Publications by authors named "Su Jin Yoo"

43 Publications

Molecular characterization of Hsf1 as a master regulator of heat shock response in the thermotolerant methylotrophic yeast Ogataea parapolymorpha.

J Microbiol 2021 Feb 1;59(2):151-163. Epub 2021 Feb 1.

Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 06974, Republic of Korea.

Ogataea parapolymorpha (Hansenula polymorpha DL-1) is a thermotolerant methylotrophic yeast with biotechnological applications. Here, O. parapolymorpha genes whose expression is induced in response to heat shock were identified by transcriptome analysis and shown to possess heat shock elements (HSEs) in their promoters. The function of O. parapolymorpha HSF1 encoding a putative heat shock transcription factor 1 (OpHsf1) was characterized in the context of heat stress response. Despite exhibiting low sequence identity (26%) to its Saccharomyces cerevisiae homolog, OpHsf1 harbors conserved domains including a DNA binding domain (DBD), domains involved in trimerization (TRI), transcriptional activation (AR1, AR2), transcriptional repression (CE2), and a C-terminal modulator (CTM) domain. OpHSF1 could complement the temperature sensitive (Ts) phenotype of a S. cerevisiae hsf1 mutant. An O. parapolymorpha strain with an H221R mutation in the DBD domain of OpHsf1 exhibited significantly retarded growth and a Ts phenotype. Intriguingly, the expression of heat-shock-protein-coding genes harboring HSEs was significantly decreased in the H221R mutant strain, even under non-stress conditions, indicating the importance of the DBD for the basal growth of O. parapolymorpha. Notably, even though the deletion of C-terminal domains (ΔCE2, ΔAR2, ΔCTM) of OpHsf1 destroyed complementation of the growth defect of the S. cerevisiae hsf1 strain, the C-terminal domains were shown to be dispensable in O. parapolymorpha. Overexpression of OpHsf1 in S. cerevisiae increased resistance to transient heat shock, supporting the idea that OpHsf1 could be useful in the development of heat-shock-resistant yeast host strains.
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http://dx.doi.org/10.1007/s12275-021-0646-2DOI Listing
February 2021

Induction of the IL-1RII decoy receptor by NFAT/FOXP3 blocks IL-1β-dependent response of Th17 cells.

Elife 2021 Jan 28;10. Epub 2021 Jan 28.

Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.

Derived from a common precursor cell, the balance between Th17 and Treg cells must be maintained within immune system to prevent autoimmune diseases. IL-1β-mediated IL-1 receptor (IL-1R) signaling is essential for Th17-cell biology. Fine-tuning of IL-1R signaling is controlled by two receptors, IL-1RI and IL-RII, IL-1R accessory protein, and IL-1R antagonist. We demonstrate that the decoy receptor, IL-1RII, is important for regulating IL-17 responses in TCR-stimulated CD4 T cells expressing functional IL-1RI via limiting IL-1β responsiveness. IL-1RII expression is regulated by NFAT via its interaction with Foxp3. The NFAT/FOXP3 complex binds to the promoter and is critical for its transcription. Additionally, IL-1RII expression is dysregulated in CD4 T cells from patients with rheumatoid arthritis. Thus, differential expression of IL-1Rs on activated CD4 T cells defines unique immunological features and a novel molecular mechanism underlies IL-1RII expression. These findings shed light on the modulatory effects of IL-1RII on Th17 responses.
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http://dx.doi.org/10.7554/eLife.61841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872515PMC
January 2021

Activated Platelets Convert CD14CD16 Into CD14CD16 Monocytes With Enhanced FcγR-Mediated Phagocytosis and Skewed M2 Polarization.

Front Immunol 2020 7;11:611133. Epub 2021 Jan 7.

Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

Monocytes are important cellular effectors of innate immune defense. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. The expansion of intermediate CD14CD16 monocytes has been reported in chronic inflammatory diseases including rheumatoid arthritis (RA). However, the mechanism underlying induction of CD16 and its role in monocytes remains poorly understood. Here, we demonstrate that activated platelets are important for induction of CD16 on classical CD14CD16 monocytes by soluble factors such as cytokines. Cytokine neutralization and signaling inhibition assays reveal that sequential involvement of plateletderived TGF-β and monocyte-derived IL-6 contribute to CD16 induction on CD14CD16 monocytes. Activated platelet-induced CD16 on monocytes participates in antibody-dependent cellular phagocytosis (ADCP) and its level is positively correlated with phagocytic activity. CD14CD16 monocytes treated with activated platelets preferentially differentiate into M2 macrophages, likely the M2c subset expressing CD163 and MerTK. Lastly, the amount of sCD62P, a marker of activated platelets, is significantly elevated in plasma of RA patients and positively correlates with clinical parameters of RA. Our findings suggest an important role of activated platelets in modulating phenotypical and functional features of human monocytes. This knowledge increases understanding of the immunological role of CD14CD16 cells in chronic inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2020.611133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817612PMC
January 2021

The effect of nicotinamide adenine dinucleotide phosphate oxidase 4 on migration and invasion of fibroblast-like synoviocytes in rheumatoid arthritis.

Arthritis Res Ther 2020 05 15;22(1):116. Epub 2020 May 15.

Research Institute for Medical Sciences, Chungnam National University School of Medicine, 266 Munhwaro, Daejeon, Republic of Korea.

Background: Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and, consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear.

Methods: FLS isolated from RA (n = 5) and osteoarthritis (OA, n = 5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes.

Results: Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels.

Conclusion: NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.
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http://dx.doi.org/10.1186/s13075-020-02204-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227051PMC
May 2020

Yeast synthetic biology for designed cell factories producing secretory recombinant proteins.

FEMS Yeast Res 2020 03;20(2)

Laboratory of Molecular Systems Biology, Department of Life Science, Chung-Ang University, Seoul 06974, South Korea.

