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1.
J Virol ; 98(4): e0177323, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38530012

ABSTRACT

Dengue vaccine candidates have been shown to improve vaccine safety and efficacy by altering the residues or accessibility of the fusion loop on the virus envelope protein domain II (DIIFL) in an ex vivo animal study. The current study aimed to comprehensively investigate the impact of DIIFL mutations on the antigenicity, immunogenicity, and protective efficacy of Japanese encephalitis virus (JEV) virus-like particles (VLPs) in mice. We found the DIIFL G106K/L107D (KD) and W101G/G106K/L107D (GKD) mutations altered the binding activity of JEV VLP to cross-reactive monoclonal antibodies but had no effect on their ability to elicit total IgG antibodies in mice. However, JEV VLPs with KD or GKD mutations induced significantly less neutralizing antibodies against JEV. Only 46% and 31% of the KD and GKD VLPs-immunized mice survived compared to 100% of the wild-type (WT) VLP-immunized mice after a lethal JEV challenge. In passive protection experiments, naïve mice that received sera from WT VLP-immunized mice exhibited a significantly higher survival rate of 46.7% compared to those receiving sera from KD VLP- and GKD VLP-immunized mice (6.7% and 0%, respectively). This study demonstrated that JEV DIIFL is crucial for eliciting potently neutralizing antibodies and protective immunity against JEV. IMPORTANCE: Introduction of mutations into the fusion loop is one potential strategy for generating safe dengue and Zika vaccines by reducing the risk of severe dengue following subsequent infections, and for constructing live-attenuated vaccine candidates against newly emerging Japanese encephalitis virus (JEV) or Japanese encephalitis (JE) serocomplex virus. The monoclonal antibody studies indicated the fusion loop of JE serocomplex viruses primarily comprised non-neutralizing epitopes. However, the present study demonstrates that the JEV fusion loop plays a critical role in eliciting protective immunity in mice. Modifications to the fusion loop of JE serocomplex viruses might negatively affect vaccine efficacy compared to dengue and zika serocomplex viruses. Further studies are required to assess the impact of mutant fusion loop encoded by commonly used JEV vaccine strains on vaccine efficacy or safety after subsequent dengue virus infection.


Subject(s)
Encephalitis Virus, Japanese , Encephalitis, Japanese , Japanese Encephalitis Vaccines , Animals , Mice , Amino Acids , Antibodies, Neutralizing , Antibodies, Viral , Dengue , Encephalitis Virus, Japanese/physiology , Encephalitis, Japanese/immunology , Encephalitis, Japanese/prevention & control , Epitopes , Japanese Encephalitis Vaccines/genetics , Viral Envelope Proteins/genetics , Zika Virus , Zika Virus Infection
2.
Nature ; 567(7748): E13, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30837740

ABSTRACT

In this Letter, in "About 75% of this reduction is expected to come from emission reductions and the remaining 25% from land use, land-use change and forestry", '25%' should read '1%' and '75%' should read '99%'. In the sentence "The carbon-sink-maximizing portfolio has a small negative effect on annual precipitation (-2 mm) and no effect on air temperature (Table 1)" the word 'precipitation' was omitted. Denmark was accidentally deleted during the conversion of Fig. 1. The original Letter has been corrected online.

3.
Small ; 20(8): e2307547, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37814367

ABSTRACT

The sluggish four-electron oxygen evolving reaction is one of the key limitations of photoelectrochemical water decomposition. Optimizing the binding of active sites to oxygen in water and promoting the conversion of *O to *OOH are the key to enhancing oxygen evolution reaction. In this work, W-doped Cu2 V2 O7 (CVO) constructs corner-sharing tetrahedrally coordinated W-V dual active sites to induce the generation of electron deficiency active centers, promote the adsorption of ─OH, and accelerate the transformation of *O to *OOH for water splitting. The photocurrent obtained by the W-modified CVO photoanode is 0.97 mA cm-2 at 1.23 V versus RHE, which is much superior to that of the reported CVO. Experimental and theoretical results show that the excellent catalytic performance may be attributed to the formation of synergistic dual active sites between W and V atoms, and the introduction of W ions reduces the charge migration distance and prolongs the lifetime of photogenerated carriers. Meanwhile, the electronic structure in the center of the d-band is modulated, which leads to the redistribution of the electron density in CVO and lowers the energy barrier for the conversion of the rate-limiting step *O to *OOH.

