78 results on '"Huh E"'
Search Results
2. The Modeling and Traffic Feedback Control for QoS Management on Local Network
- Author
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Park, Jongjin, Huh, E. -N., Mun, Y., Lee, B. -G., Goos, Gerhard, editor, Hartmanis, Juris, editor, van Leeuwen, Jan, editor, Kumar, Vipin, editor, Gavrilova, Marina L., editor, Tan, Chih Jeng Kenneth, editor, and L’Ecuyer, Pierre, editor
- Published
- 2003
- Full Text
- View/download PDF
3. Accommodating QoS Prediction in an Adaptive Resource Management Framework
- Author
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Huh, E., Welch, L. R., Shirazi, B. A., Tjaden, B., Cavanaugh, C. D., and Rolim, José, editor
- Published
- 2000
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4. Risk-Aware Energy Scheduling for Edge Computing with Microgrid : A Multi-Agent Deep Reinforcement Learning Approach
- Author
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Munir, M. S., Abedin, Sarder, Tran, N. H., Han, Z., Huh, E., Hong, C. S., Munir, M. S., Abedin, Sarder, Tran, N. H., Han, Z., Huh, E., and Hong, C. S.
- Abstract
In recent years, multi-access edge computing (MEC) is a key enabler for handling the massive expansion of Internet of Things (IoT) applications and services. However, energy consumption of a MEC network depends on volatile tasks that induces risk for energy demand estimations. As an energy supplier, a microgrid can facilitate seamless energy supply. However, the risk associated with energy supply is also increased due to unpredictable energy generation from renewable and non-renewable sources. Especially, the risk of energy shortfall is involved with uncertainties in both energy consumption and generation. In this paper, we study a risk-aware energy scheduling problem for a microgrid-powered MEC network. First, we formulate an optimization problem considering the conditional value-at-risk (CVaR) measurement for both energy consumption and generation, where the objective is to minimize the expected residual of scheduled energy for the MEC networks and we show this problem is an NP-hard problem. Second, we analyze our formulated problem using a multi-agent stochastic game that ensures the joint policy Nash equilibrium, and show the convergence of the proposed model. Third, we derive the solution by applying a multi-agent deep reinforcement learning (MADRL)-based asynchronous advantage actor-critic (A3C) algorithm with shared neural networks. This method mitigates the curse of dimensionality of the state space and chooses the best policy among the agents for the proposed problem. Finally, the experimental results establish a significant performance gain by considering CVaR for high accuracy energy scheduling of the proposed model than both the single and random agent models.
- Published
- 2021
- Full Text
- View/download PDF
5. Dynamic Threshold for Monitor Systems on Grid Service Environments
- Author
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Huh, E. N., primary
- Published
- 2004
- Full Text
- View/download PDF
6. The Modeling and Traffic Feedback Control for QoS Management on Local Network
- Author
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Park, Jongjin, primary, Huh, E. -N., additional, Mun, Y., additional, and Lee, B. -G., additional
- Published
- 2003
- Full Text
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7. A Case of Aplasia Cutis Congenita with Widespread Multifocal Skin Defects Without Extracutaneous Abnormalities
- Author
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Kim, J, primary, Kim, J, additional, Lee, M, additional, Huh, E, additional, Lim, J, additional, Park, K, additional, and Oh, S, additional
- Published
- 2019
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8. Abstract No. 474 Readability of Spanish-language patient education materials from RadiologyInfo.org
- Author
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Huh, E., primary, Yi, P., additional, and Hui, F., additional
- Published
- 2018
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9. 4:21 PM Abstract No. 80 Readability of patient education materials from RadiologyInfo.org: has there been progress over the past 5 years?
- Author
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Huh, E., primary, Yi, P., additional, and Hui, F., additional
- Published
- 2018
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10. Abstract No. 469 Representation of developing countries in interventional radiology research
- Author
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Choi, W., primary, Yi, P., additional, Kim, T., additional, Huh, E., additional, Lee, A., additional, and Hui, F., additional
- Published
- 2018
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11. An Architecture of IoT Service Delegation and Resource Allocation Based on Collaboration between Fog and Cloud Computing
- Author
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Alsaffar, A.A. (Aymen Abdullah), Pham, H.P. (Hung Phuoc), Hong, C.-S. (Choong-Seon), Huh, E.-N. (Eui-Nam), Aazam, M. (Mohammad), Alsaffar, A.A. (Aymen Abdullah), Pham, H.P. (Hung Phuoc), Hong, C.-S. (Choong-Seon), Huh, E.-N. (Eui-Nam), and Aazam, M. (Mohammad)
- Abstract
Despite the wide utilization of cloud computing (e.g., services, applications, and resources), some of the services, applications, and smart devices are not able to fully benefit from this attractive cloud computing paradigm due to the following issues: (1) smart devices might be lacking in their capacity (e.g., processing, memory, storage, battery, and resource allocation), (2) they might be lacking in their network resources, and (3) the high network latency to centralized server in cloud might not be efficient for delay-sensitive application, services, and resource allocations requests. Fog computing is promising paradigm that can extend cloud resources to edge of network, solving the abovementioned issue. As a result, in this work, we propose an architecture of IoT service delegation and resource allocation based on collaboration between fog and cloud computing. We provide new algorithm that is decision rules of linearized decision tree based on three conditions (services size, completion time, and VMs capacity) for managing and delegating user request in order to balance workload. Moreover, we propose algorithm to allocate resources to meet service level agreement (SLA) and quality of services (QoS) as well as optimizing big data distribution in fog and cloud computing. Our simulation result shows that our proposed approach can efficiently balance workload, improve resource allocation efficiently, optimize big data distribution, and show better performance than other existing methods.
- Published
- 2016
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12. The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology
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Kleiman, S., Watson, Hunna, Bulik-Sullivan, E., Huh, E., Tarantino, L., Bulik, C., Carroll, I., Kleiman, S., Watson, Hunna, Bulik-Sullivan, E., Huh, E., Tarantino, L., Bulik, C., and Carroll, I.
- Published
- 2015
13. Emerging sensor-cloud technology for pervasive services and applications
- Author
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Mehedi Hassan,M, Pathan,A-SK, Huh,E-N, Abawajy,J, Mehedi Hassan,M, Pathan,A-SK, Huh,E-N, and Abawajy,J
- Published
- 2014
14. An Improvement of Resource Allocation for Migration Process in Cloud Environment
- Author
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Nguyen, T.-D., primary, Nguyen, A. T., additional, Nguyen, M. D., additional, Van Nguyen, M., additional, and Huh, E.-N., additional
- Published
- 2013
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15. The fusiform face area is recruited more for sequential than holistic processing: an aperture viewing study
- Author
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James, T., primary, Huh, E., additional, and Kim, S., additional
- Published
- 2010
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16. Haptic exploration of facemasks recruits left fusiform gyrus
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James, T. W., primary, Kilgour, A. R., additional, Servos, P., additional, Kitada, R., additional, Huh, E., additional, and Lederman, S. J., additional
- Published
- 2010
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17. Minimizing the Intrusion Detection Modules in Wireless Sensor Networks.
- Author
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Hai, T.H. and Huh, E.-N.
- Published
- 2008
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18. Detecting Selective Forwarding Attacks in Wireless Sensor Networks Using Two-hops Neighbor Knowledge.