Yeasts are prominent hosts for the production of recombinant proteins from industrial enzymes to therapeutic proteins. Particularly, the similarity of protein secretion pathways between these unicellular eukaryotic microorganisms and higher eukaryotic organisms has made them a preferential host to produce secretory recombinant proteins. However, there are several bottlenecks, in terms of quality and quantity, restricting their use as secretory recombinant protein production hosts. In this mini-review, we discuss recent developments in synthetic biology approaches to constructing yeast cell factories endowed with enhanced capacities of protein folding and secretion as well as designed targeted post-translational modification process functions. We focus on the new genetic tools for optimizing secretory protein expression, such as codon-optimized synthetic genes, combinatory synthetic signal peptides and copy number-controllable integration systems, and the advanced cellular engineering strategies, including endoplasmic reticulum and protein trafficking pathway engineering, synthetic glycosylation, and cell wall engineering, for improving the quality and yield of secretory recombinant proteins.
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http://dx.doi.org/10.1093/femsyr/foaa009DOI Listing
March 2020

Intravitreal aflibercept for submacular hemorrhage secondary to neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Graefes Arch Clin Exp Ophthalmol 2020 Jan 18;258(1):107-116. Epub 2019 Nov 18.

Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, #156 Youngdeungpo-dong 4ga, Youngdeungpo-gu, Seoul, 150-034, South Korea.

Purpose: To evaluate the efficacy of intravitreal aflibercept monotherapy for submacular hemorrhage secondary to neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

Methods: This prospective, phase 4 clinical trial included 29 patients diagnosed with fovea-involving submacular hemorrhage secondary to neovascular AMD (7 patients) or PCV (22 patients). Patients were initially administered 3 monthly aflibercept injections, followed by 1 injection every 2 months. The primary outcome measure was changes in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) during the 56-week study period. Other key outcome measures were the proportion of patients who exhibited changes in BCVA of ≥ 15 ETDRS letters from baseline and changes in central retinal thickness (CRT).

Results: The mean size of hemorrhage was 6.2 ± 4.8-disc-diameter area. The mean BCVA significantly improved from 52.9 ± 17.8 ETDRS letters at week 0 (baseline) to 71.8 ± 16.1 letters at week 56 (P < 0.001). At week 56, improvement in BCVA of ≥ 15 letters was noted in 16 patients (55.2%), whereas none of the patients experienced a loss of ≥ 15 letters. The mean CRT significantly decreased from 498.9 ± 194.2 μm at week 0 to 248.3 ± 45.0 μm at week 56 (P < 0.001). During the study period, retinal break developed in one patient.

Conclusions: Intravitreal aflibercept administered every 2 months after the 3 initial monthly doses was found to be an effective and safe treatment method for submacular hemorrhage secondary to neovascular AMD.
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http://dx.doi.org/10.1007/s00417-019-04474-0DOI Listing
January 2020

Short bZIP homologue of sulfur regulator Met4 from Ogataea parapolymorpha does not depend on DNA-binding cofactors for activating genes in sulfur starvation.

Environ Microbiol 2020 01 19;22(1):310-328. Epub 2019 Nov 19.

Laboratory of Molecular Systems Biology, Department of Life Science, Chung-Ang University, Seoul, 06974, Korea.

The acquisition of sulfur from environment and its assimilation is essential for fungal growth and activities. Here, we describe novel features of the regulatory network of sulfur metabolism in Ogataea parapolymorpha, a thermotolerant methylotrophic yeast with high resistance to harsh environmental conditions. A short bZIP protein (OpMet4p) of O. parapolymorpha, displaying the combined structural characteristics of yeast and filamentous fungal Met4 homologues, plays a key role as a master regulator of cell homeostasis during sulfur limitation, but also its function is required for the tolerance of various stresses. Domain swapping analysis, combined with deletion analysis of the regulatory domains and genes encoding OpCbf1p, OpMet28p, and OpMet32p, indicated that OpMet4p does not require the interaction with these DNA-binding cofactors to induce the expression of sulfur genes, unlike the Saccharomyces cerevisiae Met4p. ChIP analysis confirmed the notion that OpMet4p, which contains a canonical bZIP domain, can bind the target DNA in the absence of cofactors, similar to homologues in other filamentous fungi. Collectively, the identified unique features of the O. parapolymorpha regulatory network, as the first report on the sulfur regulation by a short yeast Met4 homologue, provide insights into conservation and divergence of the sulfur regulatory networks among diverse ascomycetous fungi.
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http://dx.doi.org/10.1111/1462-2920.14849DOI Listing
January 2020

Associations of Mitochondrial Deoxyribonucleic Acid Polymorphisms With Behçet's Disease in the Korean Population.

Arch Rheumatol 2019 Jun 28;34(2):211-219. Epub 2019 Jan 28.

Department of Internal Medicine, Konyang University School of Medicine, Myunggok Medical Research Institute, Daejeon, South Korea.

Objectives: This study aims to examine the possible associations of mitochondrial single nucleotide polymorphisms (SNPs) and Behçet's disease (BD) in a larger patient group.

Patients And Methods: Whole blood or buffy coat was collected from 98 BD patients (31 males, 67 females; mean age 48±2.8 years; range 20 to 60 years) from four university hospitals located in the Chung-Cheong district of the Republic of Korea, and 196 age- and sex-matched healthy controls (HCs) (62 males, 134 females; mean age 46.91±12.90 years; range 20 to 68 years) from Konyang University Hospital. Twenty targeted mitochondrial deoxyribonucleic acids (DNAs) were genotyped and compared using the revised Cambridge Reference Sequence. Chi square and Fisher's exact tests were used to analyze association of mitochondrial DNA SNPs with BD susceptibility and its clinical characteristics.

Results: There were no differences for m.248A>G, m.304C>A, m.709G>A, m.3010G>A, m.3970C>T, m.4883C>T, m.5178C>A, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.14668C>T, m.16129G>A, and m16304T> between patient and HC groups. However, m.16182A>C and m.16183A>C were more frequently observed in the patient group than the HC group (22 [22.4%] vs. 24 [12.2%], p=0.061 and 32 [32.7%] vs. 42 [21.4%], p=0.092) but without statistical significance. m.4883C>T and m.5178C>A were associated with posterior location of oral ulcers (p=0.025 for each) and m.16183A>C was associated with deep oral ulcers (p=0.001), while m.16189T>C was associated with deep oral ulcers and thrombosis (p=0.042, 0.048, respectively).

