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Article ; Online: The Role of the Stem-Loop A RNA Promoter in Flavivirus Replication.

Choi, Kyung H

2021 Volume 13, Issue 6

Abstract: An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly ...

Abstract	An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In flaviviruses, the 5'-end of the viral RNA genome contains a 70 nucleotide-long stem-loop, called stem-loop A (SLA), which functions as a promoter for genome replication. During replication, flaviviral polymerase NS5 specifically recognizes SLA to both initiate viral RNA synthesis and to methylate the 5' guanine cap of the nascent RNA. While the sequences of this region vary between different flaviviruses, the three-way junction arrangement of secondary structures is conserved in SLA, suggesting that viruses recognize a common structural feature to replicate the viral genome rather than a particular sequence. To better understand the molecular basis of genome recognition by flaviviruses, we recently determined the crystal structures of flavivirus SLAs from dengue virus (DENV) and Zika virus (ZIKV). In this review, I will provide an overview of (1) flaviviral genome replication; (2) structures of viral SLA promoters and NS5 polymerases; and (3) and describe our current model of how NS5 polymerases specifically recognize the SLA at the 5' terminus of the viral genome to initiate RNA synthesis at the 3' terminus.
MeSH term(s)	Binding Sites ; Flavivirus/genetics ; Flavivirus/physiology ; Genome, Viral ; Inverted Repeat Sequences ; Promoter Regions, Genetic ; Protein Binding ; RNA, Viral/genetics ; Virus Replication/genetics ; Virus Replication/physiology
Chemical Substances	RNA, Viral
Language	English
Publishing date	2021-06-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13061107
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: High-resolution RNA tertiary structures in Zika virus stem-loop A for the development of inhibitory small molecules.

Tipo, Jerricho / Gottipati, Keerthi / Choi, Kyung H

RNA (New York, N.Y.)

2024

Abstract: Flaviviruses such as Zika (ZIKV) and dengue virus (DENV) are positive-sense RNA viruses belonging to Flaviviridae. The flavivirus genome contains a 5' end stem-loop promoter sequence known as stem-loop A (SLA) that is recognized by the flavivirus ... ...

Abstract	Flaviviruses such as Zika (ZIKV) and dengue virus (DENV) are positive-sense RNA viruses belonging to Flaviviridae. The flavivirus genome contains a 5' end stem-loop promoter sequence known as stem-loop A (SLA) that is recognized by the flavivirus polymerase NS5 during viral RNA synthesis and 5' guanosine cap methylation. The crystal structures of ZIKV and DENV SLAs show a well-defined fold, consisting of a bottom stem, side loop, and top stem-loop, providing unique interaction sites for small-molecule inhibitors to disrupt the promoter function. To facilitate identification of small molecule binding sites in flavivirus SLA, we determined high-resolution structures of bottom and top stems of ZIKV SLA, which contain a single U- or G-bulge, respectively. Both bulge nucleotides exhibit multiple orientations, from folded back on the adjacent nucleotide to flipped out of the helix, and are stabilized by stacking or base triple interactions. These structures suggest that even a single unpaired nucleotide can provide flexibility to RNA structures and its conformation is mainly determined by the stabilizing chemical environment. To facilitate discovery of small molecule inhibitors that interfere with the functions of ZIKV SLA, we screened and identified compounds that bind to the bottom and top stems of ZIKV SLA.
Language	English
Publishing date	2024-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079796.123
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Zs.A 4777: Show issues

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Article: A remineralizing orthodontic etchant that utilizes calcium phosphate ion clusters.

Kim, Hyeryeong / Yoo, Kyung-Hyeon / Yoon, Seog-Young / Choi, Youn-Kyung / Kim, Yong-Il

Frontiers in bioengineering and biotechnology

2022 Volume 10, Page(s) 944869

Abstract: This study aimed to investigate whether a phosphoric acid (H ...

Abstract	This study aimed to investigate whether a phosphoric acid (H
Language	English
Publishing date	2022-08-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2719493-0
ISSN	2296-4185
ISSN	2296-4185
DOI	10.3389/fbioe.2022.944869
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Article: The Role of the Stem-Loop A RNA Promoter in Flavivirus Replication

Choi, Kyung H.

