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.

A Novel High Precision Electromagnetic Flexure-Suspended Positioning Stage with an Eddy Current Damper

Chih-Hsien Lin,Shao-Kung Hung,Mei-Yung Chen,Shan-Tsung Li,Li-Chen Fu 제어로봇시스템학회 2008 제어로봇시스템학회 국제학술대회 논문집 Vol.2008 No.10

This paper proposes a novel planar electromagnetic-actuated positioning stage. The stage is suspended by the monolithic parallel flexure mechanism, which motion comes from the deformation of the flexure. A linear electromagnetic actuator which consists of a near-uniform magnetic field and four coils is designed and implementation to provide the propelling force for 3-DOF motions. In order to suppress the vibration of the flexure suspension mechanism, an eddy current damper is designed and integrated with the electromagnetic actuator. The non-contact damper is more advanced than the contact damper used in our previous researches. The design traveling range is 3mm × 3mm in planar motion. The experimental results show the vibration of the flexure mechanism could be suppressed by the designed eddy current damper. The results also show the regulation and tracking performance by a well-designed robust adaptive sliding mode controller, which can overcome the disturbance and modeling uncertainty and guarantee a satisfactory performance.

Research on Increasing the Production Yield Rate by Six Sigma Method : A Case of SMT Process of Main Board

Lin, Ching-Kun,Chen, Hsien-Ching,Li, Rong-Kwei,Chen, Ching-Piao,Tsai, Chih-Hung The Korean Society for Quality Management 2009 The Asian Journal on Quality Vol.10 No.1

Face the process yield rate improvements of motherboard, although general enterprises finish deployment goal of each functions by overall quality managements, through quality improvement methods, industry engineering methods, plan-do-check-act (PDCA) methods and other improvement solutions, but it is only can be improved partially and unable to enhance the yield rate of product to the target. It only can takes one step ahead to enhance the process yield rate of motherboard with six sigma ($6{\sigma}$) overall DMAIC process and tactics. This research aimed to use six sigma quality improvement tactics by DMAIC systematic procedure and tactics, and find the key factors that effect to the process yield rate of surface mount technology. It also identified the keys input and process and output index to satisfy customer requirements and internal process index. The results showed that the major effective factors by fishbone and process failure modes and effects analysis (PFMEA). If the index of input and output that can be quantified, the optimum parameter can be found through design of experiment to ensure that the process is stable. If the factor of input and output that cannot be quantified, we found out the effective countermeasure by Mind_Mapping, make sure whole processes can be controlled stably, to reach the high product quality and enhance the customer satisfaction.

Supplementary effects of higher levels of various disaccharides on processing yield, quality properties and sensory attributes of Chinese - style pork jerky

Chih-Ming Chen,Hsien-Tang Lin 아세아·태평양축산학회 2017 Animal Bioscience Vol.30 No.12

Objective: This study evaluated the supplementary effect of higher concentrations of various disaccharides on processing yield, major physicochemical properties, and sensory attributes of Chinese-style pork jerky (CSPJ). Methods: CSPJ samples were prepared by marinating sliced ham (4 mm) with three dissaccharides, including sucrose, lactose, and maltose, at 0%, 15%, 18%, 21%, and 24%. Subsequently, the CSPJ samples were dried and roasted. The moisture content, water activity, crude protein, moisture-to-protein ratio, pH, processing yield, shear force, color, and sensory attributes of the CSPJ samples were evaluated. Results: The quality characteristics of CSPJ samples prepared with sucrose were more acceptable. By contrast, CSPJ samples prepared with lactose showed the lowest scores. However, the processing yield and moisture content were the highest for CSPJ samples prepared with lactose, which may be associated with improved benefits for cost reduction. Furthermore, sucrose and lactose supplementation resulted in contrasting quality characteristics; for example, CSPJ samples with sucrose and maltose supplementation had higher sensory scores for color than samples with lactose supplementation. Additionally, most quality characteristics of CSPJ samples with sucrose supplementation contrasted with those of the samples with lactose supplementation; for example, the samples with sucrose supplementation had higher scores for sensory attributes than those with lactose supplementation. Conclusion: Sucrose supplementation up to 21% to 24% was associated with the highest overall acceptability scores (5.19 to 5.80), enhanced quality characteristics, increased processing yield, and reduced production cost.