Conclusion: m.16182A>C and m.16183A>C may be associated with BD in the Korean population.
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http://dx.doi.org/10.5606/ArchRheumatol.2019.7113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719587PMC
June 2019

Screening and Selection of Production Strains: Secretory Protein Expression and Analysis in Hansenula polymorpha.

Methods Mol Biol 2019 ;1923:133-151

Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, Republic of Korea.

The thermotolerant methylotrophic yeast Hansenula polymorpha has been used as a host for the high-level production of recombinant proteins from industrial enzymes to therapeutic proteins. Despite favorable characteristics of the H. polymorpha-based platform for application to heterologous gene expression, several problems and limitations, such as over-glycosylation and proteolytic degradation, can be encountered in the development of production strains for secretory proteins. Here, H. polymorpha genetic tools and host strains, developed for authentic processing and modification of secretory recombinant proteins, are introduced with the analytical protocols.
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http://dx.doi.org/10.1007/978-1-4939-9024-5_5DOI Listing
June 2019

Development of conditional cell lysis mutants of Saccharomyces cerevisiae as production hosts by modulating OCH1 and CHS3 expression.

Appl Microbiol Biotechnol 2019 Mar 31;103(5):2277-2293. Epub 2019 Jan 31.

Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 06974, South Korea.

The traditional yeast Saccharomyces cerevisiae has been widely used as a host for the production of recombinant proteins and metabolites with industrial potential. However, its thick and rigid cell wall presents problems for the effective recovery of products. In this study, we modulated the expression of ScOCH1, encoding the α-1,6-mannosyltransferase responsible for outer chain biosynthesis of N-glycans, and ScCHS3, encoding the chitin synthase III required for synthesis of the majority of cell wall chitin, by exploiting the repressible ScMET3 promoter. The conditional single mutants P-OCH1 and P-CHS3 and the double mutant P-OCH1/P-CHS3 showed comparable growth to the wild-type strain under normal conditions but exhibited increased sensitivity to temperature and cell wall-disturbing agents in the presence of methionine. Such conditional growth defects were fully recovered by supplementation with 1 M sorbitol. The osmotic lysis of the conditional mutants cultivated with methionine was sufficient to release the intracellularly expressed recombinant protein, nodavirus capsid protein, with up to 60% efficiency, compared to lysis by glass bead breakage. These mutant strains also showed approximately three-fold-enhanced secretion of a recombinant extracellular glycoprotein, Saccharomycopsis fibuligera β-glucosidase, with markedly reduced hypermannosylation, particularly in the P-OCH1 mutants. Furthermore, a substantial increase of extracellular glutathione production, up to four-fold, was achieved with the conditional mutant yeast cells. Together, our data support that the conditional cell wall lysis mutants constructed based on the modulation of ScOCH1 and ScCHS3 expression would likely be useful hosts for the improved recovery of proteins and metabolites with industrial application.
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http://dx.doi.org/10.1007/s00253-019-09614-4DOI Listing
March 2019

Impact of EUSTAR standardized training on accuracy of modified Rodnan skin score in patients with systemic sclerosis.

Int J Rheum Dis 2019 Jan 5;22(1):96-102. Epub 2018 Nov 5.

Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.

Objectives: To investigate the impact of European Scleroderma Trials and Research (EUSTAR) standardized training on the accuracy of modified Rodnan skin score (mRSS) in patients with systemic sclerosis (SSc).

Methods: Eight SSc patients (four diffuse, four limited) and 10 physicians (4 fellows, 6 professors) were included. Gold-standard mRSS was performed by a senior instructor. Training comprised a video presentation and a live demonstration. Each physician performed mRSS with no clinical information in all patients: (a) before training; (b) after video session; and (c) after live demonstration. Primary outcome was the change in scoring accuracy, which was defined as the difference from the gold-standard skin score, as analyzed using a linear mixed model.

Results: Mean (standard deviation) difference from the gold-standard score in all measurements by participants before the training was 7.7 (9.5). Completion of training significantly enhanced mRSS accuracy (adjusted β = -7.61; 95% CI: -11.91 to -3.32). This was largely attributable to the video presentation (adjusted β = -5.47; -9.16 to -1.78), although the live demonstration was associated with numerical reduction in the difference from the gold-standard score (adjusted β = -2.15; -5.84 to 1.55). Effect of training was prominent in fellows whereas professors showed an increase in the difference from gold-standard score after training (P value for interaction <0.001). The intraclass correlation coefficient for physician skin scores was acceptable. However, no significant change was observed after training.

Conclusion: New EUSTAR standardized mRSS training significantly enhanced mRSS accuracy, especially in participant with less previous experience in skin scoring.
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http://dx.doi.org/10.1111/1756-185X.13433DOI Listing
January 2019

Anti-TIF1γ antibody and the expression of TIF1γ in idiopathic inflammatory myopathies.

Int J Rheum Dis 2019 Feb 5;22(2):314-320. Epub 2018 Nov 5.

Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea.

Objective: Anti-transcriptional intermediary factor 1 (TIF1) antibody is associated with idiopathic inflammatory myopathies (IIMs). The aim of this study was to investigate the expression of TIF1s in IIMs.

Method: TIF1α, β or γ expression in the skin and muscle of patients and controls was studied by immunohistochemistry. Serum myositis-specific autoantibodies were detected by immunoblot.

Results: TIF1α was expressed in the skin of most dermatomyositis (DM) patients but not in the controls (80% vs 0%, P < 0.001). TIF1β was expressed in all tissues of patients and controls. TIF1γ was expressed in the muscle of DM patients compared to controls (42.1% vs 0%, P = 0.039) and associated with tubuloreticular bodies (P = 0.003). Anti-TIF1γ was related with TIF1γ expression in the muscle (P = 0.042).

