Publications by authors named "Minsuk Kim"

48 Publications

Majority-vote model with degree-weighted influence on complex networks.

Phys Rev E 2021 Feb;103(2-1):022302

Department of Physics and Research Institute for Basic Sciences, Kyung Hee University, Seoul 130-701, Korea.

We study the phase transition of the degree-weighted majority vote (DWMV) model on Erdős-Rényi networks (ERNs) and scale-free networks (SFNs). In this model, a weight parameter α adjusts the level of influence of each node on its connected neighbors. Through the Monte Carlo simulations and the finite-size scaling analysis, we find that the DWMV model on ERNs and SFNs with degree exponents λ>5 belongs to the mean-field Ising universality class, regardless of α. On SFNs with 3<λ<5 the model belongs to the Ising universality class only when α=0. For α>0 we find that the critical exponents continuously change as α increases from α=0. However, on SFNs with λ<3 we find that the model undergoes a continuous transition only for α=0, but the critical exponents significantly deviate from those for the mean-field Ising model. For α>0 on SFNs with λ<3 the model is always in the disordered phase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1103/PhysRevE.103.022302DOI Listing
February 2021

Irregular Work Hours and the Risk of Sleep Disturbance Among Korean Service Workers Required to Suppress Emotion.

Int J Environ Res Public Health 2021 Feb 5;18(4). Epub 2021 Feb 5.

Department of Occupational and Environmental Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.

Although a necessity in a modern society, irregular work schedule can lead to sleep problems. We investigated the effect of work schedule irregularity on sleep disturbance of 17,846 Korean service workers using the fifth Korean Working Conditions Survey. The odds ratio (OR) and 95% confidence interval (CI) for sleep disturbance occurrence were calculated through a multiple logistic regression model. The adjusted ORs for moderate and severe sleep disturbances for those with irregular work hours were 2.11 (95% CI 1.90-2.33) and 3.10 (95% CI 2.62-3.66), respectively. Work schedule irregularity and emotion suppression at work showed synergistic effect on both moderate and severe sleep disturbances. Sleep disturbances can lead to brain function deterioration and work-related injuries; therefore, appropriate measures should be addressed for the vulnerable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18041517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915650PMC
February 2021

Apoptosis inhibitor of macrophage (AIM) contributes to IL-10-induced anti-inflammatory response through inhibition of inflammasome activation.

Cell Death Dis 2021 Jan 4;12(1):19. Epub 2021 Jan 4.

Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.

Apoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM mice. Treatment of BMDM from both wild type (WT) and IL-10 mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-03332-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791024PMC
January 2021

A predictive index for health status using species-level gut microbiome profiling.

Nat Commun 2020 09 15;11(1):4635. Epub 2020 Sep 15.

Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.

Providing insight into one's health status from a gut microbiome sample is an important clinical goal in current human microbiome research. Herein, we introduce the Gut Microbiome Health Index (GMHI), a biologically-interpretable mathematical formula for predicting the likelihood of disease independent of the clinical diagnosis. GMHI is formulated upon 50 microbial species associated with healthy gut ecosystems. These species are identified through a multi-study, integrative analysis on 4347 human stool metagenomes from 34 published studies across healthy and 12 different nonhealthy conditions, i.e., disease or abnormal bodyweight. When demonstrated on our population-scale meta-dataset, GMHI is the most robust and consistent predictor of disease presence (or absence) compared to α-diversity indices. Validation on 679 samples from 9 additional studies results in a balanced accuracy of 73.7% in distinguishing healthy from non-healthy groups. Our findings suggest that gut taxonomic signatures can predict health status, and highlight how data sharing efforts can provide broadly applicable discoveries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18476-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492273PMC
September 2020

Motion microscopy for label-free detection of circulating breast tumor cells.

Biosens Bioelectron 2020 Jun 1;158:112131. Epub 2020 Apr 1.

Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea. Electronic address:

Circulating tumor cells (CTCs) are cancer cells that have been shed from a primary tumor and circulate in the bloodstream during progression of cancer. They may thus serve as circulating biomarkers that can predict, diagnose and guide therapy. Moreover, phenotypic and genotypic analysis of CTCs can facilitate prospective assessment of mutations and enable personalized treatment. A number of methodologies based on biological and physical differences between circulating tumor and non-tumor cells have been developed over the past few years. However, these methods did not have sufficient sensitivity or specificity. In this work, a remote analysis protocol was designed using motion microscopy that amplifies cellular micro motions in a captured video by re-rendering small motions to generate extreme magnified visuals to detect dynamic motions that are not otherwise visible by naked eye. Intriguingly, motion microscopy demonstrated fluctuations around breast tumor cells, which we referred to herein as cellular trail. Phenomena of cellular trail mostly emerged between 0.5 and 1.5 Hz on amplified video images. Interestingly, cellular trails were associated with cell surface proteins and flow rates rather than mitochondrial activity. Moreover, cellular trails were present only around circulating tumor cells from individuals with breast cancer under conditions of 20-30 μm/s and 0.5-1.5 Hz. Thus, motion microscopy based CTC detection method can offer a valuable supplementary diagnostic tool for assessment of drug efficacy and identifying physical characteristics of tumor cells for further research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bios.2020.112131DOI Listing
June 2020

Comparison of Shear Stress-Induced Thrombotic and Thrombolytic Effects Among 3 Different Antithrombotic Regimens in Patients With Acute Coronary Syndrome.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620912814

