Publications by authors named "Wooyoung Choi"

39 Publications

The laboratory test procedure to confirm rotavirus vaccine infection in severe complex immunodeficiency patients.

Osong Public Health Res Perspect 2021 Aug 13;12(4):269-273. Epub 2021 Aug 13.

Division of Viral Diseases, Bureau of Infectious Diseases Diagnosis Control, Korea Disease Control and Prevention Agency, Cheongju, Korea.

The rotavirus vaccine is a live vaccine, and there is a possibility of infection by the virus strain used in the vaccine. We investigated the process of determining whether an infection was caused by the vaccine strain in a severe complex immunodeficiency (SCID) patient with rotavirus infection. The patient was vaccinated with RotaTeq prior to being diagnosed with SCID. The testing process was conducted in the following order: confirming rotavirus infection, determining its genotype, and confirming the vaccine strain. Rotavirus infection was confirmed through enzyme immunoassay and VP6 gene detection. G1 and P[8] were identified by multiplex polymerase chain reaction for the genotype, and G3 was further identified using a single primer. By detecting the fingerprint gene (WC3) of RotaTeq, it was confirmed that the detected virus was the vaccine strain. Genotypes G1 and P[8] were identified, and the infection was suspected of having been caused by rotavirus G1P[8]. G1P[8] is the most commonly detected genotype worldwide and is not included in the recombinant strains used in vaccines. Therefore, the infection was confirmed to have been caused by the vaccine strain by analyzing the genetic relationship between VP4 and VP7. Rotavirus infection by the vaccine strain can be identified through genotyping and fingerprint gene detection. However, genetic linkage analysis will also help to identify vaccine strains.
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http://dx.doi.org/10.24171/j.phrp.2021.0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408412PMC
August 2021

Can gait kinetic data predict femoral bone mineral density in elderly men and women aged 50 years and older?

J Biomech 2021 06 12;123:110520. Epub 2021 May 12.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, South Korea. Electronic address:

This retrospective study was conducted to investigate the correlation between kinetic gait parameters and femoral bone mineral density (BMD) in elderly subjects aged 50 years and older that could walk independently. Four hundred and twenty-six subjects (158 men and 258 women; mean age 68.7 years, standard deviation (SD) 7.9 years) were included in the study. BMDs (g/cm) of the femoral neck, trochanter, shaft, and total proximal femur were collected. Kinetic data including maximum hip power and hip power-time integral was obtained from a three-dimensional gait analysis with self-selected walking speed. Correlation between BMDs of proximal femur and gait kinetic data was analyzed. Multiple regression analysis was also performed to identify factors significantly associated with BMD. Correlation between BMD and hip kinetic data was not prominent in elderly men. In women, BMD was significantly correlated with hip kinetic data. Hip power-time integral showed greater correlation with BMD than maximum hip power during gait in elderly women. Age (p < 0.001), weight (p = 0.007) and hip power-time integral (p = 0.008) were significant factors associated with femoral neck BMD, and these factors explained 25.4% of femoral neck BMD. In conclusion, the association between the mechanical load and BMD in the different sexes provokes future research into these issues. The effects of various types of exercises on BMD should be investigated more precisely using a gait analysis tool.
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http://dx.doi.org/10.1016/j.jbiomech.2021.110520DOI Listing
June 2021

Non-Polio Enteroviruses from Acute Flaccid Paralysis Surveillance in Korea, 2012-2019.

Viruses 2021 03 5;13(3). Epub 2021 Mar 5.

Division of Viral Diseases, Korea Disease Control and Prevention Agency, Cheongju 28159, Korea.

The risk of polio importation and re-emergence persists since epidemic polio still occurs in some countries, and the resurgence of polio occurring almost 20 years after polio eradication was declared in Asia has been reported. We analyzed the results of acute flaccid paralysis (AFP) surveillance in Korea to assess the quality of AFP surveillance and understand the etiology of non-polio enterovirus (NPEV)-associated central nervous system diseases in a polio-free area. We investigated 637 AFP patients under 15 years of age whose cases were confirmed during 2012-2019 by virus isolation, real-time reverse transcription polymerase chain reaction, and VP1 gene sequencing. Among the 637 AFP cases, NPEV was detected in 213 (33.4%) patients, with the majority observed in EV-A71, with 54.9% of NPEV positives. EV-A71 has been shown to play a role as a major causative agent in most neurological diseases except for Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis (ADEM), and meningitis. This study provides information on the AFP surveillance situation in Korea and highlights the polio eradication stage in the monitoring and characterization of NPEV against the outbreak of neurological infectious diseases such as polio.
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http://dx.doi.org/10.3390/v13030411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001888PMC
March 2021

Radiographic differences in the concomitant deformities in two types of medial ankle osteoarthritis.