Conclusion: TIF1α expression in the skin and TIF1γ in the muscle of DM was increased compared to controls. TIF1γ expression in the muscle of IIMs was related to anti-TIF1γ antibody.
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http://dx.doi.org/10.1111/1756-185X.13424DOI Listing
February 2019

Clinical and Laboratory Characteristics and Mortality in Korean Patients with Systemic Sclerosis: A Nationwide Multicenter Retrospective Cohort Study.

J Rheumatol 2018 08 15;45(9):1281-1288. Epub 2018 Jul 15.

From the Division of Rheumatology, Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon; Department of Rheumatology, Chonnam National University Medical School, Gwangju; Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine; Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul; Division of Rheumatology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon; Division of Rheumatology, Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan; Division of Rheumatology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju; Department of Rheumatology, Yonsei University Wonju College of Medicine, Wonju; Division of Rheumatology, Department of Internal Medicine, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Korea.

Objective: We aimed to investigate demographic and clinical features and predictors of mortality in Korean patients with systemic sclerosis (SSc).

Methods: We performed a retrospective multicenter medical chart review in Korean patients diagnosed with SSc from 1986 to 2016 at 11 university hospitals representing each geographic area of Korea. SSc patients were defined according to the American College of Rheumatology preliminary classification criteria and subtyped as limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) SSc.

Results: We enrolled 751 patients (female, 86.7%; mean age at diagnosis, 48.9 yrs). The most common organ involvement was interstitial lung disease (52.7%), followed by gastroesophageal reflux disease (32.9%) and pulmonary arterial hypertension (13.6%). Patients with lcSSc were more common than those with dcSSc (64.8 vs 35.2%), whereas anti-Scl-70 and anticentromere antibody positivity were identified in 302 (42.5%) and 175 (25.5%) patients, respectively. In the 46 (6.1%) patients who developed a malignancy, lung cancer (23.9%) was the most common diagnosis, followed by gastric (13%) and breast cancer (13%). During the study period, 57 (7.6%) patients died, and the 5- and 10-year survival rates were 94% and 87%, respectively. Increased age at diagnosis, cardiovascular involvement, and anti-Scl-70 antibody positivity were significant predictors of death.

Conclusion: Clinical manifestations and survival rates in Korean SSc patients are similar to those of other populations. However, the prevalence of anti-Scl-70 antibody is higher in Korean SSc patients compared with whites, while the prevalence of anticentromere antibody is lower.
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http://dx.doi.org/10.3899/jrheum.171443DOI Listing
August 2018

Intrinsic changes of left ventricular function in patients with Behçet disease and comparison according to systemic disease activity.

Echocardiography 2018 06 16;35(6):809-816. Epub 2018 Feb 16.

Division of Cardiology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea.

Purpose: Although cardiac manifestation of Behçet disease (BD) has been described in sporadic reports, its timely diagnosis remains difficult. The objective of this study was to describe early cardiac manifestations of BD. We also performed a comprehensive classification of systemic BD activity and compared their cardiac manifestations.

Methods: A prospective screening using speckle tracking echocardiography was performed in 85 patients with BD who had no history of heart disease. After excluding subjects with left ventricular (LV) ejection fraction (LVEF) <50% (n = 1), atrial fibrillation (n = 2), or inadequate echocardiographic images (n = 1), we analyzed their clinical and echocardiographic parameters including LV global longitudinal strains (GLS) and compared them with those of an age- and gender-matched control group (n = 145). Systemic BD activity was classified as minimal (Group A), controlled (Group B), and active (Group C).

Results: In 81 study patients (59 females, age of 51 ± 11 years), echocardiography revealed a mean LVEF of 64 ± 5% without any significant valvular dysfunction or aortic aneurysm. Although there was no difference in LVEF between the control group and the patient group, the patient group showed significant reduction in GLS (-17.1 ± 2.9% vs -20.8 ± 2.2%, P < .001). Groups A (n = 21, 26%), B (n = 47, 58%), and C (n = 13, 58%) consistently showed reduction in GLS compared with the control group. However, there was no significant difference in cardiac manifestations among these groups according to systemic disease activity.

Conclusion: Patients with BD present intrinsic LV dysfunction despite no apparent abnormality on routine echocardiography. However, their cardiac manifestations are not proportional to systemic BD activity.
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http://dx.doi.org/10.1111/echo.13844DOI Listing
June 2018

A Novel Mitochondrial Serine O-Acetyltransferase, OpSAT1, Plays a Critical Role in Sulfur Metabolism in the Thermotolerant Methylotrophic Yeast Ogataea parapolymorpha.

Sci Rep 2018 02 5;8(1):2377. Epub 2018 Feb 5.

Department of Life Science, Chung-Ang University, Seoul, 06974, Korea.

In most bacteria and plants, direct biosynthesis of cysteine from sulfide via O-acetylserine (OAS) is essential to produce sulfur amino acids from inorganic sulfur. Here, we report the functional analysis of a novel mitochondrial serine O-acetyltransferase (SAT), responsible for converting serine into OAS, in the thermotolerant methylotrophic yeast Ogataea parapolymorpha. Domain analysis of O. parapolymorpha SAT (OpSat1p) and other fungal SATs revealed that these proteins possess a mitochondrial targeting sequence (MTS) at the N-terminus and an α/β hydrolase 1 domain at the C-terminal region, which is quite different from the classical SATs of bacteria and plants. Noticeably, OpSat1p is functionally interchangeable with Escherichia coli SAT, CysE, despite that it displays much less enzymatic activity, with marginal feedback inhibition by cysteine, compared to CysE. The Opsat1Δ-null mutant showed remarkably reduced intracellular levels of cysteine and glutathione, implying OAS generation defect. The MTS of OpSat1p directs the mitochondrial targeting of a reporter protein, thus, supporting the localization of OpSat1p in the mitochondria. Intriguingly, the OpSat1p variant lacking MTS restores the OAS auxotrophy, but not the cysteine auxotrophy of the Opsat1Δ mutant strain. This is the first study on a mitochondrial SAT with critical function in sulfur assimilatory metabolism in fungal species.
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http://dx.doi.org/10.1038/s41598-018-20630-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799214PMC
February 2018

TNFα and IL-1β in the synovial fluid facilitate mucosal-associated invariant T (MAIT) cell migration.