Cardiovascular Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

Shear stress (SS)-induced platelet activation is suggested as an essential mechanism of the acute coronary syndrome (ACS). We aimed to compare SS-induced thrombotic and thrombolytic activities among 3 treatment regimens in patients with ACS who underwent percutaneous coronary intervention (PCI). Patients were nonrandomly enrolled and treated with one of 3 regimens (TICA: ticagrelor 180 mg/d; RIVA: clopidogrel 75 mg/d and rivaroxaban 5 mg/d; CLP: clopidogrel 75 mg/d), administered in addition to aspirin (100 mg/d) for 30 days. The global thrombosis test was applied to measure SS-induced thrombotic (occlusion time [OT]) and thrombolytic activity (lysis time [LT]) at day 2 and 30. Aspirin reaction unit (ARU) and P2Y12 reaction unit (PRU) were simultaneously measured using VerifyNow. Group differences in the OT, LT, ARU, and PRU were evaluated. Seventy-five patients (25 patients in each group) finished 30 days of follow-up. Clinical and angiographic characteristics did not differ among the 3 groups, except ACS subtype and pre-PCI coronary flow. No major adverse cardiovascular events occurred in any group during follow-up. The OT and LT did not differ among the 3 groups at day 30 (OT: TICA, 447.2 ± 87.1 vs RIVA, 458.5 ± 70.3, vs CLP, 471.9 ± 90.7, LT: 1522.3 ± 426.5 vs 1734.6 ± 454.3 vs 1510.2 ± 593.9) despite significant differences in the PRU among the 3 groups. Shear stress-induced thrombotic and thrombolytic activities did not differ among the 3 investigated antithrombotic treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1076029620912814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289065PMC
April 2020

Fecal Metabolomic Signatures in Colorectal Adenoma Patients Are Associated with Gut Microbiota and Early Events of Colorectal Cancer Pathogenesis.

mBio 2020 02 18;11(1). Epub 2020 Feb 18.

Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Colorectal adenomas are precancerous lesions of colorectal cancer (CRC) that offer a means of viewing the events key to early CRC development. A number of studies have investigated the changes and roles of gut microbiota in adenoma and carcinoma development, highlighting its impact on carcinogenesis. However, there has been less of a focus on the gut metabolome, which mediates interactions between the host and gut microbes. Here, we investigated metabolomic profiles of stool samples from patients with advanced adenoma (= 102), matched controls (= 102), and patients with CRC (= 36). We found that several classes of bioactive lipids, including polyunsaturated fatty acids, secondary bile acids, and sphingolipids, were elevated in the adenoma patients compared to the controls. Most such metabolites showed directionally consistent changes in the CRC patients, suggesting that those changes may represent early events of carcinogenesis. We also examined gut microbiome-metabolome associations using gut microbiota profiles in these patients. We found remarkably strong overall associations between the microbiome and metabolome data and catalogued a list of robustly correlated pairs of bacterial taxa and metabolomic features which included signatures of adenoma. Our findings highlight the importance of gut metabolites, and potentially their interplay with gut microbes, in the early events of CRC pathogenesis. Colorectal adenomas are precursors of CRC. Recently, the gut microbiota, i.e., the collection of microbes residing in our gut, has been recognized as a key player in CRC development. There have been a number of gut microbiota profiling studies for colorectal adenoma and CRC; however, fewer studies have considered the gut metabolome, which serves as the chemical interface between the host and gut microbiota. Here, we conducted a gut metabolome profiling study of colorectal adenoma and CRC and analyzed the metabolomic profiles together with paired microbiota composition profiles. We found several chemical signatures of colorectal adenoma that were associated with some gut microbes and potentially indicative of future CRC. This study highlights potential early-driver metabolites in CRC pathogenesis and guides further targeted experiments and thus provides an important stepping stone toward developing better CRC prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.03186-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029137PMC
February 2020

RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial-Mesenchymal Transition, Migration, and Invasion of Lung Alveolar Epithelial Cells.

Biomolecules 2019 10 4;9(10). Epub 2019 Oct 4.

Department of Physiology, College of Medicine, Ewha Womans University, Seoul 07804, Korea.

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a -targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom9100565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843420PMC
October 2019

Comparison of bleeding risks among non-vitamin K antagonist oral anticoagulants using the Korea adverse event reporting system database.

Ther Adv Drug Saf 2019 24;10:2042098619876737. Epub 2019 Sep 24.

Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.

Background: In order to ensure safer use of non-vitamin K antagonist oral anticoagulants (NOACs), continuously detecting unexpected adverse drug reactions (ADRs) after market approval is necessary.

Methods: We performed disproportionality analysis to evaluate association between ADRs and NOACs including apixaban, dabigatran, and rivaroxaban using data from the Korea Institute of Drug Safety and Risk Management-Korea Adverse Event Reporting System database (KIDS-KD) between 2012 and 2016. There was no significant signal other than bleeding when considering quantity, signal strength, seriousness, and causality. In order to evaluate the NOAC reports about bleeding, we selected 62 WHO-ART diagnostic codes associated with bleeding. Among the 26 codes that referred to major bleeding, 18 codes referred to gastrointestinal bleeding and 8 were referred to intracranial bleeding. We evaluated the significance of the signals using reporting odds ratios (RORs) adjusted for age and sex.

Results: Treatments with apixaban, dabigatran, and rivaroxaban were associated with 1989, 1668, and 2960 adverse events, respectively. Any type of bleeding with apixaban, dabigatran, rivaroxaban, and warfarin was reported in 174 (8.8%), 209 (12.5%), 523 (17.8%), and 620 (9.5%) events, respectively. For any bleeding, adjusted RORs of apixaban, dabigatran, and rivaroxaban were 0.99 [95% confidence interval (CI): 0.83-1.17], 1.47 (95% CI: 1.25-1.75), and 2.48 (95% CI: 2.16-2.84), respectively. With respect to major bleeding, the adjusted RORs of apixaban, dabigatran, and rivaroxaban were 1.08 (95% CI: 0.82-1.41), 1.46 (95% CI: 1.10-1.90), and 1.82 (95% CI: 1.43-2.32), respectively.