Viruses. 2021 June 09, v. 13, no. 6

2021

Abstract	An essential challenge in the lifecycle of RNA viruses is identifying and replicating the viral genome amongst all the RNAs present in the host cell cytoplasm. Yet, how the viral polymerase selectively recognizes and copies the viral RNA genome is poorly understood. In flaviviruses, the 5′-end of the viral RNA genome contains a 70 nucleotide-long stem-loop, called stem-loop A (SLA), which functions as a promoter for genome replication. During replication, flaviviral polymerase NS5 specifically recognizes SLA to both initiate viral RNA synthesis and to methylate the 5′ guanine cap of the nascent RNA. While the sequences of this region vary between different flaviviruses, the three-way junction arrangement of secondary structures is conserved in SLA, suggesting that viruses recognize a common structural feature to replicate the viral genome rather than a particular sequence. To better understand the molecular basis of genome recognition by flaviviruses, we recently determined the crystal structures of flavivirus SLAs from dengue virus (DENV) and Zika virus (ZIKV). In this review, I will provide an overview of (1) flaviviral genome replication; (2) structures of viral SLA promoters and NS5 polymerases; and (3) and describe our current model of how NS5 polymerases specifically recognize the SLA at the 5′ terminus of the viral genome to initiate RNA synthesis at the 3′ terminus.
Keywords	Dengue virus ; RNA ; Zika virus ; cytoplasm ; guanine ; models ; viral genome
Language	English
Dates of publication	2021-0609
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13061107
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Article ; Online: Trajectory of lung function in diabetic adults: A 16-year follow-up study of community-based prospective cohorts.

Choi, Wonsuk / Moon, Joon Ho / Choi, Hayoung / Lee, Hyun / Kim, Hee Kyung / Kang, Ho-Cheol / Cho, Nam H

Respirology (Carlton, Vic.)

2024 Volume 29, Issue 5, Page(s) 413–420

Abstract: Background and objective: To investigate the difference in lung function according to diabetes status in a community-based prospective study.: Methods: Individuals aged 40-69 years from two community-based cohorts were followed prospectively for 16 ... ...

Abstract	Background and objective: To investigate the difference in lung function according to diabetes status in a community-based prospective study. Methods: Individuals aged 40-69 years from two community-based cohorts were followed prospectively for 16 years. A spirometer was used to evaluate lung function at baseline, and lung function tests were carried out biennially thereafter. Multivariable linear regression analysis was performed for the cross-sectional and longitudinal analyses based on diabetes status. Results: Among the 6483 subjects, 2114 (32.6%) had prediabetes and 671 (10.4%) had diabetes. The prediabetes and diabetes groups had lower baseline % predicted values of forced expiratory volume in 1 s (FEV Conclusion: Diabetes is associated with a lower baseline lung function and a faster rate of deterioration.
MeSH term(s)	Adult ; Humans ; Follow-Up Studies ; Prospective Studies ; Prediabetic State/epidemiology ; Cross-Sectional Studies ; Diabetes Mellitus/epidemiology ; Forced Expiratory Volume ; Vital Capacity ; Lung
Language	English
Publishing date	2024-01-07
Publishing country	Australia
Document type	Journal Article
ZDB-ID	1435849-9
ISSN	1440-1843 ; 1323-7799
ISSN (online)	1440-1843
ISSN	1323-7799
DOI	10.1111/resp.14658
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Zs.A 4957: Show issues

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Article ; Online: Effect of physical activity on incident atrial fibrillation in individuals with varying duration of diabetes: a nationwide population study.

Choi, JungMin / Lee, So-Ryoung / Choi, Eue-Keun / Lee, Kyung-Yeon / Ahn, Hyo-Jeong / Kwon, Soonil / Han, Kyung-Do / Oh, Seil / Lip, Gregory Y H

Cardiovascular diabetology

2024 Volume 23, Issue 1, Page(s) 115

Abstract: Background: Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF ... ...

