, together with redox-sensitive transcription factors, including nuclear factor kappa B and nuclear factor-erythroid 2-related factor-2, were also investigated as downstream events of MAPK signaling. The results obtained suggest that LDH-NP exposure causes oxidative stress, leading to expression of antioxidant enzymes, such as catalase, glucose reductase, superoxide dismutase, and heme oxygenase-1, via a SFK-JNK and p38-nuclear factor kappa B signaling pathway. Further, activation of this signaling was also found to regulate release of inflammatory cytokines, including interleukin-6 and interleukin-8, demonstrating the inflammatory potential of LDH-NP.
doi:10.2147/IJN.S82061
PMCID: PMC4425322  PMID: 25995631
layered double hydroxide; mitogen-activated protein kinases; Src family kinases; nuclear factor kappa B; oxidative stress; inflammatory cytokine
24.  Localization of Rod Bipolar Cells in the Mammalian Retina Using an Antibody Against the α1c L-type Ca2+ Channel 
Bipolar cells transmit stimuli via graded changes in membrane potential and neurotransmitter release is modulated by Ca2+ influx through L-type Ca2+ channels. The purpose of this study was to determine whether the α1c subunit of L-type voltage-gated Ca2+ channel (α1c L-type Ca2+ channel) colocalizes with protein kinase C alpha (PKC-α), which labels rod bipolar cells. Retinal whole mounts and vertical sections from mouse, hamster, rabbit, and dog were immunolabeled with antibodies against PKC-α and α1c L-type Ca2+ channel, using fluorescein isothiocyanate (FITC) and Cy5 as visualizing agents. PKC-α-immunoreactive cells were morphologically identical to rod bipolar cells as previously reported. Their cell bodies were located within the inner nuclear layer, dendritic processes branched into the outer plexiform layer, and axons extended into the inner plexiform layer. Immunostaining showed that α1c L-type Ca2+ channel colocalized with PKC-α in rod bipolar cells. The identical expression of PKC-α and α1c L-type Ca2+ channel indicates that the α1c L-type Ca2+ channel has a specific role in rod bipolar cells, and the antibody against the α1c L-type Ca2+ channel may be a useful marker for studying the distribution of rod bipolar cells in mouse, hamster, rabbit, and dog retinas.
doi:10.1267/ahc.14049
PMCID: PMC4427564  PMID: 26019373
immunocytochemistry; rod bipolar cell; L-type Ca2+ channel; protein kinase C; mammalian retina
25.  Room-Temperature Enantioselective C–H Iodination via Kinetic Resolution 
Science (New York, N.Y.)  2014;346(6208):451-455.
The development of asymmetric C–H activation reactions through metal insertions remains in its infancy. The commonly used approach is the desymmetrization of prochiral C–H bonds on the same or different carbons of one achiral molecule using a chiral catalyst. Herein, we report a Pd-catalyzed enantioselective C–H activation reaction via kinetic resolution in which one of the enantiomers of the racemic substrates undergoes faster C–H insertion with the chiral catalysts thereby producing enantioenriched C–H functionalization products that are not accessible via desymmtrization of prochiral C–H bonds. The exceedingly high relative rate (kfast/kslow up to 244) and the subsequent iodination of the remaining enantiomerically enriched starting material using a chiral ligand with the opposite configuration allows for the conversion of both enantiomers of amines into enantiomerically pure iodinated amines.
doi:10.1126/science.1258538
PMCID: PMC4382011  PMID: 25342799

Results 1-25 (372)