Conclusion: Rivaroxaban might have stronger association with bleeding than apixaban and dabigatran.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2042098619876737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759695PMC
September 2019

In silico identification of metabolic engineering strategies for improved lipid production in by genome-scale metabolic modeling.

Biotechnol Biofuels 2019 24;12:187. Epub 2019 Jul 24.

2School of Chemical and Biological Engineering, Seoul National University, Seoul, 08826 Republic of Korea.

Background: , an oleaginous yeast, is a promising platform strain for production of biofuels and oleochemicals as it can accumulate a high level of lipids in response to nitrogen limitation. Accordingly, many metabolic engineering efforts have been made to develop engineered strains of with higher lipid yields. Genome-scale model of metabolism (GEM) is a powerful tool for identifying novel genetic designs for metabolic engineering. Several GEMs for have recently been developed; however, not many applications of the GEMs have been reported for actual metabolic engineering of . The major obstacle impeding the application of GEMs is the lack of proper methods for predicting phenotypes of the cells in the nitrogen-limited condition, or more specifically in the stationary phase of a batch culture.

Results: In this study, we showed that environmental version of minimization of metabolic adjustment (eMOMA) can be used for predicting metabolic flux distribution of under the nitrogen-limited condition and identifying metabolic engineering strategies to improve lipid production in . Several well-characterized overexpression targets, such as diglyceride acyltransferase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase, were successfully rediscovered by our eMOMA-based design method, showing the relevance of prediction results. Interestingly, the eMOMA-based design method also suggested non-intuitive knockout targets, and we experimentally validated the prediction with a mutant lacking YALI0F30745g, one of the predicted targets involved in one-carbon/methionine metabolism. The mutant accumulated 45% more lipids compared to the wild-type.

Conclusion: This study demonstrated that eMOMA is a powerful computational method for understanding and engineering the metabolism of and potentially other oleaginous microorganisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13068-019-1518-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657051PMC
July 2019

Nanogap Engineering for Enhanced Transmission of Wire Grid Polarizers in Mid-Wavelength Infrared Region.

Sci Rep 2019 Mar 12;9(1):4201. Epub 2019 Mar 12.

Department of Physics, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Republic of Korea.

Wire-grid polarizers (WGPs) have been widely used in various fields, such as polarimetry, imaging, display, spectroscopy, and optical isolation. However, conventional WGPs used in diverse mid-wavelength infrared (MWIR) applications show high reflection losses, which intrinsically arise from high refractive indices of their IR-transmitting substrates, such as silicon (Si) and germanium (Ge). This study demonstrated the enhanced transmittance of a transverse magnetic (TM) wave that surpassed ~80% over the entire MWIR range from 3000 to 5000 nm in a narrow air gap of a WGP, where aluminum (Al) was selectively deposited on a nanopatterned Si substrate using an oblique angle deposition method. Moreover, a higher TM wave transmittance was achieved by reducing the air gaps of the WGPs in the nanopatterns, which were distinctly different from the traditional WGPs comprising metal wires patterned directly on a flat substrate. A finite-difference time-domain simulation was performed to investigate optical properties of the proposed WGPs, which showed that the electric field in the air nanogap was remarkably enhanced. The characteristic performances were further investigated using a combination of an effective medium approximation and an admittance diagram, revealing that the broadband transmission enhancement could be attributed to a combined effect of a strong electric field and a better admittance matching. The approach and results described in this paper hold promise for the design and the fabrication of high-quality WGPs, as well as their numerous applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-40614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414691PMC
March 2019

Prognostic implications of late gadolinium enhancement at the right ventricular insertion point in patients with non-ischemic dilated cardiomyopathy: A multicenter retrospective cohort study.

PLoS One 2018 28;13(11):e0208100. Epub 2018 Nov 28.

Yonsei University Health System, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Introduction: The presence of late gadolinium enhancement (LGE) at the right ventricular insertion point (RVIP) on cardiac magnetic resonance (CMR) is generally believed to be nonspecific, but the clinical implication of this unique LGE pattern in patients with non-ischemic dilated cardiomyopathy (NICM) has not been elucidated.

Objectives: We investigated the prognostic significance of RVIP-LGE in NICM patients.

Methods: A total of 360 consecutive NICM patients referred for CMR (102 with no LGE, 50 with RVIP-LGE, 121 with left ventricular [LV]-LGE, and 87 with both an LV and RVIP-LGE) were studied. The primary endpoint was a composite of the all-cause death, hospitalization due to worsening of heart failure, and major arrhythmic events.

Results: During a mean follow-up of 45.2 ± 36.5 months, 149 (41.4%) patients (22 [21.6%] no LGE vs. 16 [32.0%] RVIP-LGE vs. 62 [51.2%] LV-LGE vs. 49 [56.3%] both LV and RVIP-LGE, P < 0.0001) reached the primary endpoint. A Kaplan Meier curve demonstrated that RVIP-LGE patients had an intermediate trend of an event free survival rate for the composite endpoint (log-rank P < 0.0001). In a multivariable Cox regression model, LV-LGE (P = 0.008) and both LV and RVIP-LGE (P = 0.003) were significantly associated with a worse outcome, whereas RVIP-LGE was not (P = 0.101). In addition, RVIP-LGE patients (n = 32) had a more favorable outcome compared to LV-LGE patients (n = 32) even after matching the extent of the LGE (median 3.4% [interquartile range, 3.1-3.8], 8 [25.0%] RVIP-LGE vs. 20 [62.5%] LV-LGE, P = 0.002).