PLoS One 2021 3;16(3):e0247816. Epub 2021 Mar 3.

Department of Orthopedic Surgery, Seoul National University Bundang Hospital, Seongnam, South Korea.

Objectives: Motion preserving surgeries could be unsuccessful because of underestimation of deformities of the foot and knee in ankle osteoarthritis. This study aimed to investigate the concomitant deformities in medial ankle osteoarthritis and the difference between the two types, varus angulation and medial translation.

Methods: A retrospective study was conducted using medical records and radiographic data. Patients with medial ankle osteoarthritis that underwent weight-bearing X ray imaging and radiographic measurements including tibial plafond inclination (TPI), tibiotalar tilt angle (TT), lateral talo-first metatarsal angle, naviculo-cuboid overlap, and mechanical tibiofemoral angle (mTFA) were studied. The patients were categorized into two groups, the varus angulation group (TT ≥4°) and medial translation group (TT <4°). The radiographic measurements were compared between the two groups.

Results: A total of 102 patients (male = 44; female = 58) were included; the mean age was 64.9 years (SD 8.3 years). The varus rotation group (N = 66) showed a significantly smaller lateral talo-first metatarsal angle (p<0.001), naviculo-cuboid overlap (p<0.001), and mTFA (p = 0.019) compared to the medial displacement group (N = 36). The TT showed a significant correlation with lateral talo-first metatarsal angle (r = -0.520, p<0.001), naviculo-cuboid overlap (r = -0.501, p<0.001), and mTFA (r = -0.243, p = 0.014). Lateral talo-first metatarsal angle was found to be the significant factor (p = 0.018) discriminating varus angulation and medial translation types in the binary logistic analysis.

Conclusions: Varus angulation of the ankle was correlated with knee alignment and foot deformity. Radiographic indices were different between the varus angulation and medial translation groups. The role of concomitant deformities needs to be further investigated in terms of a causal relationship. Surgeons need to pay attention to concomitant deformities in the treatment of medial ankle osteoarthritis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247816PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928528PMC
March 2021

Nationwide seroprevalence of hepatitis A in South Korea from 2009 to 2019.

PLoS One 2021 8;16(2):e0245162. Epub 2021 Feb 8.

Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Osong, Republic of Korea.

Hepatitis A, an acute type of hepatitis caused by the hepatitis A virus, occurs worldwide. Following the 2009 hepatitis A epidemic in South Korea, patient outbreak reports were collectively converted to an "all-patient report" in 2011, and national immunization programs were introduced for children in 2015. In this study, we aimed to analyze the changes and characteristics of hepatitis A antibody titers in South Korea following the epidemic. The results of hepatitis A antibody tests performed at clinical laboratories from 2009 to 2019 were analyzed based on year, age, region, sex, and medical institution. The average 2009-2018 positive anti-hepatitis A virus immunoglobulin G rate was 51.8%, but it increased (56.06%) in 2019. Significantly different antibody-positive rates were observed based on age: <10 years, 54.5%; 20-29 years, 19.5%; ≥50 years, almost 100%. The positive rate of individuals in their teens and 20s gradually increased, whereas that of those in their 30s and 40s gradually decreased. Males had higher antibody-positive rates than females, and samples from higher-level general hospitals exhibited higher antibody rates. The positive anti-hepatitis A virus immunoglobulin M rates gradually decreased after 2009 and were <1% after 2012. However, a high positive rate of 3.69% was observed in 2019 when there was an epidemic. Anti-hepatitis A virus immunoglobulin G-positive rates were similar throughout the year, but the anti-hepatitis A virus immunoglobulin M-positive rates increased from January, peaked in April, and decreased from July, exhibiting distinct seasonality. This is considered to be related to groundwater pollution during the spring drought season. The introduction of the "all-patient report" and national vaccination program for children has had an effective influence on hepatitis A management. However, for hepatitis A prevention, policy considerations for high-risk age groups with low antibody-positive rates will be necessary.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245162PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870085PMC
July 2021

Outbreak associated with Rotavirus G11,P[25] in Korea in 2018.

Infect Chemother 2020 Dec 24;52(4):616-620. Epub 2020 Nov 24.

Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Osong, Korea.

We here report the first outbreak caused by rotavirus G11,P[25] in Korea in 2018, representing a case of re-assortment with pig-derived rotavirus. The genotype constellation was identical to the virus identified in Korea in 2012 as G11-P[25]-I12-R1-C1-M1-A1-N1-T1-E1-H1. The infection source was not known exactly but it must be considered infection from swine.
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http://dx.doi.org/10.3947/ic.2020.52.4.616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779978PMC
December 2020

Trends in acute viral gastroenteritis among children aged ≤5 years through the national surveillance system in South Korea, 2013-2019.