- Author
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Tran Hoang Hai and Huh, E.-N.
- Published
- 2008
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19. Dynamic Kinetic Resolution of Allylic Alcohols Mediated by Ruthenium- and Lipase-Based Catalysts
- Author
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Lee, D., Huh, E. A., Kim, M.-J., Jung, H. M., Koh, J. H., and Park, J.
- Abstract
An enzyme−metal combo reaction has been developed for the dynamic kinetic resolution of allylic alcohols in which racemic substrates are transformed by a lipase and a ruthenium complex in the presence of an acyl donor to allylic acetates of high optical purity in over 80% yield. - Published
- 2000
20. Analysis of a Food-Borne Fungal Pathogen Outbreak: Virulence and Genome of a Mucor circinelloides Isolate from Yogurt
- Author
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Heitman, J., Carson, S., Ko, D. C., Lee, S. C., Huh, E. Y., Mieczkowski, P., Cuomo, C. A., Billmyre, R. B., Sykes, S. M., and Li, A.
- Subjects
2. Zero hunger ,food and beverages ,3. Good health - Abstract
Food-borne pathogens are ongoing problems, and new pathogens are emerging. The impact of fungi, however, is largely underestimated. Recently, commercial yogurts contaminated with Mucor circinelloides were sold, and >200 consumers became ill with nausea, vomiting, and diarrhea. Mucoralean fungi cause the fatal fungal infection mucormycosis, whose incidence has been continuously increasing. In this study, we isolated an M.circinelloides strain from a yogurt container, and multilocus sequence typing identified the strain as Mucor circinelloides f. circinelloides. M. circinelloides f. circinelloides is the most virulent M.circinelloides subspecies and is commonly associated with human infections, whereas M.circinelloides f. lusitanicus and M.circinelloides f. griseocyanus are less common causes of infection. Whole-genome analysis of the yogurt isolate confirmed it as being close to the M. circinelloides f. circinelloides subgroup, with a higher percentage of divergence with the M.circinelloides f. lusitanicus subgroup. In mating assays, the yogurt isolate formed sexual zygospores with the (−) M. circinelloides f. circinelloides tester strain, which is congruent with its sex locus encoding SexP, the (+) mating type sex determinant. The yogurt isolate was virulent in murine and wax moth larva host systems. In a murine gastromucormycosis model, Mucor was recovered from fecal samples of infected mice for up to 10days, indicating that Mucor can survive transit through the GI tract. In interactions with human immune cells, M.circinelloides f. lusitanicus induced proinflammatory cytokines but M. circinelloides f. circinelloides did not, which may explain the different levels of virulence in mammalian hosts. This study demonstrates that M.circinelloides can spoil food products and cause gastrointestinal illness in consumers and may pose a particular risk to immunocompromised patients.IMPORTANCEThe U.S. FDA reported that yogurt products were contaminated with M. circinelloides, a mucoralean fungal pathogen, and >200 consumers complained of symptoms, including vomiting, nausea, and diarrhea. The manufacturer voluntarily withdrew the affected yogurt products from the market. Compared to other food-borne pathogens, including bacteria, viruses, and parasites, less focus has been placed on the risk of fungal pathogens. This study evaluates the potential risk from the food-borne fungal pathogen M. circinelloides that was isolated from the contaminated commercial yogurt. We successfully cultured an M.circinelloides isolate and found that the isolate belongs to the species M.circinelloides f. circinelloides, which is often associated with human infections. In murine and insect host models, the isolate was virulent. While information disseminated in the popular press would suggest this fungal contaminant poses little or no risk to consumers, our results show instead that it is capable of causing significant infections in animals.
21. Coadministration of 6-Shogaol and Levodopa Alleviates Parkinson's Disease-Related Pathology in Mice.
- Author
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Kim JH, Kim JS, Ju IG, Huh E, Choi Y, Lee S, Cho JY, Park BY, and Oh MS
- Abstract
Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the nigrostriatal pathway, leading to motor and non-motor dysfunctions, such as depression, olfactory dysfunction, and memory impairment. Although levodopa (L-dopa) has been the gold standard PD treatment for decades, it only relieves motor symptoms and has no effect on non-motor symptoms or disease progression. Prior studies have reported that 6-shogaol, the active ingredient in ginger, exerts a protective effect on dopaminergic neurons by suppressing neuroinflammation in PD mice. This study investigated whether cotreatment with 6-shogaol and L-dopa could attenuate both motor and non-motor symptoms and dopaminergic neuronal damage. Both 6-shogaol (20 mg/kg) and L-dopa (80 mg/kg) were orally administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid- induced PD model mice for 26 days. The experimental results showed that L-dopa alleviated motor symptoms, but had no significant effect on non-motor symptoms, loss of dopaminergic neuron, or neuroinflammation. However, when mice were treated with 6-shogaol alone or in combination L-dopa, an amelioration in both motor and non-motor symptoms such as depression-like behavior, olfactory dysfunction and memory impairment was observed. Moreover, 6-shogaol-only or co-treatment with 6-shogaol and L-dopa protected dopaminergic neurons in the striatum and reduced neuroinflammation in the striatum and substantia nigra. Overall, these results suggest that 6-shogaol can effectively complement L-dopa by improving non-motor dysfunction and restoring dopaminergic neurons via suppressing neuroinflammation.
- Published
- 2024
- Full Text
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22. Real-time Visualization of Transcribed mRNA via Click Chemistry in a Liposomal Space.
- Author
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Jeon S, Ros C, Huh E, Choi HK, Cho SG, Jung KH, and Shin K
- Subjects
- Prospective Studies, Copper chemistry, Cycloaddition Reaction, Catalysis, Click Chemistry methods, Azides chemistry
- Abstract
We present a CuAAC (Copper-Catalyzed Azide-Alkyne Cycloaddition) reaction protocol designed for the visualization of mRNA. To achieve this, we synthesized stable mRNA molecules incorporating the modified nucleoside analog, EU, a crucial element for fluorophore attachment. Leveraging this modified mRNA, we successfully executed the CuAAC reaction, wherein the pro-fluorophore, coumarin, was conjugated to EU on the mRNA through our meticulously designed CuAAC process. This innovative approach resulted in the emission of fluorescence, enabling both precise quantification and visual observation of mRNA. Furthermore, we demonstrated the feasibility of concurrent mRNA synthesis and visualization by seamlessly integrating the CuAAC reaction mix into the mRNA transcription process. Additionally, our novel methodology opens avenues for prospective real-time monitoring of mRNA transcription within artificial cells. These advancements hold significant promise for expanding our comprehension of fundamental cellular processes and finding applications across diverse biological contexts in the future.
- Published
- 2024
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23. P. mirabilis-derived pore-forming haemolysin, HpmA drives intestinal alpha-synuclein aggregation in a mouse model of neurodegeneration.