Abstract	Background: Diabetes mellitus (DM) duration affects incident atrial fibrillation (AF) risk; the effect of physical activity on mitigating AF risk related to varying DM duration remains unknown. We assessed the effect of physical activity on incident AF in patients with DM with respect to known DM duration. Methods: Patients with type 2 DM who underwent the Korean National Health Insurance Service health examination in 2015-2016 were grouped by DM duration: new onset and < 5, 5-9, and ≥ 10 years. Physical activity was classified into four levels: 0, < 500, 500-999, 1,000-1,499, and ≥ 1,500 metabolic equivalent task (MET)-min/week, with the primary outcome being new-onset AF. Results: The study enrolled 2,392,486 patients (aged 59.3 ± 12.0 years, 39.8% female) with an average follow-up of 3.9 ± 0.8 years and mean DM duration of 5.3 ± 5.1 years. Greater physical activity was associated with a lower AF risk. Lowering of incident AF risk varied with different amounts of physical activity in relation to known DM duration. Among patients with new-onset DM, DM duration < 5 years and 5-9 years and 1,000-1,499 MET-min/week exhibited the lowest AF risk. Physical activity ≥ 1,500 MET-min/week was associated with the lowest incident AF risk in patients with DM duration ≥ 10 years (by 15%), followed DM duration of 5-9 years (12%) and < 5 years (9%) (p-for-interaction = 0.002). Conclusions: Longer DM duration was associated with a high risk of incident AF, while increased physical activity generally reduced AF risk. Engaging in > 1,500 MET-min/week was associated with the greatest AF risk reduction in patients with longer DM duration, highlighting the potential benefits of higher activity levels for AF prevention.
MeSH term(s)	Humans ; Female ; Male ; Atrial Fibrillation/diagnosis ; Atrial Fibrillation/epidemiology ; Atrial Fibrillation/prevention & control ; Risk Factors ; Incidence ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/epidemiology ; Diabetes Mellitus, Type 2/complications ; Exercise
Language	English
Publishing date	2024-03-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2093769-6
ISSN	1475-2840 ; 1475-2840
ISSN (online)	1475-2840
ISSN	1475-2840
DOI	10.1186/s12933-024-02194-2
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Article ; Online: Association between antithrombotic therapy after stroke in patients with atrial fibrillation and the risk of net clinical outcome: an observational cohort study.

Ahn, Hyo-Jeong / Lee, So-Ryoung / Choi, JungMin / Lee, Kyung-Yeon / Kwon, Soonil / Choi, Eue-Keun / Oh, Seil / Lip, Gregory Y H

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

2024 Volume 26, Issue 2

Abstract: Aims: Data on the optimal use of antithrombotic drugs and associated clinical outcomes in patients with atrial fibrillation (AF) and acute ischaemic stroke (IS) are limited. We investigated the prescription patterns of antithrombotics in community ... ...