Cytokine 2017 11 27;99:91-98. Epub 2017 Jul 27.

Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT), Daejeon 305-600, Republic of Korea. Electronic address:

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affect the joints and inflammatory cell migration into inflamed articular sites contribute to this disease. Among the inflammatory cells, human mucosal-associated invariant T (MAIT) cells were recently recognized as critical cellular component with a pathological role in RA. However, their migratory characteristics are poorly understood. The aim of this study was to determine whether human MAIT cells preferentially traffick to inflamed synovial sites in rheumatoid arthritis patients and to elucidate the underlying mechanism. First, we found that TNFα and IL-1β were elevated in synovial fluid (SF) of RA patients, which resulted in increased expression of E-selectin, ICAM-1 and V-CAM-1 on blood vessel endothelial cells. To understand whether TNFα and IL-1β in the SF facilitated MAIT cell migration, we analyzed CD161 TCRα7.2 MAIT and other CD3 T cells for differences in migratory capacity. Collectively, our results demonstrate that TNFα and IL-1β in the SF facilitated MAIT cell migration dependent on expression of selectin ligand, sialyl Lewis (sLe) and CCR6 on MAIT cells. We also showed that MAIT cells in the SF from RA patients equipped upregulated sLe compared to the peripheral blood of RA patients and healthy persons, which suggest that TNFα and IL-1β mediated expression of E-selectin preferentially attract sLe mediated MAIT cell migration into the SF of RA patients.
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http://dx.doi.org/10.1016/j.cyto.2017.07.007DOI Listing
November 2017

Natural Short-term Course of Recurrent Macular Edema Following Intravitreal Bevacizumab Therapy in Branch Retinal Vein Occlusion.

Korean J Ophthalmol 2017 Apr 21;31(2):95-101. Epub 2017 Mar 21.

Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.

Purpose: To evaluate the 3-month natural course of recurrent macular edema secondary to branch retinal vein occlusion (BRVO) treated with intravitreal bevacizumab.

Methods: This retrospective, observational study included 36 eyes with macular edema secondary to BRVO. All patients were initially treated with intravitreal bevacizumab for macular edema. Recurrence of macular edema was either not treated (untreated group) or treated with a single intravitreal bevacizumab injection (treated group). Central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were compared at the time of recurrence and 3 months later.

Results: At the time of recurrence, the mean CFT and logarithm of the minimum angle of resolution BCVA were 484.9 ± 124.1 µm and 0.58 ± 0.26 in the untreated group (n = 19) and 456.3 ± 126.8 µm and 0.51 ± 0.21 in the treated group (n = 17), respectively. Three months later, the mean CFT and BCVA had changed to 493.7 ± 123.9 µm and 0.62 ± 0.29 in the untreated group and 294.7 ± 104.4 µm and 0.40 ± 0.24 in the treated group, respectively. The differences in CFT and BCVA between the two time points were not significant in the untreated group ( = 0.106 and = 0.687, respectively), whereas statistically significant differences were noted in the treated group ( = 0.002 and < 0.001, respectively).

Conclusions: Unlike the first episode of macular edema following BRVO, recurrent macular edema following intravitreal bevacizumab therapy did not spontaneously resolve, suggesting the potential benefit of prompt treatment.
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http://dx.doi.org/10.3341/kjo.2017.31.2.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368096PMC
April 2017

Prevalence of Pulmonary Arterial Hypertension in Korean Adult Patients with Systemic Sclerosis: Result of a Pilot Echocardiographic Screening Study.

J Cardiovasc Ultrasound 2016 Dec 28;24(4):312-316. Epub 2016 Dec 28.

Division of Rheumatology, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea.

Background: Pulmonary arterial hypertension (PAH) is a major cause of morbidity and mortality among patients with systemic sclerosis (SSc). Early detection and prompt treatment of PAH associated with SSc (SSc-PAH) result in better prognosis. We conducted echocardiographic study to presume the prevalence of PAH in Korean adult SSc patients and to diagnose SSc-PAH in their early stages with right heart catheterization (RHC).

Methods: We performed free of charge echocardiographic study including 37 adult SSc patients at the Chungnam National University Hospital. The possibility of PAH is determined by the estimation of pulmonary arterial pressure by peak tricuspid regurgitation velocity of > 3.0 m/s. Patients with possible PAH were recommended to undergo RHC to confirm the diagnosis.

Results: In 37 patients, 8 patients were suspected with PAH. Among them, 6 patients agreed to be examined with RHC, and 4 were confirmed with PAH. The prevalence of possible PAH was 21.6% (8 of 37 patients), and that of confirmed PAH was 10.8% (4 of 37 patients). Four patients who were confirmed with SSc-PAH through RHC have been treated with specific pulmonary vasodilators and maintained stable.

Conclusion: Eight patients (21.6%) were possible PAH and 4 (10.8%) were diagnosed as SSc-PAH by RHC after the echocardiographic screening study of 37 adult SSc patients.
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http://dx.doi.org/10.4250/jcu.2016.24.4.312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234342PMC
December 2016

Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases.

Lung 2016 10 2;194(5):745-53. Epub 2016 Jul 2.

Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, South Korea.

Objective: Lung diseases (LD) are common extra-articular manifestations in rheumatoid arthritis (RA). However, little is known about factors associated with susceptibility to rheumatoid arthritis-related lung diseases (RA-LD). The aim of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) of PADI4 and HLA-DRB1 alleles were associated with RA-LD.