4.
Nature ; 562(7726): 259-262, 2018 10.
Article in English | MEDLINE | ID: mdl-30305744

ABSTRACT

The Paris Agreement promotes forest management as a pathway towards halting climate warming through the reduction of carbon dioxide (CO2) emissions1. However, the climate benefits from carbon sequestration through forest management may be reinforced, counteracted or even offset by concurrent management-induced changes in surface albedo, land-surface roughness, emissions of biogenic volatile organic compounds, transpiration and sensible heat flux2-4. Consequently, forest management could offset CO2 emissions without halting global temperature rise. It therefore remains to be confirmed whether commonly proposed sustainable European forest-management portfolios would comply with the Paris Agreement-that is, whether they can reduce the growth rate of atmospheric CO2, reduce the radiative imbalance at the top of the atmosphere, and neither increase the near-surface air temperature nor decrease precipitation by the end of the twenty-first century. Here we show that the portfolio made up of management systems that locally maximize the carbon sink through carbon sequestration, wood use and product and energy substitution reduces the growth rate of atmospheric CO2, but does not meet any of the other criteria. The portfolios that maximize the carbon sink or forest albedo pass only one-different in each case-criterion. Managing the European forests with the objective of reducing near-surface air temperature, on the other hand, will also reduce the atmospheric CO2 growth rate, thus meeting two of the four criteria. Trade-off are thus unavoidable when using European forests to meet climate objectives. Furthermore, our results demonstrate that if present-day forest cover is sustained, the additional climate benefits achieved through forest management would be modest and local, rather than global. On the basis of these findings, we argue that Europe should not rely on forest management to mitigate climate change. The modest climate effects from changes in forest management imply, however, that if adaptation to future climate were to require large-scale changes in species composition and silvicultural systems over Europe5,6, the forests could be adapted to climate change with neither positive nor negative  climate effects.


Subject(s)
Carbon Sequestration , Forestry , Forests , Global Warming/legislation & jurisprudence , Global Warming/prevention & control , Goals , Sustainable Development/legislation & jurisprudence , Air , Atmosphere/chemistry , Carbon Dioxide/analysis , Europe , Geographic Mapping , International Cooperation , Temperature
5.
Appl Microbiol Biotechnol ; 108(1): 242, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38416210

ABSTRACT

Flavivirus virus-like particles (VLPs) exhibit a striking structural resemblance to viral particles, making them highly adaptable for various applications, including vaccines and diagnostics. Consequently, increasing VLPs production is important and can be achieved by optimizing expression plasmids and cell culture conditions. While attempting to express genotype III (GIII) Japanese encephalitis virus (JEV) VLPs containing the G104H mutation in the envelope (E) protein, we failed to generate VLPs in COS-1 cells. However, VLPs production was restored by cultivating plasmid-transfected cells at a lower temperature, specifically 28 °C. Furthermore, we observed that the enhancement in JEV VLPs production was independent of amino acid mutations in the E protein. The optimal condition for JEV VLPs production in plasmid-transfected COS-1 cells consisted of an initial culture at 37 °C for 6 h, followed by a shift to 28 °C (37/28 °C) for cultivation. Under 37/28 °C cultivation conditions, flavivirus VLPs production significantly increased in various mammalian cell lines regardless of whether its expression was transiently transfected or clonally selected cells. Remarkably, clonally selected cell lines expressing flavivirus VLPs consistently achieved yields exceeding 1 µg/ml. Binding affinity analyses using monoclonal antibodies revealed similar binding patterns for VLPs of genotype I (GI) JEV, GIII JEV, West Nile virus (WNV), and dengue virus serotype 2 (DENV-2) produced under both 37 °C or 37/28 °C cultivation conditions. In summary, our study demonstrated that the production of flavivirus VLPs can be significantly improved under 37/28 °C cultivation conditions without affecting the conformational structure of the E protein. KEYPOINTS: • Low-temperature culture (37/28 °C) enhances production of flavivirus VLPs. • Flavivirus VLPs consistently achieved yields exceeding 1 µg/ml. • 37/28 °C cultivation did not alter the structure of flavivirus VLPs.