- Author
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Huh E, Choi JG, Choi Y, Ju IG, Kim B, Shin YJ, An JM, Park MG, Yim SV, Chung SJ, Seo SU, Kim D, Kim CH, Kim DH, and Oh MS
- Subjects
- Animals, Male, Mice, Anti-Bacterial Agents, Base Composition, Hemolysin Proteins, Phylogeny, Proteus mirabilis, RNA, Ribosomal, 16S, Sequence Analysis, DNA, Virulence Factors, alpha-Synuclein genetics, Mirabilis
- Abstract
Background: Recent studies suggesting the importance of the gut-microbiome in intestinal aggregated alpha synuclein (α-syn) have led to the exploration of the possible role of the gut-brain axis in central nervous system degeneration. Proteus mirabilis (P. mirabilis), a gram-negative facultative anaerobic bacterium, has been linked to brain neurodegeneration in animal studies. We hypothesised that P. mirabilis-derived virulence factors aggregate intestinal α-synuclein and could prompt the pathogenesis of dopaminergic neurodegeneration in the brain., Methods: We used vagotomised- and antibiotic-treated male murine models to determine the pathogenesis of P. mirabilis during brain neurodegeneration. The neurodegenerative factor that is driven by P. mirabilis was determined using genetically mutated P. mirabilis. The pathological functions and interactions of the virulence factors were determined in vitro., Findings: The results showed that P. mirabilis-induced motor dysfunction and neurodegeneration are regulated by intestinal α-syn aggregation in vagotomised- or antibiotic-treated murine models. We deduced that the specific virulence factor, haemolysin A (HpmA), plays a role in the pathogenesis of P. mirabilis. HpmA is involved in α-synuclein oligomerisation and membrane pore formation, resulting in the activation of mTOR-mediated autophagy signalling in intestinal neuroendocrine cells., Interpretation: Taken together, the results of the present study suggest that HpmA can interact with α-syn and act as a possible indicator of brain neurodegenerative diseases that are induced by P. mirabilis., Funding: This study was supported by a grant from the National Research Foundation of Korea., Competing Interests: Declaration of interests EH, JGC, DHK and MSO are inventors with a provisional patent, “Method for diagnosing neurodegenerative disease using HpmA” that is licensed to MetaCen Therapeutics. MGP is a co-founder of MetaCen Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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24. A Self-Regenerating Artificial Cell, that is One Step Closer to Living Cells: Challenges and Perspectives.
- Author
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Tror S, Jeon S, Nguyen HT, Huh E, and Shin K
- Subjects
- DNA, Cell Division, Synthetic Biology, Artificial Cells metabolism
- Abstract
Controllable, self-regenerating artificial cells (SRACs) can be a vital advancement in the field of synthetic biology, which seeks to create living cells by recombining various biological molecules in the lab. This represents, more importantly, the first step on a long journey toward creating reproductive cells from rather fragmentary biochemical mimics. However, it is still a difficult task to replicate the complex processes involved in cell regeneration, such as genetic material replication and cell membrane division, in artificially created spaces. This review highlights recent advances in the field of controllable, SRACs and the strategies to achieve the goal of creating such cells. Self-regenerating cells start by replicating DNA and transferring it to a location where proteins can be synthesized. Functional but essential proteins must be synthesized for sustained energy generation and survival needs and function in the same liposomal space. Finally, self-division and repeated cycling lead to autonomous, self-regenerating cells. The pursuit of controllable, SRACs will enable authors to make bold advances in understanding life at the cellular level, ultimately providing an opportunity to use this knowledge to understand the nature of life., (© 2023 Wiley-VCH GmbH.)
- Published
- 2023
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25. Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity.
- Author
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Gao W, Liu L, Huh E, Gbahou F, Cecon E, Oshima M, Houzé L, Katsonis P, Hegron A, Fan Z, Hou G, Charpentier G, Boissel M, Derhourhi M, Marre M, Balkau B, Froguel P, Scharfmann R, Lichtarge O, Dam J, Bonnefond A, Liu J, and Jockers R
- Subjects
- Humans, Insulin metabolism, Adiposity genetics, Obesity genetics, Blood Glucose, Diabetes Mellitus, Type 2 genetics
- Abstract
The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity
1,2 . The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways. The defective insulin secretion of GLP1R LoF variants is rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200,000 participants from the UK Biobank show that impaired GLP1R cell surface expression contributes to poor glucose control and increased adiposity with increased glycated haemoglobin A1c and body mass index. This study defines impaired GLP1R cell surface expression as a risk factor for traits associated with type 2 diabetes and obesity and provides potential treatment options for GLP1R LoF variant carriers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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26. Peripheral metabolic alterations associated with pathological manifestations of Parkinson's disease in gut-brain axis-based mouse model.
- Author
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Huh E, Choi JG, Lee MY, Kim JH, Choi Y, Ju IG, Eo H, Park MG, Kim DH, Park HJ, Lee CH, and Oh MS
- Abstract
Introduction: Parkinson's disease (PD) is a representative neurodegenerative disease, and its diagnosis relies on the evaluation of clinical manifestations or brain neuroimaging in the absence of a crucial noninvasive biomarker. Here, we used non-targeted metabolomics profiling to identify metabolic alterations in the colon and plasma samples of Proteus mirabilis ( P. mirabilis )-treated mice, which is a possible animal model for investigating the microbiota-gut-brain axis., Methods: We performed gas chromatography-mass spectrometry to analyze the samples and detected metabolites that could reflect P. mirabilis -induced disease progression and pathology., Results and Discussion: Pattern, correlation and pathway enrichment analyses showed significant alterations in sugar metabolism such as galactose metabolism and fructose and mannose metabolism, which are closely associated with energy metabolism and lipid metabolism. This study indicates possible metabolic factors for P. mirabilis -induced pathological progression and provides evidence of metabolic alterations associated with P. mirabilis -mediated pathology of brain neurodegeneration., Competing Interests: MP was employed by MetaCen Therapeutics Inc. R&D Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huh, Choi, Lee, Kim, Choi, Ju, Eo, Park, Kim, Park, Lee and Oh.)
- Published
- 2023
- Full Text
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27. 6-Shogaol, an Active Ingredient of Ginger, Improves Intestinal and Brain Abnormalities in Proteus Mirabilis -Induced Parkinson's Disease Mouse Model.
- Author
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Huh E, Choi JG, Choi Y, Ju IG, Noh D, Shin DY, Kim DH, Park HJ, and Oh MS
- Abstract
Parkinson's disease (PD) which has various pathological mechanisms, recently, it is attracting attention to the mechanism via microbiome-gut-brain axis. 6-Shogaol, a representative compound of ginger, have been known for improving PD phenotypes by reducing neuroinflammatory responses. In the present study, we investigated whether 6-shogaol and ginger attenuate degeneration induced by Proteus mirabilis ( P. mirabilis ) on the intestine and brain, simultaneously. C57BL/6J mice received P. mirabilis for 5 days. Ginger (300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 22 days including the period of P. mirabilis treatment. Results showed that 6-shogaol and ginger improved motor dysfunction and dopaminergic neuronal death induced by P. mirabilis treatment. In addition, they suppressed P. mirabilis -induced intestinal barrier disruption, pro-inflammatory signals such as toll-like receptor and TNF-α, and intestinal α-synuclein aggregation. Moreover, ginger and 6-shogaol significantly inhibited neuroinflammation and α-synuclein in the brain. Taken together, 6-shogaol and ginger have the potential to ameliorate PD-like motor behavior and degeneration of dopaminergic neurons induced by P. mirabilis in mice. Here, these findings are meaningful in that they provide the first experimental evidence that 6-shogaol might attenuate PD via regulating gut-brain axis.