J Med Virol 2021 08 23;93(8):4875-4882. Epub 2021 Mar 23.

Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju-si, Chungcheongbuk-do, Republic of Korea.

Acute gastroenteritis is a global public health concern. This study aimed to analyze the trend and characteristics of acute viral gastroenteritis through a national surveillance network. Enteric viruses were detected in 9510 of 31,750 (30.1%) cases assessed from 2013 to 2019 by EnterNet. The most prevalent pathogens were norovirus (15.2%) and group A rotavirus (9.7%); most infections were reported in 2017 (34.0%). Norovirus and rotavirus coinfections were the most common. Norovirus infections were prevalent among 1-year-old children (1835 out of 9510 cases) during winter, and group A rotavirus infections were common during spring. Seasonality was not observed among enteric adenovirus, astrovirus, and sapovirus. The prevalent viral genotypes detected included norovirus GII.4, enteric adenovirus F41, astrovirus genotype 1, and sapovirus GI.1. However, changes in enteric virus trends were noted during the study period. Norovirus prevalence extended into spring, and new genotypes of enteric adenovirus, astrovirus, and sapovirus were identified. These surveillance data elucidate enteric virus epidemiological characteristics.
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http://dx.doi.org/10.1002/jmv.26685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360024PMC
August 2021

A Different Epidemiology of Enterovirus A and Enterovirus B Co-circulating in Korea, 2012-2019.

J Pediatric Infect Dis Soc 2021 Apr;10(4):398-407

Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Osong, Republic of Korea.

Background: Enteroviruses (EVs) occur frequently worldwide and are known to be associated with a broad spectrum of clinical manifestations from mild syndromes to neurological disease. To understand the epidemiology of EV in Korea, we characterized EV-infected cases during 2012-2019 based on national surveillance.

Methods: We collected specimens from patients with suspected EV infections and analyzed the data using real-time reverse-transcription polymerase chain reaction and VP1 gene sequencing.

Results: Among the 18 261 specimens collected, EVs were detected in 6258 (34.3%) cases. Although the most common EV types changed annually, EV-A71, echovirus 30, coxsackievirus B5, coxsackievirus A6, and coxsackievirus A10 were commonly identified. Among the human EVs, the case numbers associated with the 2 major epidemic species (EV-A and EV-B) peaked in the summer. While EV-A species affected 1-year-old children and were associated with herpangina and hand, foot, and mouth disease, EV-B species were mostly associated with neurologic manifestations. The highest incidence of EV-B species was observed in infants aged <12 months. Feces and respiratory specimens were the most predictive of EV infection. Specimens collected within 5 days of symptom onset allowed for timely virus detection.

Conclusions: EV-A and EV-B species co-circulating in Korea presented different epidemiologic trends in clinical presentation, affected subjects, and seasonality trends. This study could provide information for the characterization of EVs circulating in Korea to aid the development of EV antivirals and vaccines, as well as public health measures to control enteroviral diseases.
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http://dx.doi.org/10.1093/jpids/piaa111DOI Listing
April 2021

Correction to: Genetic diversity and evolutionary history of Korean isolates of severe fever with thrombocytopenia syndrome virus from 2013-2016.

Arch Virol 2020 Dec;165(12):3085

Pathogen Resource TF, Center for Infectious Diseases Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, 200 Osongsaengmyeong2-ro, Heungdeok-gu, Cheogju-si, Chungbuk, 28160, Republic of Korea.

Authors would like to correct the 4th author name from "Ju-Yeon Lee" to the correct version "Joo-Yeon Lee".
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http://dx.doi.org/10.1007/s00705-020-04775-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588365PMC
December 2020

An Outbreak Associated with Sapovirus GI.3 in an Elementary School in Gyeonggi-do, Korea.

J Korean Med Sci 2020 Aug 31;35(34):e281. Epub 2020 Aug 31.

Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Osong, Korea.

On October 4, 2018, an outbreak of gastroenteritis associated with sapovirus occurred among elementary school students in Gyeonggi-do, Korea. Epidemiologic studies were conducted in a retrospective cohort approach. Using self-administered questionnaires, we collected information on symptoms and food items consumed. Of the 999 subjects, 17 developed patients that met the case definition. The main symptom was vomiting (100%), and the symptomatic age was 6-12 years. Positive samples were identified by conventional reverse transcription polymerase chain reaction for sequencing. They were classified into genotype GI.3 by phylogenetic analysis. This is the first report of an outbreak associated with sapovirus GI.3 in Korea.
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http://dx.doi.org/10.3346/jkms.2020.35.e281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458851PMC
August 2020

Genetic diversity and evolutionary history of Korean isolates of severe fever with thrombocytopenia syndrome virus from 2013-2016.