The Study of the Cycle Time Improvement by Work-In-Process Statistical Process Control Method for IC Foundry Manufacturing

Lin, Yu-Cheng,Tsai, Chih-Hung,Li, Rong-Kwei,Chen, Ching-Piao,Chen, Hsien-Ching The Korean Society for Quality Management 2008 The Asian Journal on Quality Vol.9 No.3

The definition of cycle time is the time from the wafer start to the wafer output. It usually takes one or two months to get the product since customer decides to produce it. The cycle time is a critical factor for customer satisfaction because it represents the response time to the market. Long cycle time reflects the ineffective investment for the capital. The cycle time is very important for foundry because long cycle time will cause customer unsatisfied and the order loss. Consequently, all of the foundries put lots of human source in the cycle time improvement. Usually, we make decisions based on the experience in the cycle time management. We have no mechanism or theory for cycle time management. We do work-in-process (WIP) management based on turn rate and standard WIP (STD WIP) set by experiences. But the experience didn't mean the optimal solution, when the situation changed, the cycle time or the standard WIP will also be changed. The experience will not always be applicable. If we only have the experience and no mechanism, management will not be work out. After interview several foundry fab managers, all of the fab can't reflect the situation. That is, all of them will have an impact period after product mix or utilization varied. In this study, we want to develop a formula for standard WIP and use statistical process control (SPC) concept to set WIP upper/lower limit level. When WIP exceed the limit level, it will trigger action plans to compensate WIP Profile. If WIP Profile balances, we don't need too much WIP. So WIP level could be reduced and cycle time also could be reduced.

Microstructure and Texture Evolution of AA 6063 During an Ex-ECAE Process

Cheng-Hsien Liu,Hsin-Chih Lin,Yu-Tung Hsu 대한금속·재료학회 2016 METALS AND MATERIALS International Vol.22 No.3

Equal channel angular extrusion (ECAE) has been studied at the lab scale for many years. However, few successful industrial applications of the ECAE process have been reported. In the present work, a process referred to as Ex-ECAE that was composed of two processes of the direct extrusion and the ECAE via route C, was developed. The Ex-ECAE process was developed to refine the microstructure of the extrudate, particular the coarse grain layer (CGL) on the surface of the extrudate. The Ex-ECAE die with a die angle of 120° contained three segments and was used in the conventional direct extrusion press. The high friction and the continuous routes of the ECAE resulted in asymmetric dead metal zones (DMZs) to be formed at the corners of the die channel. It revealed that the visible grains in the CGL were refined and became invisible due to the intense shear deformation as the CGL flowed along the boundaries of the asymmetric DMZs. The textures of the Ex-ECAE at the various segments were studied by EBSD. This study demonstrated that the ECAE process could be scaled up using the extrusion press. Success or lack of success depended on the capacity of the extrusion press and the die design.

Sustainable Urban Regeneration in Taiwanese Old Urban Districts: From a User's Perspective

Cheng, Hsien-Hsin,Lin, Chao-Chih Sustainable Building Research Center 2010 International journal of sustainable building tech Vol.1 No.1