Subject(s)
Encephalitis Virus, Japanese , Encephalitis, Japanese , Flavivirus , Chlorocebus aethiops , Animals , Flavivirus/genetics , Temperature , Encephalitis Virus, Japanese/genetics , Cold Temperature , COS Cells , Mammals
6.
Environ Monit Assess ; 196(3): 246, 2024 Feb 08.
Article in English | MEDLINE | ID: mdl-38329592

ABSTRACT

An integrated, remotely sensed approach to assess land-use and land-cover change (LULCC) dynamics plays an important role in environmental monitoring, management, and policy development. In this study, we utilized the advantage of land-cover seasonality, canopy height, and spectral characteristics to develop a phenology-based classification model (PCM) for mapping the annual LULCC in our study areas. Monthly analysis of normalized difference vegetation index (NDVI) and near-infrared (NIR) values derived from SPOT images enabled the detection of temporal characteristics of each land type, serving as crucial indices for land type classification. The integration of normalized difference built-up index (NDBI) derived from Landsat images and airborne LiDAR canopy height into the PCM resulted in an overall performance of 0.85, slightly surpassing that of random forest analysis or principal component analysis. The development of PCM can reduce the time and effort required for manual classification and capture annual LULCC changes among five major land types: forests, built-up land, inland water, agriculture land, and grassland/shrubs. The gross change LULCC analysis for the Taoyuan Tableland demonstrated fluctuations in land types over the study period (2013 to 2022). A negative correlation (r = - 0.79) in area changes between grassland/shrubs and agricultural land and a positive correlation (r = 0.47) between irrigation ponds and agricultural land were found. Event-based LULCC analysis for Taipei City demonstrated a balance between urbanization and urban greening, with the number of urbanization events becoming comparable to urban greening events when the spatial extent of LULCC events exceeds 1000 m2. Besides, small-scale urban greening events are frequently discovered and distributed throughout the metropolitan area of Taipei City, emphasizing the localized nature of urban greening events.


Subject(s)
Environmental Monitoring , Remote Sensing Technology , Agriculture , Policy Making , Ponds
7.
Caries Res ; 57(2): 159-166, 2023.
Article in English | MEDLINE | ID: mdl-36806002

ABSTRACT

Cathepsin K (catK) modulates the degradation of dentin collagen. This study aimed to evaluate the effects of catK inhibitors on dentin erosion. Dentin beams were eroded (4 times/d for 5 days) and immersed in deionized water (negative control), 0.1 M NaCl, 0.3 M NaCl, 0.5 M NaCl, or 1 µm odanacatib (each n = 16) for 30 min after each erosive challenge. Erosive dentin loss (EDL) and demineralized organic matrix (DOM) thickness were evaluated profilometrically. Additionally, dentin beams were demineralized, immersed in the respective solutions for 30 min each (n = 5), and then incubated in artificial saliva for 5 days. Dentin collage degradation was evaluated by quantifying the levels of the C-terminal peptide of type I collagen (CTX), C-terminal cross-linked telopeptide of type I collagen (ICTP), and hydroxyproline (HYP) in the incubation media. Significantly lower EDL and dentin collagen degradation (CTX, ICTP, and HYP) and thicker DOM layers were observed in the samples treated with 0.3 m NaCl and 1 µm odanacatib than in those treated with deionized water (all p < 0.05). The samples treated with 1 µm odanacatib showed significantly lower levels of CTX and HYP than those treated with 0.3 M NaCl (all p < 0.05). The present findings support the potential use of catK inhibitors in controlling dentin erosion.


Subject(s)
Collagen Type I , Sodium Chloride , Humans , Cathepsin K/metabolism , Collagen Type I/metabolism , Sodium Chloride/pharmacology , Collagen , Dentin
8.
BMC Emerg Med ; 23(1): 103, 2023 09 07.
Article in English | MEDLINE | ID: mdl-37679682