Conclusions: LGE confined to the RVIP among NICM patients did not significantly increase the risk of adverse cardiac events, and also showed a better outcome than the same extent of LGE located in the LV. Identification of this unique LGE distribution may help refine the current risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208100PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261623PMC
May 2019

OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans.

Sci Rep 2018 11 16;8(1):16965. Epub 2018 Nov 16.

Department of Pharmacology, Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, Korea.

Organic cation transporter 3 (OCT3) is expressed in various organs in humans and plays an important role in the transport of organic cations and drugs including metformin. In this study, we identified genetic variations of the OCT3 promoter and functionally characterized each variant by in vitro assays. Next, the association between the functional haplotype of the OCT3 promoter and pharmacokinetics of metformin was evaluated. In our study population, 7 variations and 2 major haplotypes were identified, of which H2 haplotype yielded a significantly higher luciferase activity than did the wild type. Two variants of H2, c.-1603G > A and c.-1547T > G, yielded significantly lower luciferase activities, whereas the luciferase activity of another variant, c.-29G > A, was significantly higher. Two transcription factors, Sp1 and USF1, were involved in the regulation of OCT3 transcription. Analysis of clinical data revealed that 25 subjects, either homozygous or heterozygous for H2, showed increased AUC and C by 17.2% and 15.9%, respectively [P = 0.016 and 0.031, GMR (90% CI) = 1.17 (1.06-1.29) and 1.17 (1.04-1.31), respectively], compared to the 20 subjects in the control group. Our study suggests that an OCT3 promoter haplotype affects the pharmacokinetics of metformin in Koreans as well as the OCT3 transcription rate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-35322-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240047PMC
November 2018

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis.

Int J Mol Sci 2018 Oct 16;19(10). Epub 2018 Oct 16.

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC ( = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, = 19)) and to nondisease controls (NC, living donors, = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann⁻Whitney test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19103188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214107PMC
October 2018

Impact of the Health Insurance Coverage Policy on Oral Anticoagulant Prescription among Patients with Atrial Fibrillation in Korea from 2014 to 2016.

J Korean Med Sci 2018 Jun 9;33(23):e163. Epub 2018 May 9.

Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.

Background: To evaluate oral anticoagulant (OAC) utilization in patients with atrial fibrillation after the changes in the health insurance coverage policy in July 2015.

Methods: We used the Health Insurance Review and Assessment Service-National Patient Samples (HIRA-NPS) between 2014 and 2016. The HIRA-NPS, including approximately 1.4 million individuals, is a stratified random sample of 3% of the entire Korean population using 16 age groups and 2 sex groups. The HIRA-NPS comprises personal and medical information such as surgical or medical treatment provided, diagnoses, age, sex, region of medical institution, and clinician characteristics. The studied drugs included non-vitamin K antagonist OACs (NOACs) such as apixaban, dabigatran, edoxaban, and rivaroxaban, and were compared with warfarin. We analyzed drug utilization pattern under three aspects: person, time, and place.

Results: The number of patients with atrial fibrillation who were prescribed OACs was 3,114, 3,954, and 4,828; and the proportions of prescribed NOACs to total OACs were 5.1%, 36.2%, and 60.8% in 2014, 2015, and 2016, respectively. The growth rate of OACs prescription increased from 61.4 patients/quarter before June 2015 to 147.7 patients/quarter thereafter. These changes were predominantly in elderly individuals aged more than 70 years. The proportion of NOACs to OACs showed significant regional difference.

Conclusion: The change of health insurance coverage policy substantially influenced OACs prescription pattern in whole Korean region. But the impact has been significantly different among regions and age groups, which provides the evidence for developing standard clinical practice guideline on OACs use.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3346/jkms.2018.33.e163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976891PMC
June 2018

Rewiring FadR regulon for the selective production of ω-hydroxy palmitic acid from glucose in Escherichia coli.

Metab Eng 2018 05 30;47:414-422. Epub 2018 Apr 30.

School of Chemical and Biological Engineering, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea; Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea; Interdisciplinary Program of Bioengineering, Seoul National University, Seoul 08826, Republic of Korea; Institute of Engineering Research, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

ω-Hydroxy palmitic acid (ω-HPA) is a valuable compound for an ingredient of artificially synthesized ceramides and an additive for lubricants and adhesives. Production of such a fatty acid derivative is limited by chemical catalysis, but plausible by biocatalysis. However, its low productivity issue, including formations of unsaturated fatty acid (UFA) byproducts in host cells, remains as a hurdle toward industrial biological processes. In this study, to achieve selective and high-level production of ω-HPA from glucose in Escherichia coli, FadR, a native transcriptional regulator of fatty acid metabolism, and its regulon were engineered. First, FadR was co-expressed with a thioesterase with a specificity toward palmitic acid production to enhance palmitic acid production yield, but a considerable quantity of UFAs was also produced. In order to avoid the UFA production caused by fadR overexpression, FadR regulon was rewired by i) mutating FadR consensus binding sites of fabA or fabB, ii) integrating fabZ into fabI operon, and iii) enhancing the strength of fabI promoter. This approach led to dramatic increases in both proportion (48.3-83.0%) and titer (377.8 mg/L to 675.8 mg/L) of palmitic acid, mainly due to the decrease in UFA synthesis. Introducing a fatty acid ω-hydroxylase, CYP153A35, into the engineered strain resulted in a highly selective production of ω-HPA (83.5 mg/L) accounting for 87.5% of total ω-hydroxy fatty acids. Furthermore, strategies, such as i) enhancement in CYP153A35 activity, ii) expression of a fatty acid transporter, iii) supplementation of triton X-100, and iv) separation of the ω-HPA synthetic pathway into two strains for a co-culture system, were applied and resulted in 401.0 mg/L of ω-HPA production. For such selective productions of palmitic acid and ω-HPA, the rewiring of FadR regulation in E. coli is a promising strategy to develop an industrial process with economical downstream processing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymben.2018.04.021DOI Listing
May 2018

Apoptotic cells trigger the ABCA1/STAT6 pathway leading to PPAR-γ expression and activation in macrophages.