The researchers intend to approach urban regeneration issues in old urban districts from a user's perspective. Instead of experts' evaluation and professional disciplines, this research relies on the users' perceptions about the factors of the built environment on a liveable urban district. The case study areas are two historic districts in Tainan city - Chihkan district and Minsheng greenpark district. In order to measure the users' attitudes about regeneration issues, the researchers use Likert scale in questionnaire for users to fill in the right scale of their perception. The users to be surveyed can classify into two groups: 1) inhabitants in a district, 2) tourists in a district. As for inhabitants, questionnaire mainly concerns the liveability issues of an old district, for instance, the impact of high density on life quality, or satisfaction about local traffic; whilst for tourists, questionnaire concentrates on cultural tourism issues, for instance, the attractiveness of gourmet, cultural heritage or the degree of importance they feel about the retailing stores, and department stores in old districts etc. After collecting the questionnaires from both two groups, multivariate analysis is used in coding. By factor analysis, the key constructs concerning a liveable district can be concluded with priority order, for instance, cultural heritage as the most important construct, a neighbourhood for all social hierarchy as the second important construct, and a convenient neighbourhood as the third important construct and others. By descriptive statistics, the tourists' attitudes about historic districts can also be summarized, for instance, which element is more appealing to most tourists, or how important do most tourists feel about reused old buildings etc. Research results can be used to build regeneration strategies fit to the need of districts.

Value of CT in the Discrimination of Fatal from Non-Fatal Stercoral Colitis

Cheng-Hsien Wu,Chen-Chih Huang,Li-Jen Wang,Yon-Cheong Wong,Chao-Jan Wang,Wan-Chak Lo,Being-Chuan Lin,Yung-Liang Wan,Chuen Hsueh 대한영상의학회 2012 Korean Journal of Radiology Vol.13 No.3

Objective: Clinical presentation and physical signs may be unreliable in the diagnosis of stercoral colitis (SC). This study evaluates the value of computed tomography (CT) in distinguishing fatal from non-fatal SC. Materials and Methods: Ten patients diagnosed as SC were obtained from inter-specialist conferences. Additional 13 patients with suspected SC were identified via the Radiology Information System (RIS). These patients were divided into two groups; fatal and non-fatal SCs. Their CT images are reviewed by two board-certified radiologists blinded to the clinical data and radiographic reports. Results: SC occurred in older patients and displayed no gender predisposition. There was significant correlation between fatal SC and CT findings of dense mucosa (p = 0.017), perfusion defects (p = 0.026), ascites (p = 0.023), or abnormal gas (p = 0.033). The sensitivity, specificity, and accuracy of dense mucosa were 71%, 86%, and 81%, respectively. These figures were 75%, 79%, and 77% for perfusion defects; 75%, 80%, and 78% for ascites; and 50%, 93%, and 78% for abnormal gas, respectively. Each CT sign of mucosal sloughing and pericolonic abscess displayed high specificity of 100% and 93% for diagnosing fatal SC, respectively. However, this did not reach statistical significance in diagnosing fatal SC. Conclusion: CT appears to be valuable in discriminating fatal from non-fatal SC. Objective: Clinical presentation and physical signs may be unreliable in the diagnosis of stercoral colitis (SC). This study evaluates the value of computed tomography (CT) in distinguishing fatal from non-fatal SC. Materials and Methods: Ten patients diagnosed as SC were obtained from inter-specialist conferences. Additional 13 patients with suspected SC were identified via the Radiology Information System (RIS). These patients were divided into two groups; fatal and non-fatal SCs. Their CT images are reviewed by two board-certified radiologists blinded to the clinical data and radiographic reports. Results: SC occurred in older patients and displayed no gender predisposition. There was significant correlation between fatal SC and CT findings of dense mucosa (p = 0.017), perfusion defects (p = 0.026), ascites (p = 0.023), or abnormal gas (p = 0.033). The sensitivity, specificity, and accuracy of dense mucosa were 71%, 86%, and 81%, respectively. These figures were 75%, 79%, and 77% for perfusion defects; 75%, 80%, and 78% for ascites; and 50%, 93%, and 78% for abnormal gas, respectively. Each CT sign of mucosal sloughing and pericolonic abscess displayed high specificity of 100% and 93% for diagnosing fatal SC, respectively. However, this did not reach statistical significance in diagnosing fatal SC. Conclusion: CT appears to be valuable in discriminating fatal from non-fatal SC.