- Published
- 2023
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28. Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model.
- Author
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Ju IG, Lee S, Choi JG, Kim N, Huh E, Lee JK, and Oh MS
- Subjects
- Mice, Animals, Amyloid beta-Peptides metabolism, Neuroinflammatory Diseases, Mice, Transgenic, Plant Components, Aerial, Disease Models, Animal, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Houttuynia metabolism, Neurodegenerative Diseases
- Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-β (Aβ) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aβ toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aβ followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4 months. We observed that HH treatment ameliorated memory impairment and reduced Aβ deposits in the brains of the mice. HH directly inhibited Aβ aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement., (© 2023 John Wiley & Sons Ltd.)
- Published
- 2023
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29. 5-Hydroxytryptophan Reduces Levodopa-Induced Dyskinesia via Regulating AKT/mTOR/S6K and CREB/ΔFosB Signals in a Mouse Model of Parkinson's Disease.
- Author
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Choi Y, Huh E, Lee S, Kim JH, Park MG, Seo SY, Kim SY, and Oh MS
- Abstract
Long-term administration of levodopa (L-DOPA) to patients with Parkinson's disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations. From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.
- Published
- 2023
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30. Longan extract suppresses food intake through regulation of POMC/AgRP neuronal activities and endoplasmic reticulum stress in hypothalamus of db/db mice.
- Author
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Eo H, Kim SH, Ju IG, Huh E, Kim S, Choi JG, Kim SW, Son M, and Oh MS
- Abstract
Type 2 diabetes mellitus (T2DM) is one of the biggest public health issues worldwide and closely related to development of other chronic diseases such as cardiovascular diseases, cancer and neurodegenerative diseases. Considerable percentage of T2DM patients undergo have suffered from binge eating disorder which exacerbates insulin resistance and metabolic challenges. Longan ( Dimocarpus longan L. ) and its constituents are reported for their various health benefits. However, it is still unknown whether longan fruit supplementation can ameliorate glucose homeostasis and binge eating disorder found in T2DM. The current study aimed to investigate whether longan fruit extract (LE) supplementation can improve diabetic hyperglycemia through modulation of feeding center located in hypothalamus of db/db T2DM mice. As a result, LE supplementation ameliorated fasting blood glucose levels and reduced excessive epididymal fat accumulation. In addition, LE administration improved glucose tolerance and insulin sensitivity in db/db mice. Especially, LE supplemented mice showed less food consumption which was in line with increase of pro-opiomelanocortin (POMC) neuronal activities and decrease of agouti-related peptide (AgRP) neuronal activities. Furthermore, LE supplementation reduced hypothalamic endoplasmic reticulum (ER) stress which was stimulated in db/db mice. As ER stress is a crucial factor involving in appetite control and glucose homeostasis, the effect of LE supplementation on circulating glucose levels and feeding behavior might be mediated by suppression of hypothalamic ER stress. Collectively, these findings suggest that LE could be a potential nutraceutical for improvement of T2DM as well as patients with satiety issues., Competing Interests: SK, JC, SWK, and MS are employed by MThera Pharma Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Eo, Kim, Ju, Huh, Kim, Choi, Kim, Son and Oh.)
- Published
- 2023
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31. Functional variants identify sex-specific genes and pathways in Alzheimer's Disease.
- Author
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Bourquard T, Lee K, Al-Ramahi I, Pham M, Shapiro D, Lagisetty Y, Soleimani S, Mota S, Wilhelm K, Samieinasab M, Kim YW, Huh E, Asmussen J, Katsonis P, Botas J, and Lichtarge O
- Subjects
- Female, Humans, Male, Alzheimer Disease genetics, Alzheimer Disease metabolism, Sex Factors
- Abstract
The incidence of Alzheimer's Disease in females is almost double that of males. To search for sex-specific gene associations, we build a machine learning approach focused on functionally impactful coding variants. This method can detect differences between sequenced cases and controls in small cohorts. In the Alzheimer's Disease Sequencing Project with mixed sexes, this approach identified genes enriched for immune response pathways. After sex-separation, genes become specifically enriched for stress-response pathways in male and cell-cycle pathways in female. These genes improve disease risk prediction in silico and modulate Drosophila neurodegeneration in vivo. Thus, a general approach for machine learning on functionally impactful variants can uncover sex-specific candidates towards diagnostic biomarkers and therapeutic targets., (© 2023. The Author(s).)
- Published
- 2023
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32. Coevolutionary signals in metabotropic glutamate receptors capture residue contacts and long-range functional interactions.
- Author
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Huh E, Agosto MA, Wensel TG, and Lichtarge O
- Subjects
- Binding Sites, Phylogeny, Ligands, Receptors, G-Protein-Coupled genetics, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism
- Abstract
Upon ligand binding to a G protein-coupled receptor, extracellular signals are transmitted into a cell through sets of residue interactions that translate ligand binding into structural rearrangements. These interactions needed for functions impose evolutionary constraints so that, on occasion, mutations in one position may be compensated by other mutations at functionally coupled positions. To quantify the impact of amino acid substitutions in the context of major evolutionary divergence in the G protein-coupled receptor subfamily of metabotropic glutamate receptors (mGluRs), we combined two phylogenetic-based algorithms, Evolutionary Trace and covariation Evolutionary Trace, to infer potential structure-function couplings and roles in mGluRs. We found a subset of evolutionarily important residues at known functional sites and evidence of coupling among distinct structural clusters in mGluR. In addition, experimental mutagenesis and functional assays confirmed that some highly covariant residues are coupled, revealing their synergy. Collectively, these findings inform a critical step toward understanding the molecular and structural basis of amino acid variation patterns within mGluRs and provide insight for drug development, protein engineering, and analysis of naturally occurring variants., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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33. Protective effects of CCL01 against Aβ-induced neurotoxicity in 5xFAD transgenic mouse model of Alzheimer's disease.
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Ju IG, Son SY, Lee S, Im H, Huh E, Eo H, Choi JG, Sohn MW, Yim SV, Kim SY, Kim DH, Lee CH, and Oh MS
- Subjects
- Mice, Animals, Mice, Transgenic, Neuroinflammatory Diseases, Amyloid beta-Peptides toxicity, Amyloid beta-Peptides metabolism, Inflammation drug therapy, Disease Models, Animal, Alzheimer Disease metabolism
- Abstract
Alzheimer's disease (AD) is the most common dementia characterized by the excessive accumulation of amyloid-beta (Aβ) and tau aggregates, as well as neuronal damage and neuroinflammation. Metabolic disruption in AD has been noticed because metabolite alterations closely correlate with Aβ neuropathology and behavioral phenotypes. Accordingly, controlling various neuropathological processes and metabolic disruption is an efficient therapeutic strategy for AD treatment. In this study, we evaluated the effects of a combination of Cuscuta seeds and Lactobacillus paracasei NK112 (CCL01) on AD neuropathology and altered metabolism in five familial AD (5xFAD) transgenic mice and neuronal cell cultures. First, we observed that CCL01 exerted neuroprotective effects in HT22 hippocampal neurons and primary cultured neurons. CCL01 ameliorated memory decline and protected synapses and neuronal survival in 5xFAD mice. These effects were related to the inhibition of tau phosphorylation. CCL01 also inhibited the activation of mitogen-activated protein kinase (MAPK) signaling and neuroinflammatory processes. Moreover, the metabolite profile-particularly characterized by altered phospholipid metabolism-was significantly changed in the 5xFAD group, while CCL01 partly restored the alteration. Lysophosphatidylcholine (lysoPC), the levels of which were higher in the brains of 5xFAD mice, exerted neurotoxicity in vitro, whereas CCL01 protected neurons from lysoPC-induced toxicity by regulating MAPK signaling. Additionally, CCL01 administration reduced gut inflammation in the 5xFAD mice. In summary, we demonstrated that CCL01 improved the memory function of 5xFAD mice by protecting neurons against Aβ- and lysoPC-induced toxicity through the regulation of MAPK signaling, neuroinflammation, tau phosphorylation, and gut inflammation, suggesting the potential of CCL01 as treatment for AD., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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34. Yomogin, Isolated from Artemisia iwayomogi , Inhibits Neuroinflammation Stimulated by Lipopolysaccharide via Regulating MAPK Pathway.