J Leukoc Biol 2018 05 30;103(5):885-895. Epub 2018 Mar 30.

Department of Physiology, Ewha Womans University, Seoul, Korea.

The signal transducer and activator of transcription 6 (STAT6) transcription factor activates peroxisome proliferator-activated receptor gamma (PPAR-γ)-regulated gene expression in immune cells. We investigated proximal membrane signaling that was initiated in macrophages after exposure to apoptotic cells that led to enhanced PPAR-γ expression and activity, using specific siRNAs for ABCA1, STAT6, and PPAR-γ, or their antagonists. The interactions between mouse bone marrow-derived macrophages or RAW 264.7 cells and apoptotic Jurkat cells, but not viable cells, resulted in the induction of STAT6 phosphorylation as well as PPAR-γ expression and activation. Knockdown of ATP-binding cassette transporter A1 (ABCA1) after the transfection of macrophages with ABCA1-specific siRNAs reduced apoptotic cell-induced STAT6 phosphorylation as well as PPAR-γ mRNA and protein expression. ABCA1 knockdown also reduced apoptotic cell-induced liver X receptor α (LXR-α) mRNA and protein expression. Moreover, inhibition of STAT6 with specific siRNAs or the pharmacological inhibitor AS1517499AS reversed the induction of PPAR-γ, LXR-α, and ABCA1 by apoptotic Jurkat cells. PPAR-γ-specific siRNAs or the PPAR-γ antagonist GW9662 inhibited apoptotic cell-induced increases in LXR-α and ABCA1 mRNA and protein levels. Thus, these results indicate that apoptotic cells trigger the ABCA1/STAT6 pathway, leading to the activation of the PPAR-γ/LXR-α/ABCA1 pathway in macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/JLB.2A0817-341RRDOI Listing
May 2018

Genome-scale model-driven strain design for dicarboxylic acid production in Yarrowia lipolytica.

BMC Syst Biol 2018 03 19;12(Suppl 2):12. Epub 2018 Mar 19.

NUS Synthetic Biology for Clinical and Technological Innovation (SynCTI), Life Sciences Institute, National University of Singapore, 28 Medical Drive, Singapore, 117456, Singapore.

Background: Recently, there have been several attempts to produce long-chain dicarboxylic acids (DCAs) in various microbial hosts. Of these, Yarrowia lipolytica has great potential due to its oleaginous characteristics and unique ability to utilize hydrophobic substrates. However, Y. lipolytica should be further engineered to make it more competitive: the current approaches are mostly intuitive and cumbersome, thus limiting its industrial application.

Results: In this study, we proposed model-guided metabolic engineering strategies for enhanced production of DCAs in Y. lipolytica. At the outset, we reconstructed genome-scale metabolic model (GSMM) of Y. lipolytica (iYLI647) by substantially expanding the previous models. Subsequently, the model was validated using three sets of published culture experiment data. It was finally exploited to identify genetic engineering targets for overexpression, knockout, and cofactor modification by applying several in silico strain design methods, which potentially give rise to high yield production of the industrially relevant long-chain DCAs, e.g., dodecanedioic acid (DDDA). The resultant targets include (1) malate dehydrogenase and malic enzyme genes and (2) glutamate dehydrogenase gene, in silico overexpression of which generated additional NADPH required for fatty acid synthesis, leading to the increased DDDA fluxes by 48% and 22% higher, respectively, compared to wild-type. We further investigated the effect of supplying branched-chain amino acids on the acetyl-CoA turn-over rate which is key metabolite for fatty acid synthesis, suggesting their significance for production of DDDA in Y. lipolytica.

Conclusion: In silico model-based strain design strategies allowed us to identify several metabolic engineering targets for overproducing DCAs in lipid accumulating yeast, Y. lipolytica. Thus, the current study can provide a methodological framework that is applicable to other oleaginous yeasts for value-added biochemical production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12918-018-0542-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861505PMC
March 2018

Production of pikromycin using branched chain amino acid catabolism in Streptomyces venezuelae ATCC 15439.

J Ind Microbiol Biotechnol 2018 May 10;45(5):293-303. Epub 2018 Mar 10.

School of Chemical and Biological Engineering, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.

Branched chain amino acids (BCAA) are catabolized into various acyl-CoA compounds, which are key precursors used in polyketide productions. Because of that, BCAA catabolism needs fine tuning of flux balances for enhancing the production of polyketide antibiotics. To enhance BCAA catabolism for pikromycin production in Streptomyces venezuelae ATCC 15439, three key enzymes of BCAA catabolism, 3-ketoacyl acyl carrier protein synthase III, acyl-CoA dehydrogenase, and branched chain α-keto acid dehydrogenase (BCDH) were manipulated. BCDH overexpression in the wild type strain resulted in 1.3 fold increase in pikromycin production compared to that of WT, resulting in total 25 mg/L of pikromycin. To further increase pikromycin production, methylmalonyl-CoA mutase linked to succinyl-CoA production was overexpressed along with BCDH. Overexpression of the two enzymes resulted in the highest titer of total macrolide production of 43 mg/L, which was about 2.2 fold increase compared to that of the WT. However, it accumulated and produced dehydroxylated forms of pikromycin and methymycin, including their derivatives as well. It indicated that activities of pikC, P450 monooxygenase, newly became a bottleneck in pikromycin synthesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10295-018-2024-6DOI Listing
May 2018

Body mass index and the risk of low femoral artery puncture in coronary angiography under fluoroscopy guidance.