Methods: Blood samples and clinical data were collected from 116 consecutive RA patients who satisfied the 1987 American College of Rheumatology classification criteria. RA-LD was diagnosed using high-resolution computed tomography of the chest. All patients were genotyped for SNPs of PADI4 and HLA-DRB1 alleles and analyzed for full amino acid sequence of the HLA protein corresponding to a 4-digit HLA typing. Data were analyzed by independent t test (or Mann-Whitney test) for continuous variables, Chi-square test (or Fisher's exact test) and trend test for categorical variables, and logistic regression analysis.

Results: Ninety-four (81.0 %) RA patients had LD, of which eight (6.9 %) had interstitial lung disease (ILD) and 92 (79.3 %) had airway abnormalities in which 64 (55.2 %) showed bronchiectasis and 47 (40.5 %) revealed bronchial wall thickening. The recessive genotype of padi4_92 was susceptible to airway abnormalities (OR = 2.22, 95 % CI = 1.05-4.49, p = 0.034). Tryptophan at position 9 of HLA-DRB1 sequence was associated with the susceptibility to RA-ILD (OR = 22.89, 95 % CI = 1.20-432.56, p = 0.037).

Conclusion: PADI4 polymorphisms and HLA-DRB1 alleles could attribute differently to the development of airway abnormalities and ILD, respectively, in RA.
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http://dx.doi.org/10.1007/s00408-016-9916-xDOI Listing
October 2016

Serum and synovial fluid concentrations of cold-inducible RNA-binding protein in patients with rheumatoid arthritis.

Int J Rheum Dis 2018 Jan 17;21(1):148-154. Epub 2016 Jun 17.

Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea.

Aim: There is growing evidence that cold-inducible RNA-binding protein (CIRP) promotes inflammatory responses. This study investigated the relationship between CIRP and rheumatoid arthritis (RA).

Methods: Peripheral blood and synovial fluid were collected from 15 patients with RA and from 16 patients with osteoarthritis (OA). The concentration of CIRP was measured with the sandwich enzyme-linked immunosorbent assay (ELISA).

Results: The concentration of serum CIRP was significantly elevated in the RA patient group (RA patients = 26.39 ± 10.48 pg/mL, OA patients = 17.14 ± 7.24 pg/mL, P = 0.009). Furthermore, the RA patient group had a significantly higher CIRP concentration than that of the OA patient group in synovial fluid (153.56 ± 108.93 pg/mL vs. 23.63 ± 16.18 pg/mL, P < 0.001). The mean synovial fluid concentration of CIRP was significantly higher than that of the serum concentration in the RA patient group (serum concentration = 26.39 ± 10.48 pg/mL, synovial fluid = 153.56 ± 108.93 pg/mL, P < 0.001). Disease Activity Score of 28 joints (DAS28)-ESR (erythrocyte sedimentation rate) and DAS28-CRP (C-reactive protein) were positively correlated with the synovial fluid concentration of CIRP (DAS28-ESR: r = 0.582, P = 0.023; DAS28-CRP: r = 0.541, P = 0.037).

Conclusion: The serum and synovial concentrations of CIRP in the RA patients were increased compared to the OA patients. Additionally, the synovial concentration of CIRP in RA patients correlated well with disease activity, that is, the DAS28-ESR/CRP. Based on these results, CIRP mediates inflammation and is a potential marker for synovial inflammation.
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http://dx.doi.org/10.1111/1756-185X.12892DOI Listing
January 2018

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis.

J Biol Chem 2016 Feb 23;291(8):4048-57. Epub 2015 Dec 23.

From the Departments of Microbiology and Immunology and the BK21Plus Biomedical Science Project, and the Seoul National University College of Medicine, Seoul 110-799, South Korea, Biomedical Sciences and the Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul National University Hospital Biomedical Research Institute, Seoul 110-799, South Korea

B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.
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http://dx.doi.org/10.1074/jbc.M115.680298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759181PMC
February 2016

Use of the cysteine-repressible HpMET3 promoter as a novel tool to regulate gene expression in Hansenula polymorpha.

Biotechnol Lett 2015 Nov 14;37(11):2237-45. Epub 2015 Jul 14.

Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, Korea.

Objectives: The promoter of HpMET3, encoding an ATP sulfurylase, was evaluated for its potential as a repressible promoter to downregulate the expression of target genes in the thermotolerant, methylotrophic yeast Hansenula polymorpha.

Results: The expression of lacZ under the control of the 0.6 kb HpMET3 promoter was efficiently downregulated by cysteine, but not by methionine or sulfate. The HpMET3 promoter was used to generate a conditional mutant of the HpPMT2 gene encoding an O-mannosyltransferase, which is involved in post-translational protein modification. The addition of 0.5 mM cysteine adversely affected the growth of the conditional HpMET3(p)-Hppmt2 mutant strain by downregulating transcription of HpPMT2 to approx. 40 % of the normal levels, indicating that the HpPMT2 gene is essential for cell viability. However, the HpMET3 promoter was neither induced nor repressed in the heterologous host Saccharomyces cerevisiae.

Conclusion: Our results reveal that the cysteine-repressible HpMET3 promoter is a useful tool that downregulates the expression of various genes in H. polymorpha.
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http://dx.doi.org/10.1007/s10529-015-1902-5DOI Listing
November 2015

Fellow-eye neovascularization in unilateral retinal angiomatous proliferation in a Korean population.

Acta Ophthalmol 2016 Feb 17;94(1):e49-53. Epub 2015 May 17.

Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, South Korea.

Purpose: To evaluate the incidence of fellow-eye neovascularization in retinal angiomatous proliferation (RAP) in a Korean population and associated risk factors.

Method: This retrospective, observational study included 81 eyes (81 patients) diagnosed with unilateral RAP who were followed up for ≥12 months. The RAP diagnosis was based on an indocyanine green angiography reviewed by two retinal specialists. In fellow eyes experiencing neovascularization, the period between RAP diagnosis and neovascularization was compared between eyes with and without reticular pseudodrusen.