Arch Virol 2020 Nov 22;165(11):2599-2603. Epub 2020 Jul 22.

Pathogen Resource TF, Center for Infectious Diseases Research, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, 200 Osongsaengmyeong2-ro, Heungdeok-gu, Cheogju-si, Chungbuk, 28160, Republic of Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV). Although SFTS originated in China, it is an emerging infectious disease with prevalence confirmed in Japan, Korea, and Vietnam. The full-length genomes of 51 Korean SFTSV isolates from 2013 to 2016 were sequenced, and the sequences were deposited into a public database (GenBank) and analyzed to elucidate the phylogeny and evolution of the virus. Although most of the Korean SFTSV isolates were closely related to previously reported Japanese isolates, some were closely related to previously reported Chinese isolates. We identified one Korean strain that appears to have resulted from multiple inter-lineage reassortments. Several nucleotide and amino acid variations specific to the Korean isolates were identified. Future studies should focus on how these variations affect virus pathogenicity and evolution.
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http://dx.doi.org/10.1007/s00705-020-04733-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547961PMC
November 2020

The structures and gating mechanism of human calcium homeostasis modulator 2.

Nature 2019 12 27;576(7785):163-167. Epub 2019 Nov 27.

Van Andel Institute, Grand Rapids, MI, USA.

Calcium homeostasis modulators (CALHMs) are voltage-gated, Ca-inhibited nonselective ion channels that act as major ATP release channels, and have important roles in gustatory signalling and neuronal toxicity. Dysfunction of CALHMs has previously been linked to neurological disorders. Here we present cryo-electron microscopy structures of the human CALHM2 channel in the Ca-free active or open state and in the ruthenium red (RUR)-bound inhibited state, at resolutions up to 2.7 Å. Our work shows that purified CALHM2 channels form both gap junctions and undecameric hemichannels. The protomer shows a mirrored arrangement of the transmembrane domains (helices S1-S4) relative to other channels with a similar topology, such as connexins, innexins and volume-regulated anion channels. Upon binding to RUR, we observed a contracted pore with notable conformational changes of the pore-lining helix S1, which swings nearly 60° towards the pore axis from a vertical to a lifted position. We propose a two-section gating mechanism in which the S1 helix coarsely adjusts, and the N-terminal helix fine-tunes, the pore size. We identified a RUR-binding site near helix S1 that may stabilize this helix in the lifted conformation, giving rise to channel inhibition. Our work elaborates on the principles of CALHM2 channel architecture and symmetry, and the mechanism that underlies channel inhibition.
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http://dx.doi.org/10.1038/s41586-019-1781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018591PMC
December 2019

Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy.

J Vis Exp 2019 01 7(143). Epub 2019 Jan 7.

Van Andel Institute;

Transient receptor potential channels (TRPCs) of the canonical TRP subfamily are nonselective cation channels that play an essential role in calcium homeostasis, particularly store-operated calcium entry, which is critical to maintaining proper function of synaptic vesicle release and intracellular signaling pathways. Accordingly, TRPC channels have been implicated in a variety of human diseases including cardiovascular disorders such as cardiac hypertrophy, neurodegenerative disorders such as Parkinson's disease, and neurologic disorders such as spinocerebellar ataxia. Therefore, TRPC channels represent a potential pharmacologic target in human diseases. However, the molecular mechanisms of gating in these channels are still unclear. The difficulty in obtaining large quantities of stable, homogeneous, and purified protein has been a limiting factor in structure determination studies, particularly for mammalian membrane proteins such as the TRPC ion channels. Here, we present a protocol for the large-scale expression of mammalian ion channel membrane proteins using a modified baculovirus gene transfer system and the purification of these proteins by affinity and size-exclusion chromatography. We further present a protocol to collect single-particle cryo-electron microscopy images from purified protein and to use these images to determine the protein structure. Structure determination is a powerful method for understanding the mechanisms of gating and function in ion channels.
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http://dx.doi.org/10.3791/58754DOI Listing
January 2019

Aerosol transmission of severe fever with thrombocytopenia syndrome virus during resuscitation.

Infect Control Hosp Epidemiol 2019 Feb 19;40(2):238-241. Epub 2018 Dec 19.

Division of Infectious Diseases, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.