Medicine (Baltimore) 2018 Mar;97(9):e0070

Division of Cardiology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam Seoul National University College of Medicine Division of Cardiology, Department of Internal Medicine, Boramae Medical Center, Seoul, Korea.

The inferior border of the femoral head (IBFH) is widely used as a landmark in femoral artery puncture during invasive coronary angiography (ICA). However, application of this technique can be challenging especially in obese patients. This study was performed to investigate the association between body mass index (BMI) and the risk of low puncture in femoral artery puncture.A total of 464 patients (64.8 ± 11.1 years, 55.8% male) who underwent ICA via trans-femoral access were retrospectively reviewed. IBFH was used as a landmark for a skin nick and the femoral artery cannulation site was confirmed by femoral angiography. Cannulation at the bifurcation of the common femoral artery (CFA) or below were considered low puncture.Twenty-nine patients (5.8%) were identified as having an angiographically high CFA bifurcation and low femoral artery puncture occurred in 27 (93.1%) patients of them. Among patients with normal bifurcation (n = 464), low puncture occurred in 74 (15.9%) patients. Underweight (BMI < 18.5 kg/m) or obese (BMI ≥ 30 kg/m) patients were more common in the low puncture group than in the proper puncture group (36.5% vs. 5.9%, P < .001). Multivariable analysis showed underweight or obesity (odd ratio, 9.10; 95% confidential interval, 4.77-17.35; P < .001) was an independent risk factor of low puncture even after controlling for clinical covariates. The average distance from IBFH to the CFA puncture site was shorter in patients with underweight (1.74 ± 0.71 cm) or obesity (1.75 ± 0.60 cm) than in those with normal BMI or overweight (2.07 ± 0.83 cm) (P = .030). Trigonometric calculation showed that the average distance from IBFH to the CFA puncture site was 0.5 to 2.59 cm (mean = 1.32 cm) shorter in underweight patients compared with those of normal weight or overweight patients.In patients with normal CFA bifurcation, underweight or obesity were associated with increased risk of low puncture. The puncture site should be chosen about 1 finger width more proximal to IBFH for ICA in such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000010070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5851760PMC
March 2018

Exploiting transcriptomic data for metabolic engineering: toward a systematic strain design.

Curr Opin Biotechnol 2018 12 9;54:26-32. Epub 2018 Feb 9.

School of Chemical and Biological Engineering, Institute of Molecular Biology and Genetics, and Bioengineering Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

Transcriptomics is now recognized as a primary tool for metabolic engineering as it can be used for identifying new strain designs by diagnosing current states of microbial cells. This review summarizes current application of transcriptomic data for strain design. Along with a few successful examples, limitations of conventionally used differentially expressed gene-based strain design approaches have been discussed, which have been major reasons why transcriptomic data are considerably underutilized. Recently, integrative network-based approaches interpreting transcriptomic data in the context of biological networks were invented to provide complimentary solutions for metabolic engineering by overcoming the limitations of conventional approaches. Here, we highlight recent pioneering studies in which integrative network-based methods have been used for providing novel strain designs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.copbio.2018.01.020DOI Listing
December 2018

Fluid shear stress regulates the expression of Lectin-like oxidized low density lipoprotein receptor-1 via KLF2-AP-1 pathway depending on its intensity and pattern in endothelial cells.

Atherosclerosis 2018 03 31;270:76-88. Epub 2018 Jan 31.

Medical Research Institute, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea; Department of Internal Medicine, Cardiology Division, School of Medicine, Ewha Womans University, Seoul, 158-710, Republic of Korea. Electronic address:

Background And Aims: Vascular endothelial cells (ECs) are exposed to fluid shear stress (FSS), which modulates vascular pathophysiology. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is crucial in endothelial dysfunction and atherosclerosis. We elucidated the mechanism regulating LOX-1 expression in ECs by FSS.

Methods: Human umbilical vein endothelial cells were exposed to laminar shear stress (LSS) of indicated intensities using a unidirectional steady flow, or to oscillatory shear stress (OSS) using a bidirectional disturbed flow. In vivo studies were performed in a mouse model of partial carotid ligation and human pulmonary artery sections.

Results: Within ECs, OSS upregulated LOX-1 expression, while LSS (20 dyne/cm) downregulated it. We confirmed that OSS-induced LOX-1 expression was suppressed when the mechanotransduction was inhibited by knockdown of the mechanosensory complex. In addition, we demonstrated that Kruppel-like factor 2 (KLF2) has an inhibitory role on OSS-induced LOX-1 expression. Next, we determined that activator protein-1 (AP-1) was the key transcription factor inducing LOX-1 expression by OSS, which was inhibited by KLF2 overexpression. To explore whether the intensity of LSS affects LOX-1 expression, we tested three different intensities (20, 60, and 120 dyne/cm) of LSS. We observed higher LOX-1 expression with high shear stresses of 120 dyne/cm compared to 20 and 60 dyne/cm, with OSS-like KLF2-AP-1 signaling patterns. Furthermore, ECs within disturbed flow regions showed upregulated LOX-1 expression in vivo.

