Virtual Screening and Testing of GSK-3 Inhibitors Using Human SH-SY5Y Cells Expressing Tau Folding Reporter and Mouse Hippocampal Primary Culture under Tau Cytotoxicity

Lin Chih-Hsin,Hsieh Yu-Shao,Sun Ying-Chieh,Huang Wun-Han,Chen Shu-Ling,Weng Zheng-Kui,Lin Te-Hsien,Wu Yih-Ru,Chang Kuo-Hsuan,Huang Hei-Jen,Lee Guan-Chiun,Hsieh-Li Hsiu Mei,Lee-Chen Guey-Jen 한국응용약물학회 2023 Biomolecules & Therapeutics(구 응용약물학회지) Vol.31 No.1

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that implicates in multiple cellular processes and links with the neurodegenerative diseases including Alzheimer’s disease (AD). In this study, structure-based virtual screening was performed to search database for compounds targeting GSK-3β from Enamine’s screening collection. Of the top-ranked compounds, 7 primary hits underwent a luminescent kinase assay and a cell assay using human neuroblastoma SH-SY5Y cells expressing Tau repeat domain (TauRD) with pro-aggregant mutation ΔK280. In the kinase assay for these 7 compounds, residual GSK-3β activities ranged from 36.1% to 90.0% were detected at the IC50 of SB-216763. In the cell assay, only compounds VB-030 and VB-037 reduced Tau aggregation in SH-SY5Y cells expressing ΔK280 TauRD-DsRed folding reporter. In SH-SY5Y cells expressing ΔK280 TauRD, neither VB-030 nor VB-037 increased expression of GSK-3α Ser21 or GSK-3β Ser9. Among extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT), mitogen-activated protein kinase 14 (P38) and mitogenactivated protein kinase 8 (JNK) which modulate Tau phosphorylation, VB-037 attenuated active phosphorylation of P38 Thr180/ Tyr182, whereas VB-030 had no effect on the phosphorylation status of ERK, AKT, P38 or JNK. However, both VB-030 and VB-037 reduced endogenous Tau phosphorylation at Ser202, Thr231, Ser396 and Ser404 in neuronally differentiated SH-SY5Y expressing ΔK280 TauRD. In addition, VB-030 and VB-037 further improved neuronal survival and/or neurite length and branch in mouse hippocampal primary culture under Tau cytotoxicity. Overall, through inhibiting GSK-3β kinase activity and/or p-P38 (Thr180/Tyr182), both compounds may serve as promising candidates to reduce Tau aggregation/cytotoxicity for AD treatment.

Mucopolysaccharidoses in Taiwan

Lin, Hsiang-Yu,Chuang, Chih-Kuang,Lin, Shuan-Pei Association for Research of MPS and Rare Diseases 2018 Journal of mucopolysaccharidosis and rare disease Vol.4 No.1

Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic disorders caused by specific lysosomal enzyme deficiencies leading to the sequential degradation of glycosaminoglycans, causing substrate accumulation in various cells and tissues and progressive multiple organ dysfunction. The rare disease medical care team at Mackay Memorial Hospital in Taiwan has been dedicated to the study of MPSs for more than 20 years. Since 1999, more than 50 academic papers focusing on MPSs have been published in international medical journals. Topics of research include the following items regarding MPSs: incidence, natural history, clinical manifestations, gene mutation characteristics, cardiac function, bone mineral density, sleep studies, pulmonary function tests, hearing assessments, percutaneous endoscopic gastrostomy, anesthetic experience, imaging analysis, special biochemical tests, laboratory diagnostics, global expert consensus conferences, prenatal diagnosis, new drug clinical trials, newborn screening, and treatment outcomes. Of these published academic research papers, more than half were cross-domain, cross-industry, and international studies with results in cooperation with experts from European, American and other Asian countries. A cross-specialty collaboration platform was established based on high-risk population screening criteria with the acronym "BECARE" (Bone and joints, Eyes, Cardiac and central nervous system, Abdomen and appearance, Respiratory system, and Ear, nose, and throat involvement). Through this platform, orthopedic surgeons, rheumatologists, ophthalmologists, cardiologists, rehabilitation physicians, gastroenterologists, otorhinolaryngologists, and medical geneticists have been educated with regards to awareness of suspected cases of MPSs patients to allow for a further confirmative diagnosis of MPSs. Because of the progressive nature of the disease, an early diagnosis and early multidisciplinary therapeutic interventions including surgery, rehabilitation programs, symptom-based treatments, hematopoietic stem cell transplantation, and enzyme replacement therapy, are very important.