ABSTRACT

BACKGROUND: The purpose of the study was to investigate the relationship between the independent practice time of residents and the quality of care provided in the Emergency Department (ED) across three urban hospitals in Taiwan. The study focused on non-pediatric and non-obstetric complaints, aiming to provide insights into the optimal balance between resident autonomy and patient safety. METHODS: A comprehensive retrospective study was conducted using de-identified electronic health records (EHRs) from the hospital's integrated medical database (iMD) from August 2015 to July 2019. The independent practice time was defined as the duration from the first medical order by a resident to the first modifications by the attending physician. The primary outcome was revisits to the ED within 72 h following discharge. Statistical analysis was conducted using RStudio and pyGAM. RESULTS: The study identified several factors associated with shorter independent practice times (< 30 minutes), including older patient age, male sex, higher body temperature, higher heart rate, lower blood pressure, and the presence of certain comorbidities. Residents practicing independently for 30-120 minutes were associated with similar adjusted odds of patient revisits to the ED (OR 1.034, 95% CI 0.978-1.093) and no higher risk of 7-day mortality (OR 0.674, 95% CI 0.592-0.767) compared to the group with less autonomy. However, independent practice times exceeding 120 minutes were associated with higher odds of revisiting the ED within 72 h. For the group with 120-210 minutes of independent practice time, the OR was 1.113 (95% CI: 1.025-1.208, p = 0.011). For the group with > 210 minutes, the OR was 1.259 (95% CI: 1.094-1.449, p = 0.001), indicating an increased risk of adverse outcomes as the independent practice time increasing. CONCLUSIONS: The study concludes that while providing residents an independent practice time between 30 to 120 minutes may be beneficial, caution should be exercised when this time exceeds 120 minutes. The findings underscore the importance of optimal supervision in enhancing patient care quality and safety. Further research is recommended to explore the long-term effects of different levels of resident autonomy on patient outcomes and the professional development of the residents themselves.


Subject(s)
Emergency Service, Hospital , Hospitals, Urban , Humans , Male , Taiwan/epidemiology , Retrospective Studies , Blood Pressure
9.
Bioorg Chem ; 121: 105675, 2022 04.
Article in English | MEDLINE | ID: mdl-35182882

ABSTRACT

Fms-like tyrosine kinase 3 (FLT3) is considered a promising therapeutic target for acute myeloid leukemia (AML) in the clinical. However, monotherapy with FLT3 inhibitor is usually accompanied by drug resistance. Dual inhibitors might be therapeutically beneficial to patients with AML due to their ability to overcome drug resistance. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) phosphorylate eukaryotic translation initiation factor 4E (eIF4E), which brings together the RAS/RAF/ERK and PI3K/AKT/mTOR oncogenic pathways. Therefore, dual inhibition of FLT3 and MNK2 might have an additive effect against AML. Herein, a structure-based virtual screening approach was performed to identify dual inhibitors of FLT3 and MNK2 from the ChemDiv database. Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC50 values of 680 and 406 nM, respectively. In addition, the compound showed selectivity for both FLT3 and MNK2 in a panel of 82 kinases. The structure-activity relationship analysis and common interactions revealed interactions between K783-0308 analogs and FLT3 and MNK2. Furthermore, K783-0308 inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest. Taken together, the dual inhibitor K783-0308 showed promising results and can be potentially optimized as a lead compound for AML treatment.


Subject(s)
Leukemia, Myeloid, Acute , fms-Like Tyrosine Kinase 3 , Apoptosis , Cell Line, Tumor , Cell Proliferation , Humans , Intracellular Signaling Peptides and Proteins , Leukemia, Myeloid, Acute/drug therapy , Mutation , Phosphatidylinositol 3-Kinases , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases
10.
Mar Drugs ; 20(12)2022 Dec 16.
Article in English | MEDLINE | ID: mdl-36547930

ABSTRACT

κ-carrageenases are members of the glycoside hydrolase family 16 (GH16) that hydrolyze sulfated galactans in red algae, known as κ-carrageenans. In this study, a novel κ-carrageenase gene from the marine bacterium Rhodopirellula sallentina SM41 (RsCgk) was discovered via the genome mining approach. There are currently no reports on κ-carrageenase from the Rhodopirellula genus, and RsCgk shares a low identity (less than 65%) with κ- carrageenase from other genera. The RsCgk was heterologously overexpressed in Escherichia coli BL21 and characterized for its enzymatic properties. RsCgk exhibited maximum activity at pH 7.0 and 40 °C, and 50% of its initial activity was retained after incubating at 30 °C for 2 h. More than 70% of its activity was maintained after incubation at pH 6.0-8.0 and 4 °C for 24 h. As a marine derived enzyme, RsCgk showed excellent salt tolerance, retaining full activity in 1.2 M NaCl, and the addition of NaCl greatly enhanced its thermal stability. Mass spectrometry analysis of the RsCgk hydrolysis products revealed that the enzyme had high degradation specificity and mainly produced κ-carrageenan disaccharide. Comparative molecular dynamics simulations revealed that the conformational changes of tunnel-forming loops under salt environments may cause the deactivation or stabilization of RsCgk. Our results demonstrated that RsCgk could be utilized as a potential tool enzyme for efficient production of κ-carrageenan oligosaccharides under high salt conditions.