Conclusions: We concluded that LOX-1 expression on ECs is regulated via FSS depending on its intensity as well as pattern. Furthermore, this is mediated through the KLF2-AP1 pathway of mechanotransduction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.atherosclerosis.2018.01.038DOI Listing
March 2018

Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction.

Cell Metab 2018 02 21;27(2):450-460.e6. Epub 2017 Dec 21.

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address:

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2017.11.003DOI Listing
February 2018

Memory characteristics of silicon nanowire transistors generated by weak impact ionization.

Sci Rep 2017 09 29;7(1):12436. Epub 2017 Sep 29.

Department of Electrical Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.

In this study, we demonstrate the static random access memory (SRAM) characteristics generated by weak impact ionization in bendable field-effect transistors (FETs) with n-p-n silicon nanowire (SiNW) channels. Our bendable SiNW FETs show not only superior switching characteristics such as an on/off current ratio of ~10 and steep subthreshold swing (~5 mV/dec) but also reliable SRAM characteristics. The SRAM characteristics originate from the positive feedback loops in the SiNW FETs generated by weak impact ionization. This paper describes in detail the operating mechanism of our device and demonstrates the potential of bendable SiNW FETs for future SRAM applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-12347-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622113PMC
September 2017

Selective tubular activation of hypoxia-inducible factor-2α has dual effects on renal fibrosis.

Sci Rep 2017 09 12;7(1):11351. Epub 2017 Sep 12.

College of Medicine, Yonsei University, Seoul, Korea.

Hypoxia-inducible factor (HIF) is a key transcriptional factor in the response to hypoxia. Although the effect of HIF activation in chronic kidney disease (CKD) has been widely evaluated, the results have been inconsistent until now. This study aimed to investigate the effects of HIF-2α activation on renal fibrosis according to the activation timing in inducible tubule-specific transgenic mice with non-diabetic CKD. HIF-2α activation in renal tubular cells upregulated mRNA and protein expressions of fibronectin and type 1 collagen associated with the activation of p38 mitogen-activated protein kinase. In CKD mice, activation of HIF-2α at the beginning of CKD significantly aggravated renal fibrosis, whereas it did not lead to renal dysfunction. However, activation at a late-stage of CKD abrogated both renal dysfunction and fibrosis, which was associated with restoration of renal vasculature and amelioration of hypoxia through increased renal tubular expression of VEGF and its isoforms. As with tubular cells with HIF-2α activation, those under hypoxia also upregulated VEGF, fibronectin, and type 1 collagen expressions associated with HIF-1α activation. In conclusion, late-stage renal tubular HIF-2α activation has protective effects on renal fibrosis and the resultant renal dysfunction, thus it could represent a therapeutic target in late stage of CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-11829-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596020PMC
September 2017

Extracellular matrix-derived extracellular vesicles promote cardiomyocyte growth and electrical activity in engineered cardiac atria.

Biomaterials 2017 Nov 4;146:49-59. Epub 2017 Sep 4.

Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, Republic of Korea. Electronic address:

Extracellular matrix (ECM) plays a critical role in the provision of the necessary microenvironment for the proper regeneration of the cardiac tissue. However, specific mechanisms that lead to ECM-mediated cardiac regeneration are not well understood. To elucidate the potential mechanisms, we investigated ultra-structures of the cardiac ECM using electron microscopy. Intriguingly, we observed large quantities of micro-vesicles from decellularized right atria. RNA and protein analyses revealed that these contained exosomal proteins and microRNAs (miRNAs), which we referred to herein as ECM-derived extracellular vesicles (ECM-EVs). One particular miRNA from ECM-EVs, miR-199a-3p, promoted cell growth of isolated neonatal cardiomyocytes and sinus nodal cells by repressing homeodomain-only protein (HOPX) expression and increasing GATA-binding 4 (Gata4) acetylation. To determine the mechanisms, we knocked down Gata4 and showed that miR-199a-3p actions required Gata4 for cell proliferation in isolated neonatal cardiomyocytes and sinus nodal cells. To further explore the role of this miRNA, we isolated neonatal cardiac cells and recellularized into atrial ECM, referred here has engineered atria. Remarkably, miR-199a-3p mediated the enrichment of cardiomyocyte and sinus nodal cell population, and enhanced electrocardiographic signal activity of sinus nodal cells in the engineered atria. Importantly, antisense of miRNA (antagomir) against miR-199a-3p was capable of abolishing these actions of miR-199a-3p in the engineered atria. We further showed in Ang II-infused animal model of sinus nodal dysfunction that miR-199-3p-treated cardiac cells remarkably ameliorated and restored the electrical activity as shown by normalization of the ECG, in contrast to untreated cells, which did not show electrical recovery. In conclusion, these results provide clear evidence of the critical role of ECM, in not only providing a scaffold for cardiac tissue growth, but also in promoting atrial electrical function through ECM-derived miR-199a-3p.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2017.09.001DOI Listing
November 2017

Clinical implication of an impaired fasting glucose and prehypertension related to new onset atrial fibrillation in a healthy Asian population without underlying disease: a nationwide cohort study in Korea.

Eur Heart J 2017 Sep;38(34):2599-2607

Department of Cardiology, College of Medicine, Ewha Womans University, 1071, Annyangcheon-ro, Yangcheon-gu, Seoul 07985, Republic of Korea.

Aims: For healthy populations without comorbidities, whether prehypertension and impaired fasting glucose (IFG) are associated with new onset atrial fibrillation (AF) is not well known.