Application of physical vapor deposition process to modify activated carbon fibers for ozone reduction

Yu-Chih Lin,Chung-Liang Chang,Tser-Sheng Lin,Hsunling Bai,Ming-Gu Yan,Fu-Hsiang Ko,Chia-Tien Wu,Cheng-Hsiung Huang 한국화학공학회 2008 Korean Journal of Chemical Engineering Vol.25 No.3

This study utilized the activated carbon fiber (ACF) modified with metal catalyst via physical vapor deposition (PVD) process (ACF/PVD) to diminish ozone. Furthermore, the ozone removal efficiency of ACF/PVD was compared with that of original ACF and ACF modified with metal catalyst via impregnation process (ACF/impregnation). In addition to the kinds of coated metal and the inlet ozone concentrations, the effects of the coating thickness and the reaction temperature on ACF/PVD for ozone removal were also examined. The results indicate that the ozone removal efficiency of ACF/PVD is better than that of original ACF and ACF/impregnation. The ozone removal efficiency of different metal-coated ACF/PVD in the superior order is gold (Au), and manganese (Mn). The increase of Au-coated thickness (3 nm to 80 nm) on ACF/PVD will enhance the ozone removal. However, when the Mn-coated thickness on ACF/PVD is larger than 15 nm, the ozone removal efficiency displays a declining trend. Furthermore, a higher reaction temperature will result in a better ozone removal of ACF/PVD and the original ACF.

Simple but Organized Neurology Residency Training Improves the Quality of Acute Stroke Care: From the Outset to Long-Term Effect

Yu-Ming Chang,Chun-Min Wang,Po-Yu Lin,Pi-Shan Sung,Sheng-Hsiang Lin,Chih-Hung Chen 대한뇌졸중학회 2021 Journal of stroke Vol.23 No.2

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Resonant vibration of piezoceramic plates in fluid

Lin, Yu-Chih,Ma, Chien-Ching Techno-Press 2008 Interaction and multiscale mechanics Vol.1 No.2

In this paper, both experimental measurement and theoretical analysis are used to investigate the out-of-plane resonant characteristics of a cantilevered piezoceramic plate in air and three different kinds of fluid. The experimental method, amplitude-fluctuation electronic speckle pattern interferometry (AF-ESPI), is the major technique used in this study to measure the resonant characteristics of the cantilivered piezoceramic plate. Both resonant frequencies and full-field mode shapes are obtained from this experimental technique. Numerical computations based on the finite element analysis are presented for comparison with the experimental results. Good quality of mode shapes for the cantilevered piezoceramic plate in air is obtained from the AF-ESPI technique. However, the quality decreases as the viscosity of fluids increases. From the results provided from experimental measurements and numerical computations, it is indicated that the resonant frequencies of the cantilevered piezoceramic plate in fluid decrease with the increase of the viscosity of fluids. Good agreements between the experimental measured data and the numerical calculated results are found for both resonant frequencies and mode shapes of the cantilevered piezoceramic plate in fluid.

Early Diagnosis for Mucopolysaccharidosis I - A 6-month-old Female Infant Presenting with Gibbus, Hirsutism and Mongolian Spots in a Well Baby Clinic

Lin, Hsiang-Yu,Chuang, Chih-Kuang,Chang, Jui-Hsing,Lin, Shuan-Pei Association for Research of MPS and Rare Diseases 2016 Journal of mucopolysaccharidosis and rare disease Vol.2 No.1

Mucopolysaccharidosis (MPS) I is a rare, progressive and multisystemic disease with insidious initial signs and symptoms, and making an early diagnosis can be a challenge for the first-line general medical practitioner. We report a 6-month-old girl who was brought to our well baby clinic for regular immunization with the manifestations of lumbar gibbus, hirsutism, large Mongolian spots over back and buttock, and mild bilateral legs spasticity noticed by the general pediatrician, and then newly diagnosed with MPS I after referral to the geneticist in time. Her surgical history included inguinal hernia repair at 1 month old, $CO_2$ laser supraglottoplasty for laryngomalacia and tracheostomy due to chronic respiratory failure with ventilator dependence at 2 months old. Understanding and identification of the early signs and symptoms of this disease have the potential to early diagnosis and timely appropriate treatment, which could contribute to a better clinical outcome.