Results: The mean age (±standard deviation) of the 81 patients was 74.7 ± 6.1 years. The mean follow-up period was 27.8 ± 12.4 months. Fellow-eye neovascularization was noted in 31 patients (38.3%), and 24 of these (77.4%) was a RAP subtype. Fellow-eye involvement was noted within 12 months in 13 eyes (16.0%). The period between diagnosis and fellow-eye neovascularization was significantly shorter in eyes with reticular pseudodrusen (mean 13.8 ± 8.5 months) than in eyes without reticular pseudodrusen (mean 21.2 ± 9.1 months; p = 0.031).

Conclusion: In our cohort of unilateral RAP patients, fellow-eye neovascularization was noted in 38.3% in 27.8 months. The presence of reticular pseudodrusen in the fellow eye was closely associated with relatively early onset.
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http://dx.doi.org/10.1111/aos.12748DOI Listing
February 2016

Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.

Exp Mol Med 2015 Feb 20;47:e142. Epub 2015 Feb 20.

1] Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea [2] BK21Plus Program & Department of Smart Life-Care Convergence, Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.

Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.
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http://dx.doi.org/10.1038/emm.2014.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346486PMC
February 2015

Surgical outcomes of 23-gauge vitrectomy for the management of lens fragments dropped into the vitreous cavity during cataract surgery.

Saudi J Ophthalmol 2014 Oct 3;28(4):253-6. Epub 2014 Feb 3.

Department of Ophthalmology, Kim's Eye Hospital, Myung-Gok Eye Research Institute, Konyang University College of Medicine, Seoul, Republic of Korea.

Purpose: To assess the clinical features and surgical outcomes of 23-Gauge (G) vitrectomy for lens fragments dropped into the vitreous during cataract surgery.

Methods: A retrospective, non-comparative, interventional case series at a single medical center. The medical records of 45 eyes from 45 consecutive patients who were referred to our hospital for surgical retrieval of phacoemulsification dropped lens fragments and who underwent 23-G vitrectomy were retrospectively reviewed. Data pertaining to patient demographics, pre- and post-operative Snellen visual acuity, and postoperative complications were recorded. Factors associated with dropped lens fragments were also examined.

Results: Mean patient age was 68.18 ± 11.47 years. The preoperative and postoperative mean logarithm of minimum angle of resolution (logMAR) visual acuity was 1.91 ± 0.59 (Snellen equivalent 0.06 ± 0.15) and 0.42 ± 0.51 (Snellen equivalent 0.54 ± 0.31), respectively. Forty-two eyes (93.3%) had dislocated lens fragments <50% of the total lens size. Two eyes (4.4%) had a large and hard lens nucleus, which necessitated the use of a 20-G fragmatome to efficiently and completely remove the lens material. At the final examination, 30 eyes (66.6%) had a visual acuity better than 20/40. Post-vitrectomy complications included elevated IOP for at least 3 months (n = 5 eyes, 11.1%), intraocular lens dislocation (n = 2 eyes, 4.4%), and cystoid macular edema (n = 1 eye, 2.2%). No cases of postoperative endophthalmitis or retinal detachment were observed.

Conclusions: A 23-G vitrectomy is safe and efficient for the surgical management of dropped lens fragments following cataract surgery.
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http://dx.doi.org/10.1016/j.sjopt.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250484PMC
October 2014

Intravitreal anti-vascular endothelial growth factor for typical exudative age-related macular degeneration in eyes with good baseline visual acuity.

Korean J Ophthalmol 2014 Dec 19;28(6):466-72. Epub 2014 Nov 19.

Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.

Purpose: To investigate 12-month treatment outcomes of anti-vascular endothelial growth factor therapy in eyes with typical exudative age-related macular degeneration with good baseline visual acuity.

Methods: This retrospective observational case series included 18 eyes (18 patients) with typical exudative age-related macular degeneration with a baseline best-corrected visual acuity of 20 / 25 or better. Patients were treated with anti-vascular endothelial growth factor monotherapy during the 12-month follow-up period. Baseline visual acuity and central foveal thickness were compared to the values at 12 months.

Results: Patients received an average of 4.4 ± 1.3 intravitreal anti-vascular endothelial growth factor injections. The mean logarithm of minimum angle of resolution visual acuity was 0.08 ± 0.04, 0.08 ± 0.07, 0.12 ± 0.09, and 0.16 ± 0.11 at baseline, three months, six months, and 12 months, respectively. Visual acuity at 12 months was significantly worse than the baseline value at diagnosis (p = 0.017), and the mean central foveal thickness at the defined time points was 270.2 ± 55.6, 204.4 ± 25.4, 230.1 ± 56.3, and 216.8 ± 48.7 µm, respectively. The central foveal thickness at 12 months was significantly less than the baseline value at diagnosis (p = 0.042).

Conclusions: Deterioration in visual acuity was noted in eyes with typical exudative age-related macular degeneration with good baseline visual acuity, suggesting the need for close patient monitoring and prompt treatment even in patients with good baseline visual acuity.
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http://dx.doi.org/10.3341/kjo.2014.28.6.466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239465PMC
December 2014

Functional phenotype of synovial monocytes modulating inflammatory T-cell responses in rheumatoid arthritis (RA).

PLoS One 2014 17;9(10):e109775. Epub 2014 Oct 17.

Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University, Seoul, Korea; Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul, Korea.