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Kim JH, Ju IG, Kim N, Huh E, Son SR, Hong JP, Choi Y, Jang DS, and Oh MS
- Abstract
Neuroinflammation causes various neurological disorders, including depression and neurodegenerative diseases. Therefore, regulation of neuroinflammation is a promising therapeutic strategy for inflammation-related neurological disorders. This study aimed to investigate whether yomogin, isolated from Artemisia iwayomogi, has anti-neuroinflammatory effects. First, we evaluated the effects of yomogin by assessing pro-inflammatory mediators and cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The results showed that yomogin inhibited the increase in neuroinflammatory factors, including nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, and tumor necrosis factor-α, and suppressed phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase and p38, which participate in the mitogen-activated protein kinase (MAPK) pathway. To confirm these effects in vivo, we measured the activation of astrocyte and microglia in LPS-injected mouse brains. Results showed that yomogin treatment decreased astrocyte and microglia activations. Collectively, these results suggest that yomogin suppresses neuroinflammation by regulating the MAPK pathway and it could be a potential candidate for inflammation-mediated neurological diseases.
- Published
- 2022
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35. Petasites japonicus leaf extract inhibits Alzheimer's-like pathology through suppression of neuroinflammation.
- Author
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Eo H, Lee S, Kim SH, Ju IG, Huh E, Lim J, Park S, and Oh MS
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Calcium metabolism, Inflammation metabolism, Interleukin-6 genetics, Interleukin-6 metabolism, JNK Mitogen-Activated Protein Kinases metabolism, Lipopolysaccharides adverse effects, Mice, Microglia, Nitric Oxide metabolism, Plant Extracts metabolism, RNA, Messenger metabolism, Tumor Necrosis Factor-alpha metabolism, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Petasites
- Abstract
Neuroinflammation is a crucial pathogenic process involved in the development and deterioration of Alzheimer's disease (AD). Petasites japonicus is known for its beneficial effects on various disease states such as allergic reaction, oxidative stress and inflammation. However, it is still unknown whether P. japonicus has protective effects on neuroinflammation, especially microgliosis related to AD. The current study aimed to investigate whether an extract of P. japonicus (named KP-1) protects from microglial cell activation in vitro and in vivo . To demonstrate the anti-neuroinflammation effects of KP-1, the current study adopted the most widely used experimental models including the lipopolysaccharide (LPS)-induced microgliosis in vitro model and amyloid beta (Aβ) oligomer (AβO)-induced neuroinflammation in vivo model, respectively. As a result, KP-1 pre-treatment reduced nitric oxide (NO) production, protein levels of inducible NO synthase (iNOS) and c-Jun N-terminal kinase (JNK) phosphorylation in BV2 cells which were significantly promoted by 100 ng ml
-1 LPS treatment. Similarly, KP-1 administration protected mice from AβO-induced memory impairment scored by Y-maze and novel object recognition test (NORT). Moreover, KP-1 administration suppressed AβO-induced microglial cell activation measured by counting the number of ionized calcium binding adaptor molecule 1 (Iba-1)-positive cells in both the cortex and hippocampal dentate gyrus and measuring the mRNA expression of TNFα, IL-1β and IL-6. Furthermore, AβO-induced synaptotoxicity was prevented by KP-1 administration which is in line with behavioral changes. Collectively, these findings suggest that KP-1 could be a potential functional food for protection against neuroinflammation, and prevents or delays the progression of AD.- Published
- 2022
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36. In vitro and in vivo neuroprotective effect of novel mPGES-1 inhibitor in animal model of Parkinson's disease.
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Yang S, Huh E, Moon GH, Ahn J, Woo J, Han HS, Lee HH, Chung KS, Lee KT, Oh MS, and Lee JY
- Subjects
- Animals, Disease Models, Animal, Dopaminergic Neurons, Mice, Oxidopamine pharmacology, Prostaglandins E pharmacology, Prostaglandins E therapeutic use, Rats, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Parkinson Disease drug therapy
- Abstract
mPGES-1 is found to be up-regulated in the dopaminergic neurons of the substantia nigra pars compacta (SNpc) of postmortem brain tissue from Parkinson's disease (PD) patients and neurotoxin 6-hydroxydopamine (6-OHDA)-induced PD mice. Since the genetic deletion of mPGES-1 abolished 6-OHDA-induced PGE
2 production and 6-OHDA-induced dopaminergic neurodegeneration in vitro and in vivo models, mPGES-1 enzyme has the potential to be an important target for PD therapy. In the present work, we investigated whether a small organic molecule as mPGES-1 inhibitor could exhibit the neuroprotective effects against 6-OHDA-induced neurotoxicity in in vitro and in vivo models. For this research goal, a new series of arylsulfonyl hydrazide derivatives was prepared and investigated whether these compounds may protect neurons against 6-OHDA-induced neurotoxicity in both in vitro and in vivo studies. Among them, compound 7s (MPO-0144) as a mPGES-1 inhibitor (PGE2 IC50 = 41.77 nM; mPGES-1 IC50 = 1.16 nM) exhibited a potent neuroprotection (ED50 = 3.0 nM) against 6-OHDA-induced in PC12 cells without its own neurotoxicity (IC50 = >10 μM). In a 6-OHDA-induced mouse model of PD, administration of compound 7s (1 mg/kg/day, for 7 days, i.p.) ameliorated motor impairments and dopaminergic neuronal damage. These significant biological effects of compound 7s provided the first pharmacological evidence that mPGES-1 inhibitor could be a promising therapeutic agent for PD patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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37. DA-9805, a Herbal Mixture, Restores Motor Manifestations in 6-Hydroxydopamine-induced Parkinson's Disease Mouse Model by Regulating Striatal Dopamine and Acetylcholine Levels.