We investigated potential nosocomial aerosol transmission of severe fever with thrombocytopenia syndrome virus (SFTSV) with droplet precautions. During aerosol generating procedures, SFTSV was be transmitted from person to person through aerosols. Thus, airborne precautions should be added to standard precautions to avoid direct contact and droplet transmission.
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http://dx.doi.org/10.1017/ice.2018.330DOI Listing
February 2019

Production of Ebola virus-like particles in Drosophila melanogaster Schneider 2 cells.

J Virol Methods 2018 11 23;261:156-159. Epub 2018 Aug 23.

Division of Arboviruses, Center for Immunology and Pathology, National Institute of Health, Korea Center for Disease Control & Prevention, Chungcheongbuk-do, Republic of Korea. Electronic address:

In this study, we generated recombinant virus-like particles (VLPs) against family Filoviridae, genus Ebolavirus, species Zaire ebolavirus, strain Makona (EBOV) in Drosophila melanogaster Schneider 2 (S2) cells using the EBOV Makona. S2 cells were cotransfected with four viral plasmids encoding EBOV Makona proteins and protein expression was analyzed by immunoblotting. We confirmed that EBOV Makona proteins were successfully expressed in S2 cells. Additionally, we further examined the formation of intracellular and extracellular VLPs by electron microscopy. eVLPs were produced by sucrose gradient ultracentrifugation of S2 cells transfected with EBOV Makona genes, and production of VLPs was confirmed by immunoblot analysis. Collectively, our findings showed that the S2 cell system could be a promising tool for efficient production of eVLPs.
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http://dx.doi.org/10.1016/j.jviromet.2018.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113664PMC
November 2018

Structure of the human lipid-gated cation channel TRPC3.

Elife 2018 05 4;7. Epub 2018 May 4.

Van Andel Institute, Grand Rapids, United States.

The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present a structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. We identified two lipid-binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located.
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http://dx.doi.org/10.7554/eLife.36852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967863PMC
May 2018

Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC).

Sci Rep 2018 02 13;8(1):2918. Epub 2018 Feb 13.

Northwestern University Feinberg School of Medicine, Department of Medicine, Chicago, IL, USA.

Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers. EMT was associated with exclusion of immune cells critical in the immune response to cancer, with significantly lower infiltration of CD4 T-cells in lung adenocarcinoma and CD4/CD8 T-cells in squamous cell carcinoma. EMT was also associated with increased expression of multiple immunosuppressive cytokines, including IL-10 and TGF-β. Furthermore, overexpression of targetable immune checkpoints, such as CTLA-4 and TIM-3 were associated with EMT in both NSCLCs. An association may exist between immune exclusion and EMT in NSCLC. Further investigation is merited as its mechanism is not completely understood and a better understanding of this association could lead to the development of biomarkers that could accurately predict response to immunotherapy.
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http://dx.doi.org/10.1038/s41598-018-21061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811447PMC
February 2018

Overexpression of adhesion molecules and barrier molecules is associated with differential infiltration of immune cells in non-small cell lung cancer.

Sci Rep 2018 01 18;8(1):1023. Epub 2018 Jan 18.

Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, 60611, USA.

Immunotherapy is emerging as a promising option for lung cancer treatment. Various endothelial adhesion molecules, such as integrin and selectin, as well as various cellular barrier molecules such as desmosome and tight junctions, regulate T-cell infiltration in the tumor microenvironment. However, little is known regarding how these molecules affect immune cells in patients with lung cancer. We demonstrated for the first time that overexpression of endothelial adhesion molecules and cellular barrier molecule genes was linked to differential infiltration of particular immune cells in non-small cell lung cancer. Overexpression of endothelial adhesion molecule genes is associated with significantly lower infiltration of activated CD4 and CD8 T-cells, but higher infiltration of activated B-cells and regulatory T-cells. In contrast, overexpression of desmosome genes was correlated with significantly higher infiltration of activated CD4 and CD8 T-cells, but lower infiltration of activated B-cells and regulatory T-cells in lung adenocarcinoma. This inverse relation of immune cells aligns with previous studies of tumor-infiltrating B-cells inhibiting T-cell activation. Although overexpression of endothelial adhesion molecule or cellular barrier molecule genes alone was not predictive of overall survival in our sample, these genetic signatures may serve as biomarkers of immune exclusion, or resistance to T-cell mediated immunotherapy.
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http://dx.doi.org/10.1038/s41598-018-19454-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773521PMC
January 2018

Molecular genomic characterization of tick- and human-derived severe fever with thrombocytopenia syndrome virus isolates from South Korea.

PLoS Negl Trop Dis 2017 Sep 22;11(9):e0005893. Epub 2017 Sep 22.

Division of Arboviruses, National Research Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju-si, Republic of Korea.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne viral disease caused by the SFTS virus (SFTSV) from Bunyaviridae that is endemic in East Asia. However, the genetic and evolutionary characteristics shared between tick- and human-derived Korean SFTSV strains are still limited.