Monocytes function as crucial innate effectors in the pathogenesis of chronic inflammatory diseases, including autoimmunity, as well as in the inflammatory response against infectious pathogens. Human monocytes are heterogeneous and can be classified into three distinct subsets based on CD14 and CD16 expression. Although accumulating evidence suggests distinct functions of monocyte subsets in inflammatory conditions, their pathogenic roles in autoimmune diseases remain unclear. Thus, we investigated the phenotypic and functional characteristics of monocytes derived from synovial fluid and peripheral blood in RA patients in order to explore the pathogenic roles of these cells. In RA patients, CD14+CD16+, but not CD14dimCD16+, monocytes are predominantly expanded in synovial fluid and, to a lesser degree, in peripheral blood. Expression of co-signaling molecules of the B7 family, specifically CD80 and CD276, was markedly elevated on synovial monocytes, while peripheral monocytes of RA and healthy controls did not express these molecules without stimulation. To explore how synovial monocytes might gain these unique properties in the inflammatory milieu of the synovial fluid, peripheral monocytes were exposed to various stimuli. CD16 expression on CD14+ monocytes was clearly induced by TGF-β, although co-treatment with IL-1β, TNF-α, or IL-6 did not result in any additive effects. In contrast, TLR stimulation with LPS or zymosan significantly downregulated CD16 expression such that the CD14+CD16+ monocyte subset could not be identified. Furthermore, treatment of monocytes with IFN-γ resulted in the induction of CD80 and HLA-DR expression even in the presence of TGF-β. An in vitro assay clearly showed that synovial monocytes possess the unique capability to promote Th1 as well as Th17 responses of autologous peripheral CD4 memory T cells. Our findings suggest that the cytokine milieu of the synovial fluid shapes the unique features of synovial monocytes as well as their cardinal role in shaping inflammatory T-cell responses in RA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109775PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201467PMC
July 2015

Yeast synthetic biology for the production of recombinant therapeutic proteins.

FEMS Yeast Res 2015 02 14;15(1):1-16. Epub 2015 Jan 14.

Department of Life Science, Chung-Ang University, Seoul, Korea

The production of recombinant therapeutic proteins is one of the fast-growing areas of molecular medicine and currently plays an important role in treatment of several diseases. Yeasts are unicellular eukaryotic microbial host cells that offer unique advantages in producing biopharmaceutical proteins. Yeasts are capable of robust growth on simple media, readily accommodate genetic modifications, and incorporate typical eukaryotic post-translational modifications. Saccharomyces cerevisiae is a traditional baker's yeast that has been used as a major host for the production of biopharmaceuticals; however, several nonconventional yeast species including Hansenula polymorpha, Pichia pastoris, and Yarrowia lipolytica have gained increasing attention as alternative hosts for the industrial production of recombinant proteins. In this review, we address the established and emerging genetic tools and host strains suitable for recombinant protein production in various yeast expression systems, particularly focusing on current efforts toward synthetic biology approaches in developing yeast cell factories for the production of therapeutic recombinant proteins.
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http://dx.doi.org/10.1111/1567-1364.12195DOI Listing
February 2015

Novel cysteine-centered sulfur metabolic pathway in the thermotolerant methylotrophic yeast Hansenula polymorpha.

PLoS One 2014 24;9(6):e100725. Epub 2014 Jun 24.

Department of Life Science, Chung-Ang University, Seoul, Korea.

In yeast and filamentous fungi, sulfide can be condensed either with O-acetylhomoserine to generate homocysteine, the precursor of methionine, or with O-acetylserine to directly generate cysteine. The resulting homocysteine and cysteine can be interconverted through transsulfuration pathway. Here, we systematically analyzed the sulfur metabolic pathway of the thermotolerant methylotrophic yeast Hansenula polymorpha, which has attracted much attention as an industrial yeast strain for various biotechnological applications. Quite interestingly, the detailed sulfur metabolic pathway of H. polymorpha, which was reconstructed based on combined analyses of the genome sequences and validation by systematic gene deletion experiments, revealed the absence of de novo synthesis of homocysteine from inorganic sulfur in this yeast. Thus, the direct biosynthesis of cysteine from sulfide is the only pathway of synthesizing sulfur amino acids from inorganic sulfur in H. polymorpha, despite the presence of both directions of transsulfuration pathway Moreover, only cysteine, but no other sulfur amino acid, was able to repress the expression of a subset of sulfur genes, suggesting its central and exclusive role in the control of H. polymorpha sulfur metabolism. 35S-Cys was more efficiently incorporated into intracellular sulfur compounds such as glutathione than 35S-Met in H. polymorpha, further supporting the cysteine-centered sulfur pathway. This is the first report on the novel features of H. polymorpha sulfur metabolic pathway, which are noticeably distinct from those of other yeast and filamentous fungal species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069077PMC
March 2015

Patient's self-recognition of reduced visual acuity due to recurrence of macular edema and prompt visitation to the hospital in retinal vein occlusion.

Korean J Ophthalmol 2014 Jun 19;28(3):213-9. Epub 2014 May 19.

Department of Ophthalmology, Kim's Eye Hospital, Konyang University College of Medicine, Seoul, Korea.

Purpose: To evaluate patients' self-recognition of reduced visual acuity due to recurring macular edema in retinal vein occlusion.

Methods: A retrospective review of medical records of patients who were diagnosed with recurring macular edema secondary to retinal vein occlusion was performed. The proportion of patients who recognized reduced visual acuity due to the recurrence of macular edema and who visited the hospital before the scheduled follow-up date was determined. Parameters including age, sex, diagnosis, visual acuity before recurrence of macular edema, and extent of visual acuity reduction due to recurrence of macular edema were compared in patients who recognized a reduction in visual acuity and those who did not. The proportion of patients who visited the hospital promptly was also determined.

Results: Forty eyes of 40 patients were included in the analysis. Sixteen and 24 patients were diagnosed with central retinal vein occlusion and branch retinal vein occlusion, respectively. Twenty-one patients (52.5%) recognized reduced visual acuity due to recurring macular edema. These patients were younger (59.2 ± 7.6 vs. 64.8 ± 9.4 years, p = 0.046), had better visual acuity before recurrence of macular edema (0.52 ± 0.48 vs. 1.02 ± 0.46, p = 0.002), and exhibited a greater reduction in visual acuity after recurrence of macular edema (0.34 ± 0.24 vs. 0.14 ± 0.13, p = 0.003). Only four patients visited the hospital before the scheduled follow-up date, and all of these patients lived relatively close to the hospital.

Conclusions: For prompt treatment of recurring macular edema, more intensive education about the self-estimation of visual acuity is necessary, particularly for elderly patients who have relatively poor visual acuity. In addition, a simple and easy way to identify the recurrence of macular edema at the local clinic should be established for patients who live relatively far from the hospital.
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http://dx.doi.org/10.3341/kjo.2014.28.3.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038726PMC
June 2014