A P2P-to-UPnP Proxy Gateway Architecture for Home Multimedia Content Distribution

( Chih-lin Hu ),( Hsin-cheng Lin ),( Yu-feng Hsu ),( Bing-jung Hsieh ) 한국인터넷정보학회 2012 KSII Transactions on Internet and Information Syst Vol.6 No.1

Deploying advanced home networking technologies and modern home-networked devices in residential environments provides a playground for new home applications and services. Because home multimedia entertainment is among the most essential home applications, this paper presents an appealing home media content sharing scenario: home-networked devices can discover neighboring devices and share local media content, as well as enormous amounts of Internet media content in a convenient and networked manner. This ideal scenario differs from traditional usages that merely offer local media content and require tedious manual operations of connection setup and file transfer among various devices. To achieve this goal, this study proposes a proxy gateway architecture for home multimedia content distribution. The proposed architecture integrates several functional mechanisms, including UPnP-based device discovery, home gateway, Internet media provision, and in-home media content delivery. This design addresses several inherent limitations of device heterogeneity and network interoperability on home and public networks, and allows diverse home-networked devices to play media content in an identical and networked manner. Prototypical implementation of the proposed proxy gateway architecture develops a proof-of-concept software, integrating a BitTorrent peer-to-peer client, a UPnP protocol stack, and a UPnP AV media server, as well as media distribution and management components on the OSGi home gateway platform. Practical demonstration shows the proposed design and scenario realization, offering users an unlimited volume of media content for home multimedia entertainment.

Newborn Screening for Lysosomal Storage Diseases in Taiwan

Lin, Hsiang-Yu,Chuang, Chih-Kuang,Lin, Shuan-Pei Association for Research of MPS and Rare Diseases 2017 Journal of mucopolysaccharidosis and rare disease Vol.3 No.1

Lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders caused by the deficiency of specific lysosomal enzymes and subsequent accumulation of substrates. Enzyme deficiency leads to progressive intra-lysosomal accumulation of the incompletely degraded substances, which cause dysfunction and destruction of the cell and eventually multiple organ damage. Patients have a broad spectrum of clinical phenotypes which are generally not specific for some LSDs, leading to missed or delayed diagnosis. Due to the availability of treatment including enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation for some LSDs, early diagnosis is important. ERT products have been approved with optimal outcomes for some LSDs in the recent decades, including Gaucher, Fabry, mucopolysaccharidosis (MPS) I, Pompe, MPS VI, MPS II, and MPS IVA diseases. ERT can stabilize the clinical condition, prevent disease progression, and improve the long-term outcome of these diseases, especially if started prior to irreversible organ damage. Based on the availability of therapy and suitable screening methods in the recent years, some LSDs, including Pompe, Fabry, Gaucher, MPS I, MPS II, and MPS VI diseases have been incorporated into nationwide newborn screening panels in Taiwan.

Thermal Stability, Adhesion and Electrical Studies on (Ti,Zr)Nx Thin Films as Low Resistive Diffusion Barriers between Cu and Si

Cheng-Lin Huang,Chih-Huang Lai,Po-Hao Tsai,Yu-Lin Kuo,Jing-Cheng Lin,Chiapyng Lee 대한금속·재료학회 2014 ELECTRONIC MATERIALS LETTERS Vol.10 No.3

In this study, we investigated the thermal stability, wettability, adhesion and reliability of (Ti,Zr)Nx films used as the diffusion barrier between Cu and Si. (Ti,Zr)Nx films were prepared by DC reactive magnetron sputtering from a Ti-5 at. % Zr alloy target in N2/Ar gas mixtures. A minimum film resistivity of 59.3 μΩ cm was obtained at an N2/Ar flow ratio of 2.75, which corresponds to the near stoichiometric composition (N/(Ti,Zr) ratio ~0.95). The sheet resistance of Cu/(Ti,Zr)N0.95/Si was not significantly increased until annealing above 750°C, indicating good thermal stability. On the other hand, the adhesion energy between Cu and the (Ti,Zr)Nx film was reduced as the N/Ti ratio was increased. To obtain reliable performance on stress-induced-voiding (SIV) and electromigration (EM) tests, we proposed to use (Ti,Zr)/(Ti,Zr)Nx/(Ti,Zr) tri-layers. We suggest that the interfacial adhesion between barrier and Cu plays an important role in reliability. The proposed tri-layer structure may be a promising candidate for a barrier, as it exhibits excellent reliability without increasing resistance.

Management of Hyperacute Stroke during the Coronavirus Disease of 2019 Pandemic: The Modified Code Stroke in a Medical Center in Taiwan

Po-Yu Lin,Yu-Ming Chang,Chih-Yuan Huang,Chih-Hao Lin,Ming-Tsung Chuang,Po-Lin Chen,Pi-Shan Sung,Chih-Hung Chen 대한뇌졸중학회 2020 Journal of stroke Vol.22 No.2

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