Methods And Results: We included 366 507 subjects (age ≥20 years) not diagnosed with non-valvular AF from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2003 to 2008. In total, 139 306 subjects diagnosed with AF-related comorbidities were excluded, and a 227 102 healthy population was followed up until 2013. The body mass index (BMI), blood pressure (BP), and fasting blood glucose (BG) level were acquired during National health check-ups. Subjects with IFG [hazard ratio (HR) 1.16, P = 0.017] had a higher AF risk and the diastolic BP (HR 1.11, P = 0.045) was a stronger indicator for an AF incidence than the systolic BP. After dividing the subjects into two mutually exclusive groups, AF incidence was increased dramatically by the combination effect of both prehypertension and an IFG in BMI <25 kg/m2 group, but, in BMI ≧25 kg/m2 group, did not show this tendency. An IFG related to AF risk was more prominent in the BMI <25 kg/m2 population (HR 1.18, P = 0.025) than those with a BMI ≥25 kg/m2, and subjects with both an IFG and prehypertension had a greater AF risk (HR 1.27, P = 0.016) than those without.

Conclusion: Even in a healthy Asian populations without comorbidities, prehypertension and IFG were important risk factors of AF. Specifically, when prehypertension, including systolic and diastolic BPs, was finally combined with the IFG, the risk of new onset AF was increased especially in the BMI <25 kg/m2 group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehx316DOI Listing
September 2017

ULK1 prevents cardiac dysfunction in obesity through autophagy-meditated regulation of lipid metabolism.

Cardiovasc Res 2017 Aug;113(10):1137-1147

Department of Pharmacology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.

Aims: Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis.

Methods And Results: In both genetic and dietary models of obesity, we observed a substantial increase in cardiac LPL protein levels without any change in messenger ribonucleic acid (mRNA). This was accompanied by a dramatic down-regulation of autophagy in the heart, as revealed by reduced levels of unc-51 like kinase-1 (ULK1) protein. To further explore the relationship between cardiac LPL and autophagy, we generated cardiomyocyte-specific knockout mice for ulk1 (Myh6-cre/ulk1fl/fl), Lpl (Myh6-cre/Lplfl/fl), and mice with a combined deficiency (Myh6-cre/ulk1fl/flLplfl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1fl/fl mice had a substantial increase in cardiac LPL levels. When these mice were fed a high-fat diet (HFD), they showed elevated cardiac TG levels and deterioration in heart function. However, with combined deletion of LPL and ULK1 in Myh6-cre/ulk1fl/flLplfl/fl mice, HFD feeding did not lead to alterations in levels of TG or diacylglycerol, or in cardiac function. To further elucidate the role of autophagy in cardiac lipid metabolism, we infused a peptide that enhanced autophagy (D-Tat-beclin1). This effectively lowered LPL levels at the coronary lumen by restoring autophagy in the genetic model of obesity. This decrease in cardiac luminal LPL was associated with a reduction in TG levels and recovery of cardiac function.

Conclusion: These results provide clear evidence of the critical role of modulating cardiac LPL activity through autophagy-mediated proteolytic clearance as a potential novel strategy to overcome obesity-related cardiomyopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvx064DOI Listing
August 2017

Steep switching characteristics of single-gated feedback field-effect transistors.

Nanotechnology 2017 Feb 29;28(5):055205. Epub 2016 Dec 29.

Department of Electrical Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul, 02841, Korea.

In this study, we propose newly designed feedback field-effect transistors that utilize the positive feedback of charge carriers in single-gated silicon channels to achieve steep switching behaviors. The band diagram, I-V characteristics, subthreshold swing, and on/off current ratio are analyzed using a commercial device simulator. Our proposed feedback field-effect transistors exhibit subthreshold swings of less than 0.1 mV dec, an on/off current ratio of approximately 10, and an on-current of approximately 10 A at room temperature, demonstrating that the switching characteristics are superior to those of other silicon-based devices. In addition, the device parameters that affect the device performance, hysteresis characteristics, and temperature-dependent device characteristics are discussed in detail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6528/28/5/055205DOI Listing
February 2017

A Novel Approach for Gene Expression Optimization through Native Promoter and 5' UTR Combinations Based on RNA-seq, Ribo-seq, and TSS-seq of Streptomyces coelicolor.

ACS Synth Biol 2017 03 22;6(3):555-565. Epub 2016 Dec 22.

Department of Biological Sciences and KI for the BioCentury, Korea Advanced Institute of Science and Technology , Daejeon 34141, Republic of Korea.

Streptomycetes are Gram-positive mycelial bacteria, which synthesize a wide range of natural products including over two-thirds of the currently available antibiotics. However, metabolic engineering in Streptomyces species to overproduce a vast of natural products are hampered by a limited number of genetic tools. Here, two promoters and four 5' UTR sequences showing constant strengths were selected based upon multiomics data sets from Streptomyces coelicolor M145, including RNA-seq, Ribo-seq, and TSS-seq, for controllable transcription and translation. A total eight sets of promoter/5' UTR combinations, with minimal interferences of promoters on translation, were constructed using the transcription start site information, and evaluated with the GusA system. Expression of GusA could be controlled to various strengths in three different media, in a range of 0.03- to 2.4-fold, compared to that of the control, ermE*P/Shine-Dalgarno sequence. This method was applied to engineer three previously reported promoters to enhance gene expressions. The expressions of ActII-ORF4 and MetK were also tuned for actinorhodin overproductions in S. coelicolor as examples. In summary, we provide a novel approach and tool for optimizations of gene expressions in Streptomyces coelicolor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acssynbio.6b00263DOI Listing
March 2017