Abstract	Aims: Data on the optimal use of antithrombotic drugs and associated clinical outcomes in patients with atrial fibrillation (AF) and acute ischaemic stroke (IS) are limited. We investigated the prescription patterns of antithrombotics in community practice and long-term clinical prognosis according to early post-stroke antithrombotic therapy in patients with AF and acute IS. Methods and results: Patients with AF who were admitted for acute IS at a single tertiary hospital in 2010-2020 were retrospectively reviewed. Clinical profiles including the aetiology of stroke and prescription patterns of antithrombotics were identified. The net clinical outcome (NCO)-the composite of recurrent stroke, any bleeding, hospitalization or emergency department visits for cardiovascular (CV) events, and death-was compared according to the antithrombotic therapy at the first outpatient clinic visit [oral anticoagulation (OAC) alone vs. antiplatelet (APT) alone vs. OAC/APT(s)] following discharge. A total of 918 patients with AF and acute IS (mean age, 72.6 years; male, 59.3%; mean CHA₂DS₂-VASc score 3.3) were analysed. One-third (33.9%, n = 310) of patients were simultaneously diagnosed with AF and IS. The most common aetiology of IS was cardioembolism (71.2%), followed by undetermined aetiology (19.8%) and large artery atherosclerosis (6.0%). OAC, APT(s), and concomitant OAC and APT(s) were prescribed in 33.4%, 11.1%, and 53.4% of patients during admission that changed to 67.0%, 9.1%, and 21.7% at the first outpatient clinic, and were mostly continued up to one year after IS. Non-prescription of OAC was observed in 11.3% of post-stroke patients with AF. During a median follow-up of 2.1 years, the overall incidence rate of NCO per 100 patient-year (PY) was 20.14. APT(s) monotherapy presented the highest cumulative risk of NCO (adjusted hazard ratio 1.47, 95% confidence interval 1.08-2.00, P = 0.015; with reference to OAC monotherapy) mainly driven by the highest rates of recurrent stroke and any bleeding. OAC/APT(s) combination therapy was associated with a 1.62-fold significantly higher risk of recurrent stroke (P = 0.040) and marginally higher risk of any bleeding than OAC monotherapy. Conclusion: Approximately one-third of acute IS in AF have a distinctive mechanism from cardioembolism. Although APT was frequently prescribed in post-stroke patients with AF, no additive clinical benefit was observed. Adherence to OAC treatment is essential to prevent further CV adverse events in patients with AF and IS.
MeSH term(s)	Humans ; Male ; Aged ; Stroke/diagnosis ; Stroke/epidemiology ; Stroke/etiology ; Atrial Fibrillation/diagnosis ; Atrial Fibrillation/drug therapy ; Atrial Fibrillation/epidemiology ; Fibrinolytic Agents/adverse effects ; Anticoagulants/adverse effects ; Platelet Aggregation Inhibitors/adverse effects ; Retrospective Studies ; Brain Ischemia ; Risk Factors ; Hemorrhage/chemically induced ; Cohort Studies ; Ischemic Stroke ; Treatment Outcome ; Administration, Oral
Chemical Substances	Fibrinolytic Agents ; Anticoagulants ; Platelet Aggregation Inhibitors
Language	English
Publishing date	2024-01-29
Publishing country	England
Document type	Observational Study ; Journal Article
ZDB-ID	1449879-0
ISSN	1532-2092 ; 1099-5129
ISSN (online)	1532-2092
ISSN	1099-5129
DOI	10.1093/europace/euae033
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Zs.A 5434: Show issues

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Article ; Online: Flavivirus proteases: The viral Achilles heel to prevent future pandemics.

Teramoto, Tadahisa / Choi, Kyung H / Padmanabhan, Radhakrishnan

Antiviral research

2022 Volume 210, Page(s) 105516

Abstract: Flaviviruses are important human pathogens and include dengue (DENV), West Nile (WNV), Yellow fever virus (YFV), Japanese encephalitis (JEV) and Zika virus (ZIKV). DENV, transmitted by mosquitoes, causes diseases ranging in severity from mild dengue ... ...

Abstract	Flaviviruses are important human pathogens and include dengue (DENV), West Nile (WNV), Yellow fever virus (YFV), Japanese encephalitis (JEV) and Zika virus (ZIKV). DENV, transmitted by mosquitoes, causes diseases ranging in severity from mild dengue fever with non-specific flu-like symptoms to fatal dengue hemorrhagic fever and dengue shock syndrome. DENV infections are caused by four serotypes, DENV1-4, which interact differently with antibodies in blood serum. The incidence of DENV infection has increased dramatically in recent decades and the CDC estimates 400 million dengue infections occur each year, resulting in ∼25,000 deaths mostly among children and elderly people. Similarly, ZIKV infections are caused by infected mosquito bites to humans, can be transmitted sexually and through blood transfusions. If a pregnant woman is infected, the virus can cross the placental barrier and can spread to her fetus, causing severe brain malformations in the child including microcephaly and other birth defects. It is noteworthy that the neurological manifestations of ZIKV were also observed in DENV endemic regions, suggesting that pre-existing antibody response to DENV could augment ZIKV infection. WNV, previously unknown in the US (and known to cause only mild disease in Middle East), first arrived in New York city in 1999 (NY99) and spread throughout the US and Canada by Culex mosquitoes and birds. WNV is now endemic in North America. Thus, emerging and re-emerging flaviviruses are significant threat to human health. However, vaccines are available for only a limited number of flaviviruses, and antiviral therapies are not available for any flavivirus. Hence, there is an urgent need to develop therapeutics that interfere with essential enzymatic steps, such as protease in the flavivirus lifecycle as these viruses possess significant threat to future pandemics. In this review, we focus on our E. coli expression of NS2B hydrophilic domain (NS2BH) covalently linked to NS3 protease domain (NS3Pro) in their natural context which is processed by the combined action of both subunits of the NS2B-NS3Pro precursor. Biochemical activities of the viral protease such as solubility and autoproteolysis of NS2BH-NS3Pro linkage depended on the C-terminal portion of NS2BH linked to the NS3Pro domain. Since 2008, we also focus on the use of the recombinant protease in high throughput screens and characterization of small molecular compounds identified in these screens.
MeSH term(s)	Animals ; Female ; Humans ; Pregnancy ; Dengue/prevention & control ; Dengue Virus ; Flavivirus/enzymology ; Pandemics ; Peptide Hydrolases ; Placenta ; Zika Virus ; Zika Virus Infection/prevention & control ; Flavivirus Infections/prevention & control
Chemical Substances	Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2022-12-29
Publishing country	Netherlands
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2022.105516
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Zs.A 1627: Show issues