Methodology/principal Findings: In this study we identify, for the first time, the genome sequence of a tick (Haemaphysalis longicornis)-derived Korean SFTSV strain (designated as KAGWT) and compare this virus with recent human SFTSV isolates to identify the genetic variations and relationships among SFTSV strains. The genome of the KAGWT strain is consistent with the described genome of other members of the genus Phlebovirus with 6,368 nucleotides (nt), 3,378 nt, and 1,746 nt in the Large (L), Medium (M) and Small (S) segments, respectively. Compared with other completely sequenced human-derived Korean SFTSV strains, the KAGWT strain had highest sequence identities at the nucleotide and deduced amino acid level in each segment with the KAGWH3 strain which was isolated from SFTS patient within the same region, although there is one unique amino acid substitution in the Gn protein (A66S). Phylogenetic analyses of complete genome sequences revealed that at least four different genotypes of SFTSV are co-circulating in South Korea, and that the tick- and human-derived Korean SFTSV strains (genotype B) are closely related to one another. Although we could not detect reassortant, which are commonly observed in segmented viruses, further large-scale surveillance and detailed genomic analysis studies are needed to better understand the molecular epidemiology, genetic diversity, and evolution of SFTSV.

Conclusions/significance: Full-length sequence analysis revealed a clear association between the genetic origins of tick- and human-derived SFTSV strains. While the most prevalent Korean SFTSV is genotype B, at least four different genotypes of SFTSV strains are co-circulating in South Korea. These findings provide information regarding the molecular epidemiology, genetic diversity, and evolution of SFTSV in East Asia.
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http://dx.doi.org/10.1371/journal.pntd.0005893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627960PMC
September 2017

One-Step Reverse Transcription-Polymerase Chain Reaction for Ebola and Marburg Viruses.

Osong Public Health Res Perspect 2016 Jun 6;7(3):205-9. Epub 2016 May 6.

Division of Arboviruses, Center for Immunology and Pathology, Korea National Institute of Health, Cheongju, Korea.

Objectives: Ebola and Marburg viruses (EBOVs and MARVs, respectively) are causative agents of severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. In 2014, there was a major Ebola outbreak in various countries in West Africa, including Guinea, Liberia, Republic of Sierra Leone, and Nigeria. EBOV and MARV are clinically difficult to diagnose and distinguish from other African epidemic diseases. Therefore, in this study, we aimed to develop a method for rapid identification of the virus to prevent the spread of infection.

Methods: We established a conventional one-step reverse transcription-polymerase chain reaction (RT-PCR) assay for these pathogens based on the Superscript Reverse Transcriptase-Platinum Taq polymerase enzyme mixture. All assays were thoroughly optimized using in vitro-transcribed RNA.

Results: We designed seven primer sets of nucleocapsid protein (NP) genes based on sequences from seven filoviruses, including five EBOVs and two MARVs. To evaluate the sensitivity of the RT-PCR assay for each filovirus, 10-fold serial dilutions of synthetic viral RNA transcripts of EBOV or MARV NP genes were used to assess detection limits of viral RNA copies. The potential for these primers to cross react with other filoviruses was also examined. The results showed that the primers were specific for individual genotype detection in the examined filoviruses.

Conclusion: The assay established in this study may facilitate rapid, reliable laboratory diagnosis in suspected cases of Ebola and Marburg hemorrhagic fevers.
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http://dx.doi.org/10.1016/j.phrp.2016.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927680PMC
June 2016

Molecular detection of severe fever with thrombocytopenia syndrome and tick-borne encephalitis viruses in ixodid ticks collected from vegetation, Republic of Korea, 2014.

Ticks Tick Borne Dis 2016 07 9;7(5):970-978. Epub 2016 May 9.

Division of Arboviruses, National Institute of Health, Korea Centers for Disease Control and Prevention, Cheongju-si, Chungcheongbuk-do (Province), 28159, Republic of Korea. Electronic address:

Ticks play an important role in transmission of arboviruses responsible for emerging infectious diseases, and have a significant impact on human, veterinary, and wildlife health. In the Republic of Korea (ROK), little is known about information regarding the presence of tick-borne viruses and their vectors. A total of 21,158 ticks belonging to 3 genera and 6 species collected at 6 provinces and 4 metropolitan areas in the ROK from March to October 2014 were assayed for selected tick-borne pathogens. Haemaphysalis longicornis (n=17,570) was the most numerously collected, followed by Haemaphysalis flava (n=3317), Ixodes nipponensis (n=249), Amblyomma testudinarium (n=11), Haemaphysalis phasiana (n=8), and Ixodes turdus (n=3). Ticks were pooled (adults 1-5, nymphs 1-30, and larvae 1-50) and tested by one-step reverse transcription polymerase chain reaction (RT-PCR) or nested RT-PCR for the detection of severe fever with thrombocytopenia virus (SFTSV), tick-borne encephalitis virus (TBEV), Powassan virus (POWV), Omsk hemorrhagic fever virus (OHFV), and Langat virus (LGTV). The overall maximum likelihood estimation (MLE) [estimated numbers of viral RNA positive ticks/1000 ticks] for SFTSV and TBEV was 0.95 and 0.43, respectively, while, all pools were negative for POWV, OHFV, and LGTV. The purpose of this study was to determine the prevalence of SFTSV, TBEV, POWV, OHFV, and LGTV in ixodid ticks collected from vegetation in the ROK to aid our understanding of the epidemiology of tick-borne viral diseases. Results from this study emphasize the need for continuous tick-based arbovirus surveillance to monitor the emergence of tick-borne diseases in the ROK.
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http://dx.doi.org/10.1016/j.ttbdis.2016.05.003DOI Listing
July 2016

First Isolation of Severe Fever with Thrombocytopenia Syndrome Virus from Haemaphysalis longicornis Ticks Collected in Severe Fever with Thrombocytopenia Syndrome Outbreak Areas in the Republic of Korea.

Vector Borne Zoonotic Dis 2016 Jan 8;16(1):66-70. Epub 2016 Jan 8.

1 Division of Arboviruses, National Institute of Health , Korea Centers for Disease Control and Prevention, Cheongju-si, Republic of Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease that is endemic to China, Japan, and the Republic of Korea (ROK). In this study, 8313 ticks collected from SFTS outbreak areas in the ROK in 2013 were used to detect the SFTS virus (SFTSV). A single SFTSV was isolated in cell culture from one pool of Haemaphysalis longicornis ticks collected from Samcheok-si, Gangwon Province, in the ROK. Phylogenetic analysis showed that the SFTSV isolate was clustered with the SFTSV strain from Japan, which was isolated from humans. To the best of our knowledge, this is the first isolation in the world of SFTSV in ticks collected from vegetation.
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http://dx.doi.org/10.1089/vbz.2015.1832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742983PMC
January 2016

Needle-Stick Injury Caused by a Patient With Severe Fever With Thrombocytopenia Syndrome in Korea.

Infect Control Hosp Epidemiol 2016 Mar 7;37(3):368-9. Epub 2016 Jan 7.

2Division of Arboviruses,National Institute of Health,Korea Centers for Disease Control and Prevention,Choungcheonbuk-do,Republic of Korea.

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http://dx.doi.org/10.1017/ice.2015.322DOI Listing
March 2016

Full-genome sequences of severe Fever with thrombocytopenia syndrome virus, isolated from South Korea in 2014.

Genome Announc 2015 Apr 16;3(2). Epub 2015 Apr 16.

Division of Biosafety Evaluation and Control, Korea National Institute of Health, Korea Center for Disease Control and Prevention, Chungcheongbuk-do, Republic of Korea

Here, we present the full-length genome sequencing of severe fever with thrombocytopenia syndrome (SFTS) virus, isolated from South Korea in 2014. The five Korean strains were compared by phylogenetic analysis with full SFTS genome sequences of two neighboring nations, China and Japan.
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http://dx.doi.org/10.1128/genomeA.00181-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400419PMC
April 2015

Nosocomial transmission of severe fever with thrombocytopenia syndrome in Korea.

Clin Infect Dis 2015 Jun 18;60(11):1681-3. Epub 2015 Feb 18.

Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Of the 27 healthcare workers (HCWs) who had contact with a fatally ill patient with severe thrombocytopenia syndrome in Korea (SFTS), 4 who were involved in cardiopulmonary resuscitation complained of fever and were diagnosed with SFTS via seroconversion. Exposure to respiratory secretions, blood, or gowns soiled by body fluids was significantly associated with infection of HCWs.
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http://dx.doi.org/10.1093/cid/civ128DOI Listing
June 2015

Cloning and Expression of Recombinant Tick-Borne Encephalitis Virus-like Particles in Pichia pastoris.

Osong Public Health Res Perspect 2014 Oct 4;5(5):274-8. Epub 2014 Sep 4.

Division of Arboviruses, Korea National Institute of Health, Cheongju, Korea.

Objectives: The purpose of this study was to verify the feasibility of using the glyceraldehyde-3-phosphate dehydrogenase (GAP) promotor based Pichia pastoris expression system to produce tick-borne encephalitis virus (TBEV) virus-like particles (VLPs).

