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Suppressed humoral immunity is associated with dengue nonstructural protein NS1-elicited anti-death receptor antibody fractions in mice
(2020-04-14)
Tsai, Chung-Lin
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Sun, Der-Shan
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Su, Mei-Tzu
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Lien, Te-Sheng
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Chen, Yen-Hsu
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF). Suppressed protective immunity was shown in these patients. Although several hypotheses have been formulated, the mechanism of DENV-induced immunosuppression remains unclear. Previously, we found that cross-reactive antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]) were elicited in DHF patients, and that anti-DR4 autoantibody fractions were elicited by nonstructural protein 1 (NS1) immunizations in experimental mice. In this study, we found that anti-DR4 antibodies could suppress B lymphocyte function in vitro and in vivo. Treatment with the anti-DR4 immunoglobulin (Ig) induced caspase-dependent cell death in immortalized B lymphocyte Raji cells in vitro. Anti-DR4 Igs elicited by NS1 and DR4 immunizations markedly suppressed mouse spleen transitional T2 B (IgM(+)IgD(+)), bone marrow pre-pro-B (B220(+)CD43(+)), pre-B (B220(+)CD43(-)), and mature B cell (B220(+)IgD(+)) subsets in mice. Furthermore, functional analysis revealed that the pre-elicitation of anti-NS1 and anti-DR4 Ig titers suppressed subsequently neutralizing antibody production by immunization with DENV envelop protein. Our data suggest that the elicitation of anti-DR4 titers through DENV NS1 immunization plays a suppressive role in humoral immunity in mice.
Google Trends-based non-English language query data and epidemic diseases: a cross-sectional study of the popular search behaviour in Taiwan
(2020-01-01)
Chang, Yu-Wei
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Chiang, Wei-Lun
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Wang, Wen-Hung
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Lin, Chun-Yu
;
Hung, Ling-Chien
Objective This study developed a surveillance system suitable for monitoring epidemic outbreaks and assessing public opinion in non-English-speaking countries. We evaluated whether social media reflects social uneasiness and fear during epidemic outbreaks and natural catastrophes. Design Cross-sectional study. Setting Freely available epidemic data in Taiwan. Main outcome measure We used weekly epidemic incidence data obtained from the Taiwan Centers for Disease Control and online search query data obtained from Google Trends between 4 October 2015 and 2 April 2016. To validate whether non-English query keywords were useful surveillance tools, we estimated the correlation between online query data and epidemic incidence in Taiwan. Results With our approach, we noted that keywords (sic)& x5192; ('common cold'), & x767c;& x71d2; ('fever') and & x54b3;& x55fd; ('cough') exhibited good to excellent correlation between Google Trends query data and influenza incidence (r=0.898, p<0.001; r=0.773, p<0.001; r=0.796, p<0.001, respectively). They also displayed high correlation with influenza-like illness emergencies (r=0.900, p<0.001; r=0.802, p<0.001; r=0.886, p<0.001, respectively) and outpatient visits (r=0.889, p<0.001; r=0.791, p<0.001; r=0.870, p<0.001, respectively). We noted that the query & x8178;(sic)& x6bd2; ('enterovirus') exhibited excellent correlation with the number of enterovirus-infected patients in emergency departments (r=0.914, p<0.001). Conclusions These results suggested that Google Trends can be a good surveillance tool for epidemic outbreaks, even in Taiwan, the non-English-speaking country. Online search activity indicates that people are concerned about epidemic diseases, even if they do not visit hospitals. This prompted us to develop useful tools to monitor social media during an epidemic because such media usage reflects infectious disease trends more quickly than does traditional reporting.
Design of Fin-Diode-Triggered Rotated Silicon-Controlled Rectifier for High-Speed Digital Application in 16-nm FinFET Process
(2020-07-01)
Chang, Rong-Kun
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Lin, Chun-Yu
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Ker, Ming-Dou
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電子工程學系及電子研究所
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Department of Electronics Engineering and Institute of Electronics
The FinFET architecture has widely been used in the digital circuit application, due to the good short channel effect control and driving current boost. However, the worse thermal dispassion and smaller effective silicon volume would cause the significant impacts during the circuits under electrostatic discharge (ESD) event. Thus, the ESD protection device should be installed into the high-speed digital circuit to enhance the ESD robustness. To avoid the effect of circuit performance, the parasitic capacitance of ESD device must be as low as possible. In this article, two types of Fin-diode-triggered rotated silicon-controlled rectifier (SCR) with dual ESD current path have been proposed and verified in a 16-nm FinFET CMOS process. The proposed devices have better current-handling capability, sufficiently low parasitic, compact layout area, and low leakage current.
ABLGenomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo
(2020-06-01)
Chen, Shu-Huey
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Hsieh, Yao-Yu
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Tzeng, Huey-En
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Lin, Chun-Yu
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Hsu, Kai-Wen
Chronic myelogenous leukemia (CML) is the most common type of leukemia in adults, and more than 90% of CML patients harbor the abnormal Philadelphia chromosome (Ph) that encodes the BCR-ABL oncoprotein. Although the ABL kinase inhibitor (imatinib) has proven to be very effective in achieving high remission rates and improving prognosis, up to 33% of CML patients still cannot achieve an optimal response. Here, we used CRISPR/Cas9 to specifically target theBCR-ABLjunction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety ofBCR-ABLjunctions in CML patients, we utilized gene editing of the humanABLgene for clinical applications. Using theABLgene-edited virus in K562 cells, we detected 41.2% indels inABLsgRNA_2-infected cells. TheABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced theABLgene-edited virus into a systemic K562 leukemia xenograft mouse model, and bioluminescence imaging of the mice showed a significant reduction in the leukemia cell population inABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with theABLgene-edited virus resulted in more than 30.9% indels and significant cancer cell death. Notably, no off-target effects or bone marrow cell suppression was found using theABLgene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of theABLgene in maintaining CML cell survival and tumorigenicity in vitro and in vivo.ABLgene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients.
An Integrated Genomic Strategy to Identify CHRNB4 as a Diagnostic/Prognostic Biomarker for Targeted Therapy in Head and Neck Cancer
(2020-05-01)
Chuang, Yi-Hsuan
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Lee, Chia-Hwa
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Lin, Chun-Yu
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Liu, Chia-Lin
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Huang, Sing-Han
Although many studies have shown the association between smoking and the increased incidence and adverse prognosis of head and neck squamous cell carcinoma (HNSCC), the mechanisms and pharmaceutical targets involved remain unclear. Here, we integrated gene expression signatures, genetic alterations, and survival analyses to identify prognostic indicators and therapeutic targets for smoking HNSCC patients, and we discovered that the FDA-approved drug varenicline inhibits the target for cancer cell migration/invasion. We first identified 18 smoking-related and prognostic genes for HNSCC by using RNA-Seq and clinical follow-up data. One of these genes, CHRNB4 (neuronal acetylcholine receptor subunit beta-4), increased the risk of death by approximately threefold in CHRNB4-high expression smokers compared to CHRNB4-low expression smokers (log rank, p = 0.00042; hazard ratio, 2.82; 95% CI, 1.55-5.14), former smokers, and non-smokers. Furthermore, we examined the functional enrichment of co-regulated genes of CHRNB4 and its 246 frequently occurring copy number alterations (CNAs). We found that these genes were involved in promoting angiogenesis, resisting cell death, and sustaining proliferation, and contributed to much worse outcomes for CHRNB4-high patients. Finally, we performed CHRNB4 gene editing and drug inhibition assays, and the results validate these observations. In summary, our study suggests that CHRNB4 is a prognostic indicator for smoking HNSCC patients and provides a potential new therapeutic drug to prevent recurrence or distant metastasis.
Improved and fast biotissue imaging by temporal focusing widefield multiphoton microscopy with spatially modulated illumination
(2019-01-01)
Chang, Chia-Yuan
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Lin, Chun-Yu
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Hovhannisyan, Vladimir A.
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Chen, Shean-Jen
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光電學院
A developed temporal focusing-based multiphoton microscope (TFMPM) has a digital micromirror device (DMD) which is adopted not only as a blazed grating for light spatial dispersion but also for patterned illumination simultaneously. Herein, the TFMPM has been extended to implement spatially modulated illumination at structured frequency and orientation to increase the beam coverage at the back-focal aperture of the objective lens. The axial excitation confinement (AEC) of TFMPM can be condensed from 3.0 mu m to 1.5 mu m for a 50% improvement. Furthermore, a multiline scanning mechanism based on the DMD can push its AEC nearly equivalent to line scanning-based TFMPM to 1.5 mu m from optimal 3.0 mu m of the conventional TFMPM. By using the TFMPM with structured illumination and multiline scanning, reconstructed biotissue images according to the condensed AEC structured illumination are shown obviously superior in contrast and better scattering suppression.