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Huh E, Kwon Y, Choi JG, Lim MG, Jeong JS, Park AY, Kim JH, Pak YK, Hong SP, and Oh MS
- Abstract
Loss of dopamine (DA) is one of the primary features of Parkinson's disease (PD); however, imbalances of non-dopaminergic neurotransmitters significantly contribute to the disabilities noted in advanced PD patients. DA-9805 is the ethanolic extraction of the root bark of Paeonia × suffruticosa Andrews ( Paeoniaceae ), the root of Angelica dahurica (Hoffm.) Benth. and Hook.f. ex Franch. and Sav. ( Apiaceae ) and the root of Bupleurum falcatum L. ( Apiaceae ), which have been widely utilized as an enhancer of motor function in East Asia. This study aimed to investigate whether DA-9805 modified motor dysfunctions and imbalances associated with DA and other neurotransmitters in a 6-hydroxydopamine-induced PD mouse. We confirmed the expressions of proteins related with neurotransmissions in the striatum. In addition, we measured the striatal neurotransmitters using HPLC and analyzed their correlation. DA-9805 significantly improved motor impairments and restored the altered levels of neurotransmitters in the striatum. Moreover, DA-9805 improved the altered expressions of tyrosine hydroxylase (TH), DA transporter, and choline acetyltransferase (ChAT) in the ipsilateral part of mouse striatum or SNpc, which implies the neuroprotection. We also found that the level of striatal acetylcholine (Ach) has the moderate negative correlation with motor functions and TH expression in the SNpc. This study indicates that DA-9805 restores motor dysfunctions by normalizing the increased levels of striatal Ach via modulating DA transmission and ChAT expressions as well as its neuroprotective effects., Competing Interests: JSJ and AP were employed by the company R&D Center of Dong-A ST. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huh, Kwon, Choi, Lim, Jeong, Park, Kim, Pak, Hong and Oh.)
- Published
- 2022
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38. Development of Endovascular Thrombectomy Services for Acute Ischemic Stroke via On-Site Training of Interventional Radiologists.
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England RW, Ring NY, Huh E, Bhagat N, Srinivas A, Akman A, Johnson B, Hong K, Leigh R, and Hui FK
- Subjects
- Humans, Radiologists, Thrombectomy, Treatment Outcome, Brain Ischemia diagnostic imaging, Brain Ischemia surgery, Endovascular Procedures, Ischemic Stroke, Stroke diagnostic imaging, Stroke surgery
- Published
- 2022
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39. A general calculus of fitness landscapes finds genes under selection in cancers.
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Hsu TK, Asmussen J, Koire A, Choi BK, Gadhikar MA, Huh E, Lin CH, Konecki DM, Kim YW, Pickering CR, Kimmel M, Donehower LA, Frederick MJ, Myers JN, Katsonis P, and Lichtarge O
- Subjects
- Biological Evolution, Genetic Fitness, Genotype, Humans, Models, Genetic, Phenotype, Selection, Genetic, Calculi, Neoplasms genetics
- Abstract
Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype-phenotype relationship and discover genes associated with complex traits and diseases., (© 2022 Hsu et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2022
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40. Recurrent high-impact mutations at cognate structural positions in class A G protein-coupled receptors expressed in tumors.
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Huh E, Gallion J, Agosto MA, Wright SJ, Wensel TG, and Lichtarge O
- Subjects
- Calcium, Cell Line, Tumor, Computer Simulation, Enzyme-Linked Immunosorbent Assay, Humans, Mutation, Neoplasms genetics, Protein Conformation, Receptors, G-Protein-Coupled genetics, beta-Arrestins genetics, Gene Expression Regulation, Neoplastic physiology, Neoplasms metabolism, Receptors, G-Protein-Coupled metabolism, beta-Arrestins metabolism
- Abstract
G protein-coupled receptors (GPCRs) are the largest family of human proteins. They have a common structure and, signaling through a much smaller set of G proteins, arrestins, and effectors, activate downstream pathways that often modulate hallmark mechanisms of cancer. Because there are many more GPCRs than effectors, mutations in different receptors could perturb signaling similarly so as to favor a tumor. We hypothesized that somatic mutations in tumor samples may not be enriched within a single gene but rather that cognate mutations with similar effects on GPCR function are distributed across many receptors. To test this possibility, we systematically aggregated somatic cancer mutations across class A GPCRs and found a nonrandom distribution of positions with variant amino acid residues. Individual cancer types were enriched for highly impactful, recurrent mutations at selected cognate positions of known functional motifs. We also discovered that no single receptor drives this pattern, but rather multiple receptors contain amino acid substitutions at a few cognate positions. Phenotypic characterization suggests these mutations induce perturbation of G protein activation and/or β-arrestin recruitment. These data suggest that recurrent impactful oncogenic mutations perturb different GPCRs to subvert signaling and promote tumor growth or survival. The possibility that multiple different GPCRs could moonlight as drivers or enablers of a given cancer through mutations located at cognate positions across GPCR paralogs opens a window into cancer mechanisms and potential approaches to therapeutics., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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41. Correction: CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis.
- Author
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Ju IG, Hong SM, Yun SW, Huh E, Kim DH, Kim SY, and Oh MS
- Abstract
Correction for 'CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis' by In Gyoung Ju et al. , Food Funct. , 2021, 12 , 10690-10699, DOI: 10.1039/D1FO01403J.
- Published
- 2021
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42. CCL01, a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, enhances memory function via nerve growth factor-mediated neurogenesis.
- Author
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Ju IG, Hong SM, Yun SW, Huh E, Kim DH, Kim SY, and Oh MS
- Subjects
- Animals, Cell Line, Tumor, Cyclic AMP Response Element-Binding Protein genetics, Cyclic AMP Response Element-Binding Protein metabolism, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation drug effects, Glioma drug therapy, Male, Mice, Mice, Inbred ICR, Neuroblastoma drug therapy, Neurogenesis physiology, Neurons drug effects, Nootropic Agents pharmacology, Phytotherapy, Piracetam pharmacology, Rats, Receptor, trkA genetics, Receptor, trkA metabolism, Synaptophysin genetics, Synaptophysin metabolism, Cuscuta chemistry, Lacticaseibacillus paracasei, Memory drug effects, Nerve Growth Factor drug effects, Neurogenesis drug effects, Seeds chemistry
- Abstract
Memory decline occurs due to various factors, including stress, depression, and aging, and lowers the quality of life. Several nutritional supplements and probiotics have been used to enhance memory function, and efforts have been made to develop mixed supplements with maximized efficacy. In this study, we aimed to examine whether a novel formulation composed of Cuscuta seeds and Lactobacillus paracasei NK112, CCL01, enhances memory function and induces neurogenesis via nerve growth factor (NGF) induction. Firstly, we orally administered CCL01 to normal mice and assessed their memory function 4 weeks after the first administration by performing a step-through passive avoidance test. We found that CCL01 at 100 mg kg
-1 treatment enhanced the fear-based memory function. By analyzing the expression of Ki-67 and doublecortin, which are the markers of proliferating cells and immature neurons, respectively, we observed that CCL01 induced neuronal proliferation and differentiation in the hippocampus of the mice. Additionally, we found that the expression of synaptic markers increased in the hippocampus of CCL01-treated mice. We measured the NGF expression in the supernatant of C6 cells after CCL01 treatment and found that CCL01 increased NGF release. Furthermore, treatment of CCL01-conditioned glial media on N2a cells increased neuronal differentiation via the TrkA/ERK/CREB signaling pathway and neurotrophic factor expression. Moreover, when CCL01 was administered and scopolamine was injected, CCL01 ameliorated memory decline. These results suggest that CCL01 is an effective enhancer of memory function and can be applied to various age groups requiring memory improvement.- Published
- 2021
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43. Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants.