Infusion of Human Mesenchymal Stem Cells Improves Regenerative Niche in Thioacetamide-Injured Mouse Liver

Kao Ying-Hsien,Lin Yu-Chun,Lee Po-Huang,Lin Chia-Wei,Chen Po-Han,Tai Tzong-Shyuan,Chang Yo-Chen,Chou Ming-Huei,Chang Chih-Yang,Sun Cheuk-Kwan 한국조직공학과 재생의학회 2020 조직공학과 재생의학 Vol.17 No.5

Background: This study investigated whether xenotransplantation of human Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) reduces thioacetamide (TAA)-induced mouse liver fibrosis and the underlying molecular mechanism. Methods: Recipient NOD/SCID mice were injected intraperitoneally with TAA twice weekly for 6 weeks before initial administration of WJ-MSCs. Expression of regenerative and pro-fibrogenic markers in mouse fibrotic livers were monitored post cytotherapy. A hepatic stallate cell line HSC-T6 and isolated WJ-MSCs were used for in vitro adhesion, migration and mechanistic studies. Results: WJ-MSCs were isolated from human umbilical cords by an explant method and characterized by flow cytometry. A single infusion of WJ-MSCs to TAA-treated mice significantly reduced collagen deposition and ameliorated liver fibrosis after 2-week therapy. In addition to enhanced expression of hepatic regenerative factor, hepatocyte growth factor, and PCNA proliferative marker, WJ-MSC therapy significantly blunted pro-fibrogenic signals, including Smad2, RhoA, ERK. Intriguingly, reduction of plasma fibronectin (pFN) in fibrotic livers was noted in MSC-treated mice. In vitro studies further demonstrated that suspending MSCs triggered pFN degradation, soluble pFN conversely retarded adhesion of suspending MSCs onto type I collagen-coated surface, whereas pFN coating enhanced WJ-MSC migration across mimicked wound bed. Moreover, pretreatment with soluble pFN and conditioned medium from MSCs with pFN strikingly attenuated the response of HSC-T6 cells to TGF-β1-stimulation in Smad2 phosphorylation and RhoA upregulation. Conclusion: These findings suggest that cytotherapy using WJ-MSCs may modulate hepatic pFN deposition for a better regenerative niche in the fibrotic livers and may constitute a useful anti-fibrogenic intervention in chronic liver diseases.

The Study of the Cycle Time Improvement by Work-In-Process Statistical Process Control Method for IC Foundry Manufacturing

Yu Cheng Lin,Chih Hung Tsai,Rong Kwei Li,Ching Piao Chen,Hsien Ching Chen 한국품질경영학회 2008 The Asian Journal on Quality Vol.9 No.3

The definition of cycle time is the time from the wafer start to the wafer output. It usually takes one or two months to get the product since customer decides to produce it. The cycle time is a critical factor for customer satisfaction because it represents the response time to the market. Long cycle time reflects the ineffective investment for the capital. The cycle time is very important for foundry because long cycle time will cause customer unsatisfied and the order loss. Consequently, all of the foundries put lots of human source in the cycle time improvement. Usually, we make decisions based on the experience in the cycle time management. We have no mechanism or theory for cycle time management. We do work-in-process (WIP) management based on turn rate and standard WIP (STD WIP) set by experiences. But the experience didn`t mean the optimal solution, when the situation changed, the cycle time or the standard WIP will also be changed. The experience will not always be applicable. If we only have the experience and no mechanism, management will not be work out. After interview several foundry fab managers, all of the fab can`t reflect the situation. That is, all of them will have an impact period after product mix or utilization varied. In this study, we want to develop a formula for standard WIP and use statistical process control (SPC) concept to set WIP upper/lower limit level. When WIP exceed the limit level, it will trigger action plans to compensate WIP Profile. If WIP Profile balances, we don`t need too much WIP. So WIP level could be reduced and cycle time also could be reduced.