Tellimagrandin II, A Type of Plant Polyphenol Extracted from Trapa bispinosa Inhibits Antibiotic Resistance of Drug-Resistant Staphylococcus aureus
(2019-11-01)
Chang, Yu-Wei
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Huang, Wan-Chun
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Lin, Chun-Yu
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Wang, Wen-Hung
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Hung, Ling-Chien
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), a pure compound extracted from the shells of Trapa bispinosa, exhibits antibacterial effects against MRSA. We first showed that TGII exerted potent inhibitory activity against MRSA with a minimum inhibitory concentration of 128 mu g/mL. The obtained fractional inhibitory concentration suggested that TGII could alone exert antistaphylococcal activity, and TGII combined with low doses of antibiotics displayed synergistic effects against MRSA. Moreover, we found that TGII exerted bactericidal activity by reducing the expression of mecA followed by the negative regulation of the penicillin-binding protein 2a (PBP2a) of MRSA. Transmission electron microscopy (TEM) images further confirmed that TGII destroyed the integrity of the cell wall of MRSA and caused the loss of cytoplasm content. In conclusion, we evidenced the antibacterial effects of TGII against MRSA, which enables the effective dose of current antibiotics to be reduced and the predicament of drug-resistant S. aureus isolates to be overcome.
High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity
(2019-10-01)
Lin, Chun-Yu
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Kolliopoulos, Constantinos
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Huang, Chung-Hao
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Tenhunen, Jyrki
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Heldin, Carl-Henrik
Background: A main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known. Methods: A cohort of 250 dengue patients has been followed from the onset of symptoms to the recovery phase. Set urn hyaluronan levels and several other clinical parameters were recorded. The effect of NS1 treatment of cultured fibroblasts and endothelial cells on the expressions of hyaluronan synthetic and catabolic enzymes and the hyaluronan receptor CD44, were determined, as have the effects on the formation of hyaluronan-rich matrices and endothelial permeability. Findings: Elevated serum hyaluronan levels (70 ng/ml) during early infection was found to be an independent predictor for occurrence of warning signs, and thus severe dengue fever. High circulating levels of the viral protein NS1, indicative of disease severity, correlated with high concentrations of serum hyaluronan. NS1 exposure decreased the expression of CD44 in differentiating endothelial cells impairing the integrity of vessel-like structures, and promoted the synthesis of hyaluronan in dermal fibroblasts and endothelial cells in synergy with dengue-induced pro-inflammatory mediators. Deposited hyaluronan-rich matrices around cells cultured in vitro recruited CD44-expressing macrophage-like cells, suggesting a mechanism for enhancement of inflammation. In cultured endothelial cells, perturbed hyaluronan-CD44 interactions enhanced endothelial permeability through modulation of VE-cadherin and cytoskeleton re-organization, and exacerbated the NS1-induced disruption of endothelial integrity. Interpretation: Pharmacological targeting of hyaluronan biosynthesis and/or its CD44-mediated signaling may limit the life-threatening vascular leakiness during moderate-to-severe dengue virus infection. (C) 2019 Published by Elsevier B.V.
Temporal focusing-based multiphoton excitation fluorescence images with background noise cancellation via Hilbert-Huang transform
(2019-01-01)
Hu, Yvonne Yuling
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Luo, Yuan-Rong
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Lin, Chun-Yu
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Chang, Chia-Yuan
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Chen, Shean-Jen
Temporal focusing multiphoton excitation microscopy has wide field-of-view and optical sectioning. By using digital micromirror device, it provides patterned illumination. However, without filling the back aperture of objective lens, the axial confinement is limited to micron-meters, leading the out-of-focus fluorophores excited and image blurred. In this study, Hilbert-Huang transform is proposed to reduce the background noise. The empirical mode decomposition is first applied to disassemble the image into intrinsic mode functions and then reconstruct by Hilbert transform after diminishing background residues. The axial confinement can be enhanced from 2.79 mu m to 0.73 mu m with structure frequency in 1.06 mu m(-1).
HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells
(2019-05-01)
Chen, Shu-Huey
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Chow, Jyh-Ming
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Hsieh, Yao-Yu
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Lin, Chun-Yu
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Hsu, Kai-Wen
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%-20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic.

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