- Author
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Hegron A, Huh E, Deupi X, Sokrat B, Gao W, Le Gouill C, Canouil M, Boissel M, Charpentier G, Roussel R, Balkau B, Froguel P, Plouffe B, Bonnefond A, Lichtarge O, Jockers R, and Bouvier M
- Abstract
Melatonin is a hormone mainly produced by the pineal gland and MT
1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1 , remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1 's activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1 ) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation., Competing Interests: The authors declare the following competing financial interest(s): M.B. is the president of the scientific advisory board of Domain Therapeutics which licenced-in some of the BRET-based biosensors used in the present study for their commercial use. All other authors declare no competing interests., (© 2021 The Authors. Published by American Chemical Society.)- Published
- 2021
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44. Artemisiae Iwayomogii Herba inhibits lipopolysaccharide-induced neuroinflammation by regulating NF-κB and MAPK signaling pathways.
- Author
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Ju IG, Huh E, Kim N, Lee S, Choi JG, Hong J, and Oh MS
- Subjects
- Animals, Artemisia chemistry, Cell Line, Cyclooxygenase 2 metabolism, Inflammation chemically induced, Inflammation metabolism, Inflammation Mediators metabolism, Lipopolysaccharides toxicity, MAP Kinase Signaling System drug effects, Male, Mice, Inbred C57BL, Microglia metabolism, Microglia pathology, Nitric Oxide metabolism, Nitric Oxide Synthase Type II metabolism, Plant Preparations chemistry, Tumor Necrosis Factor-alpha metabolism, Mice, Inflammation drug therapy, Microglia drug effects, NF-kappa B metabolism, Plant Preparations pharmacology
- Abstract
Background: Neuroinflammation plays a major role in the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The regulation of microglia is an efficient therapeutic approach to controlling neuroinflammation., Purpose: In this study, we aimed to determine whether Artemisiae Iwayomogii Herba (AIH), which is herbal medicine traditionally used for inflammation-related disorders, controls neuroinflammatory responses by regulating the microglia-mediated signaling pathway., Methods: BV-2 microglial cells were treated with AIH and lipopolysaccharides (LPS), then various pro-inflammatory mediators were analyzed using griess reaction, quantitative reverse-transcription polymerase chain reaction, or western blotting. C57BL/6 J mice were orally administered by AIH for 17 days and intraperitoneally injected with LPS for the last 14 days. The brains were collected and the microglial activation and nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) expression in the cortex and hippocampus were analyzed using immunohistochemistry or western blotting., Results: In BV-2 microglial cells, we found that AIH inhibited nitric oxide (NO) production induced by LPS. AIH also suppressed the expressions of pro-inflammatory mediators, including inducible NO synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-6. The study also revealed that the effects of AIH are related to the regulation of the nuclear factor kappa B (NF-κB) and the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, we found that AIH prevented the formation of NLRP3 inflammasomes. Consistent with the results of in vitro studies on the brains of LPS-injected mice, we observed that AIH suppressed microglial activation and NLRP3 expression., Conclusion: Taken together, these results suggest that AIH attenuates neuroinflammation by regulating the NF-κB and MAPK pathways, and it may be used for treating neurological diseases., (Copyright © 2021. Published by Elsevier GmbH.)
- Published
- 2021
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45. GC-TOF-MS-Based Metabolomic Analysis and Evaluation of the Effects of HX106, a Nutraceutical, on ADHD-Like Symptoms in Prenatal Alcohol Exposed Mice.
- Author
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Ju IG, Lee MY, Jeon SH, Huh E, Kim JH, Lee JK, Lee CH, and Oh MS
- Subjects
- Animals, Attention Deficit Disorder with Hyperactivity chemically induced, Disease Models, Animal, Dopamine Plasma Membrane Transport Proteins drug effects, Female, Fetal Alcohol Spectrum Disorders psychology, Gas Chromatography-Mass Spectrometry methods, Metabolomics, Mice, Pregnancy, Prenatal Exposure Delayed Effects chemically induced, Prenatal Exposure Delayed Effects psychology, Attention Deficit Disorder with Hyperactivity drug therapy, Dietary Supplements, Fetal Alcohol Spectrum Disorders drug therapy, Plant Extracts pharmacology, Prenatal Exposure Delayed Effects drug therapy
- Abstract
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in children characterized by inattention and hyperactivity. Prenatal alcohol exposure (PAE) can disrupt fetal neuronal development and cause an ADHD-like hyperactive behavior in the offspring. In this study, we hypothesized that metabolic disturbance would involve in ADHD neuropathology and aimed to investigate the changes in metabolite profile in PAE-induced ADHD-like model and the effects of HX106, a nutraceutical, on ADHD-like pathophysiology and metabolite changes. To this end, we administered HX106 to the mouse offspring affected by PAE (OPAE) and assessed the hyperactivity using the open field test. We observed that HX106-treated OPAE showed less hyperactive behavior than vehicle-treated OPAE. The effects of HX106 were found to be related to the regulation of dopamine transporter and D2 dopamine receptor expression. Furthermore, using gas chromatography time-of-flight mass spectrometry-based metabolomics, we explored the metabolite changes among the experimental groups. The metabolite profile, particularly related with the amino acids, linoleic acid and amino sugar pathways, was altered by PAE and reversed by HX106 treatment partially similar to that observed in the control group. Overall, this study suggest that metabolite alteration would be involved in ADHD pathology and that HX106 can be an efficient supplement to overcome ADHD by regulating dopamine signaling-related protein expression and metabolite changes.
- Published
- 2020
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46. A molecular approach to rationally constructing specific fluorogenic substrates for the detection of acetylcholinesterase activity in live cells, mice brains and tissues.
- Author
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Wu X, An JM, Shang J, Huh E, Qi S, Lee E, Li H, Kim G, Ma H, Oh MS, Kim D, and Yoon J
- Abstract
Acetylcholinesterase (AChE) is an extremely critical hydrolase tightly associated with neurological diseases. Currently, developing specific substrates for imaging AChE activity still remains a great challenge due to the interference from butyrylcholinesterase (BChE) and carboxylesterase (CE). Herein, we propose an approach to designing specific substrates for AChE detection by combining dimethylcarbamate choline with a self-immolative scaffold. The representative P10 can effectively eliminate the interference from CE and BChE. The high specificity of P10 has been proved via imaging AChE activity in cells. Moreover, P10 can also be used to successfully map AChE activity in different regions of a normal mouse brain, which may provide important data for AChE evaluation in clinical studies. Such a rational and effective approach can also provide a solid basis for designing probes with different properties to study AChE in biosystems and another way to design specific substrates for other enzymes., Competing Interests: The authors declare no competing financial interests., (This journal is © The Royal Society of Chemistry.)
- Published
- 2020
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47. A brain tumor-homing tetra-peptide delivers a nano-therapeutic for more effective treatment of a mouse model of glioblastoma.