Methods: The complementary DNA encoding the TBEV prM signal peptide, prM, and E proteins of TBEV Korean strain (KrM 93) was cloned into the plasmid vector pGAPZɑA, then integrated into the genome of P. pastoris, under the control of the GAP promoter. Expression of TBEV VLPs was determined by Western blotting using monoclonal antibody against TBEV envelope (E) protein.

Results: Recombinant TBEV VLPs consisting of prM and E protein were successfully expressed using the GAP promoter-based P. pastoris expression system. The results of Western blotting showed that the recombinant proteins were secreted into the culture supernatant from the P. pastoris and glycosylated.

Conclusion: This study suggests that recombinant TBEV VLPs from P. pastoris offer a promising approach to the production of VLPs for use as vaccines and diagnostic antigens.
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http://dx.doi.org/10.1016/j.phrp.2014.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225587PMC
October 2014

Generation and Characterization of Recombinant Influenza A(H1N1) Viruses Resistant to Neuraminidase Inhibitors.

Osong Public Health Res Perspect 2013 Dec 26;4(6):323-8. Epub 2013 Oct 26.

Division of Influenza Virus, Korea National Institute of Health, Osong, Korea.

Objectives: To examine the effect of neuraminidase (NA) mutations on the NA inhibitor (NAI) resistance phenotype, the recombinant influenza A/Chungbuk/4448/2008(H1N1) virus isolated in South Korea during the 2008-2009 season was generated by reverse genetics.

Methods: Site-directed mutagenesis was introduced on the NA gene of A/Chungbuk/4448/2008(H1N1) virus, and a total of 23 single, double, and triple mutants were generated. Resistance phenotype of these recombinant viruses was determined by NA-inhibition (NAI) assays based on a fluorometric method using two NAIs (oseltamivir and zanamivir).

Results: NA-inhibition assays showed that all the single and double mutants containing the Y275 except the single Y275-E119V mutant conferred important levels of resistance to oseltamivir, whereas all the single, double, and triple mutants containing the E119V mutation were associated with the resistance to zanamivir.

Conclusion: Considering the effect of mutations in NA gene on the resistance to NAIs, it is important to monitor the possible emergence and dissemination of multidrug-resistant variants in the human population due to amino acid changes at NA gene as well as to develop novel NAIs.
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http://dx.doi.org/10.1016/j.phrp.2013.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922101PMC
December 2013

Prevalence of tick-borne encephalitis virus in ixodid ticks collected from the republic of Korea during 2011-2012.

Osong Public Health Res Perspect 2012 Dec;3(4):213-21

Division of Arboviruses, Korea National Institute of Health, Osong, Korea.

Objectives: In this study, we demonstrated that TBEV-infected ticks have been distributed in the ROK, combined with our previous results. These results suggest that TBEV may exist in the ROK, and H. longicornis, H. flava, and I. nipponensis may be potential vectors of TBEV. In addition, these results emphasize the need for further epidemiological research of TBEV.

Methods: We examined for the presence of RNA of TBEV by reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) using ixodid ticks captured in 25 localities of 10 provinces. Ticks were collected by the flagging and dragging method or using sentinel BG traps at forests, grass thickets, and grassland. A total of 13,053 ticks belonging to two genera and four species were collected and pooled (1292 pools), according to collection site, species of tick, and developmental stage.

Results: Among 1292 pools, the envelope (E) protein gene of TBEV was detected using RT-nested PCR in 10 pools (3 pools of the 1,331 adult ticks and 7 pools of the 11,169 nymph ticks) collected from Gangwon-do province, Jeonrabuk-do province, and Jeju Island. The minimum infection rates for TBEV of Haemaphysalis longicornis, Haemaphysalis flava, and Ixodes nipponensis were 0.06%, 0.17%, and 2.38%, respectively. Phylogenetic analysis based on the partial E protein gene was performed to identify relationships between the TBEV strains. This showed that 10 Korean strains clustered with the Western subtype.

Conclusion: In this study, we investigated the prevalence of tick-borne encephalitis virus (TBEV) in ixodid ticks from various regions of the Republic of Korea (ROK) during 2011-2012 to identify whether TBEV is circulating and to determine the endemic regions of TBEV.
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http://dx.doi.org/10.1016/j.phrp.2012.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747658PMC
December 2012

Mechanistic insights into CED-4-mediated activation of CED-3.

Genes Dev 2013 Sep;27(18):2039-48

Ministry of Education Protein Science Laboratory, Center for Structural Biology, School of Life Sciences.

Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4-CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 Å resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4-CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.
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http://dx.doi.org/10.1101/gad.224428.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792479PMC
September 2013
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