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Article ; Online: Impact of Physical Activity on Clinical Outcomes in AF Patients Undergoing Catheter Ablation.

Kwon, Soonil / Lee, So-Ryoung / Choi, Eue-Keun / Lee, Seung-Woo / Han, Kyung-Do / Ahn, Hyo-Jeong / Oh, Seil / Lip, Gregory Y H

JACC. Asia

2023 Volume 3, Issue 5, Page(s) 819–820

Language	English
Publishing date	2023-10-17
Publishing country	United States
Document type	Journal Article
ISSN	2772-3747
ISSN (online)	2772-3747
DOI	10.1016/j.jacasi.2023.08.008
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Article: Combination of early rhythm control and healthy lifestyle on the risk of stroke in elderly patients with new-onset atrial fibrillation: a nationwide population-based cohort study.

Lim, Woo-Hyun / Lee, So-Ryoung / Choi, Eue-Keun / Lee, Seung-Woo / Han, Kyung-Do / Oh, Seil / Lip, Gregory Y H

Frontiers in cardiovascular medicine

2024 Volume 11, Page(s) 1346414

Abstract: Background: The impact of early rhythm control (ERC) combined with healthy lifestyle (HLS) on the risk of ischemic stroke in elderly patients with atrial fibrillation (AF) remains unaddressed.: Objective: To evaluate the impact of combined ERC and ... ...

Abstract	Background: The impact of early rhythm control (ERC) combined with healthy lifestyle (HLS) on the risk of ischemic stroke in elderly patients with atrial fibrillation (AF) remains unaddressed. Objective: To evaluate the impact of combined ERC and HLS on the risk of stroke in elderly patients with new-onset AF. Methods: Using the Korean National Health Insurance Service database, we included patients aged ≥75 years with new-onset AF from January 2009 to December 2016 ( Results: Median follow-up duration of the study cohort was 3.4 years. After adjusting for multiple variables, groups 2 and 3 were associated with a lower stroke risk (adjusted hazard ratio [aHR]: 95% confidence interval [CI]: 0.867, 0.794-0.948 and 0.713, 0.637-0.798, respectively) than that of group 1. Compared to Group 1, group 4 showed the lowest stroke risk (aHR: 0.694, 95% CI: 0.586-0.822) among all groups, followed by group 3 (0.713, 0.637-0.798) and group 2 (0.857, 0.794-0.948), respectively. Group 4 was associated with the lowest risk of all-cause death (aHR: 0.680, 95% CI: 0.613-0.754) and the composite outcome (aHR: 0.708, 95% CI: 0.649-0.772). Conclusion: ERC and HLS were associated with a lower risk of ischemic stroke in elderly patients with new-onset AF. Concurrently implementing ERC and maintaining HLS was associated with the lowest risk of death and the composite outcome, with a modest synergistic effect on stroke prevention.
Language	English
Publishing date	2024-02-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2781496-8
ISSN	2297-055X
ISSN	2297-055X
DOI	10.3389/fcvm.2024.1346414
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