- Author
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Kang RH, Jang JE, Huh E, Kang SJ, Ahn DR, Kang JS, Sailor MJ, Yeo SG, Oh MS, Kim D, and Kim HY
- Subjects
- Animals, Annexin A3 chemistry, Cell Line, Tumor, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Nanoparticles chemistry, Peptide Fragments chemistry, Polyethylene Glycols chemistry, Silicon chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents therapeutic use, Cell-Penetrating Peptides chemistry, Drug Carriers chemistry, Glioblastoma drug therapy, Irinotecan therapeutic use, Oligopeptides chemistry
- Abstract
Organ-specific cell-penetrating peptides (CPPs) are a class of molecules that can be highly effective at delivering therapeutic cargoes, and they are currently of great interest in cancer treatment strategies. Herein, we describe a new CPP (amino acid sequence serine-isoleucine-tyrosine-valine, or SIWV) that homes to glioblastoma multiforme (GBM) brain tumor tissues with remarkable specificity in vitro and in vivo. The SIWV sequence was identified from an isoform of annexin-A3 (AA3H), a membrane-interacting human protein. The mechanism of intracellular permeation is proposed to follow a caveolin-mediated endocytotic pathway, based on in vitro and in vivo receptor inhibition and genetic knockdown studies. Feasibility as a targeting agent for therapeutics is demonstrated in a GBM xenograft mouse model, where porous silicon nanoparticles (pSiNPs) containing the clinically relevant anticancer drug SN-38 are grafted with SIWV via a poly-(ethylene glycol) (PEG) linker. The formulation shows enhanced in vivo targeting ability relative to a formulation employing a scrambled control peptide, and significant (P < 0.05) therapeutic efficacy relative to free SN-38 in the GBM xenograft animal model.
- Published
- 2020
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48. Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice.
- Author
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Huh E, Choi JG, Noh D, Yoo HS, Ryu J, Kim NJ, Kim H, and Oh MS
- Subjects
- Animals, Colitis chemically induced, Colitis metabolism, Dopaminergic Neurons metabolism, Intestinal Mucosa innervation, Intestinal Mucosa metabolism, MPTP Poisoning metabolism, Male, Mice, Inbred C57BL, Signal Transduction drug effects, Tight Junctions metabolism, Catechols administration & dosage, Dopaminergic Neurons drug effects, Zingiber officinale chemistry, Intestinal Mucosa drug effects, Plant Extracts administration & dosage, Protective Agents administration & dosage, Tight Junctions drug effects
- Abstract
Objective: Ginger and its compound, 6-shogaol, have been known for improving gastrointestinal (GI) function and reducing inflammatory responses in GI tract. Recently, the treatment of GI dysfunction has been recognized as an important part of the management of neurodegenerative diseases, especially for Parkinson's disease (PD). In this study, we investigated whether ginger and 6-shogaol attenuate disruptions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the intestinal barrier and the enteric dopaminergic neurons. Methods: C57BL/6J mice received MPTP (30 mg/kg) for 5 days to induce GI alterations. Ginger (30, 100, 300 mg/kg) and 6-shogaol (10 mg/kg) were treated by gavage feeding for 15 days including the period of MPTP injection. Results: Ginger and 6-shogaol protected intestinal tight junction proteins disrupted by MPTP in mouse colon. In addition, ginger and 6-shogaol suppressed the increase of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α and IL-1β activated by macrophage. Moreover, ginger and 6-shogaol suppressed the MPTP-induced enteric dopaminergic neuronal damage via increasing the cell survival signaling pathway. Conclusion: These results indicate that ginger and 6-shogaol restore the disruption of intestinal integrity and enteric dopaminergic neurons in an MPTP-injected mouse PD model by inhibiting the processes of inflammation and apoptosis, suggesting that they may attenuate the GI dysfunction in PD patients.
- Published
- 2020
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49. Penta-fluorophenol: a Smiles rearrangement-inspired cysteine-selective fluorescent probe for imaging of human glioblastoma.
- Author
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An JM, Kang S, Huh E, Kim Y, Lee D, Jo H, Joung JF, Kim VJ, Lee JY, Dho YS, Jung Y, Hur JK, Park C, Jung J, Huh Y, Ku JL, Kim S, Chowdhury T, Park S, Kang JS, Oh MS, Park CK, and Kim D
- Abstract
Two of the most critical factors for the survival of glioblastoma (GBM) patients are precision diagnosis and the tracking of treatment progress. At the moment, various sophisticated and specific diagnostic procedures are being used, but there are relatively few simple diagnosis methods. This work introduces a sensing probe based on a turn-on type fluorescence response that can measure the cysteine (Cys) level, which is recognized as a new biomarker of GBM, in human-derived cells and within on-site human clinical biopsy samples. The Cys-initiated chemical reactions of the probe cause a significant fluorescence response with high selectivity, high sensitivity, a fast response time, and a two-photon excitable excitation pathway, which allows the imaging of GBM in both mouse models and human tissue samples. The probe can distinguish the GBM cells and disease sites in clinical samples from individual patients. Besides, the probe has no short or long-term toxicity and immune response. The present findings hold promise for application of the probe to a relatively simple and straightforward following of GBM at clinical sites., (This journal is © The Royal Society of Chemistry 2020.)
- Published
- 2020
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50. Diagnostic and Interventional Imaging Services are Significant Sources of Medicare Revenue for Highly Reimbursed Nonradiologist Providers.
- Author
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Degnan AJ, Yi PH, Kim N, Swietlik J, Huh E, and Nguyen JC
- Subjects
- Humans, United States, Diagnostic Imaging economics, Health Personnel economics, Medicare economics, Radiology, Interventional economics
- Abstract
Introduction: Nonradiologist providers increasingly perform diagnostic imaging examinations and imaging-guided interventions traditionally performed by radiologists, which have raised concerns regarding appropriate utilization and self-referral. The purpose of this study was to assess the contribution of imaging studies to Medicare reimbursements for highly compensated nonradiologist providers in specialties often performing imaging studies., Methods: The Medicare Provider Utilization and Payment Database was queried for provider information regarding overall reimbursement for providers in anesthesiology, cardiology, emergency medicine, neurology, obstetrics and gynecology, orthopedic surgery, neurology, and vascular surgery. Information regarding imaging studies reported and payment amounts were extracted for the 25 highest-reimbursed providers. Data were analyzed for relative contribution of imaging payments to overall medical Medicare payments., Results: Significant differences between numbers of imaging studies, types of imaging, and payment amounts were noted based on provider specialty (p < 0.001). Highest-reimbursed cardiologists received the greatest percentage of Medicare payments from imaging (18.3%) followed by vascular surgery (11.6%), obstetrics and gynecology (10.9%), orthopedic surgery (9.6%), emergency medicine (8.7%), neurology (7.8%), and anesthesiology (3.2%) providers. Mean imaging payments amongst highly reimbursed nonradiologists were greatest for cardiology ($578,265), vascular surgery ($363,912), and orthopedic surgery ($113,634). Amongst highly reimbursed specialists, most common nonradiologist imaging payments were from ultrasound (45%) and cardiac nuclear medicine studies (40%)., Conclusions: Nonradiologist performed imaging payments comprised substantial proportions of overall Medicare reimbursement for highly reimbursed physicians in several specialties, especially cardiology, vascular surgery, and orthopedic surgery. Further investigation is needed to better understand the wider economic implications of nonradiologist imaging study performance and self-referral beyond the Medicare population., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2020
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