Subject(s)
Salt Tolerance , Sodium Chloride , Carrageenan/chemistry , Bacteria/metabolism , Glycoside Hydrolases/metabolism , Bacterial Proteins/metabolism
11.
J Med Internet Res ; 24(4): e36830, 2022 04 26.
Article in English | MEDLINE | ID: mdl-35380546

ABSTRACT

BACKGROUND: Vaccination is an important intervention to prevent the incidence and spread of serious diseases. Many factors including information obtained from the internet influence individuals' decisions to vaccinate. Misinformation is a critical issue and can be hard to detect, although it can change people's minds, opinions, and decisions. The impact of misinformation on public health and vaccination hesitancy is well documented, but little research has been conducted on the relationship between the size of the population reached by misinformation and the vaccination decisions made by that population. A number of fact-checking services are available on the web, including the Islander news analysis system, a free web service that provides individuals with real-time judgment on web news. In this study, we used such services to estimate the amount of fake news available and used Google Trends levels to model the spread of fake news. We quantified this relationship using official public data on COVID-19 vaccination in Taiwan. OBJECTIVE: In this study, we aimed to quantify the impact of the magnitude of the propagation of fake news on vaccination decisions. METHODS: We collected public data about COVID-19 infections and vaccination from Taiwan's official website and estimated the popularity of searches using Google Trends. We indirectly collected news from 26 digital media sources, using the news database of the Islander system. This system crawls the internet in real time, analyzes the news, and stores it. The incitement and suspicion scores of the Islander system were used to objectively judge news, and a fake news percentage variable was produced. We used multivariable linear regression, chi-square tests, and the Johnson-Neyman procedure to analyze this relationship, using weekly data. RESULTS: A total of 791,183 news items were obtained over 43 weeks in 2021. There was a significant increase in the proportion of fake news in 11 of the 26 media sources during the public vaccination stage. The regression model revealed a positive adjusted coefficient (ß=0.98, P=.002) of vaccine availability on the following week's vaccination doses, and a negative adjusted coefficient (ß=-3.21, P=.04) of the interaction term on the fake news percentage with the Google Trends level. The Johnson-Neiman plot of the adjusted effect for the interaction term showed that the Google Trends level had a significant negative adjustment effect on vaccination doses for the following week when the proportion of fake news exceeded 39.3%. CONCLUSIONS: There was a significant relationship between the amount of fake news to which the population was exposed and the number of vaccination doses administered. Reducing the amount of fake news and increasing public immunity to misinformation will be critical to maintain public health in the internet age.


Subject(s)
COVID-19 , Social Media , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Disinformation , Humans , Internet , Prevalence , Retrospective Studies , Taiwan/epidemiology , Vaccination
12.
J Environ Manage ; 318: 115614, 2022 Sep 15.
Article in English | MEDLINE | ID: mdl-35779296

ABSTRACT

Since the 24-hr PM2.5 (particle aerodynamic diameter less than 2.5 µm) concentration standard was regulated in Taiwan in 2012, the PM2.5 concentration has been decreasing year by year, but the ozone (O3) concentration remains almost the same. In particular, the daily maximum 8-hr average O3 (MDA8 O3) concentration frequently exceeds the standard. The goal of this study is to find a solution for reducing PM2.5 and O3 simultaneously by numerical modeling. After the Volatile Organic Compounds (VOCS)-limited and nitrogen oxides (NOX)-limited areas were defined in Taiwan, then, in total, 50 scenarios are simulated in this study. In terms of the average in Taiwan, the effect of VOCS emission reduction is better than that of NOX on the decrease in PM2.5 concentration, when the same reduction proportion (20%, 40%) is implemented. While the effect of further NOX emission reduction (60%) will exceed that of VOCS. The decrease in PM2.5 is proportional to the reduction in precursor emissions such as NOX, VOCS, sulfur dioxides (SO2), and ammonia (NH3). The lower reduction of NOX emission for whole Taiwan caused O3 increases on average but higher reduction can ease the increase, which suggests the implement of NOX emission reductions must be cautious. When comparing administrative jurisdictions in terms of grids, districts/towns, and cities/counties, it was found that controlling NOX and VOCS at a finer spatial resolution of control units did not benefit the decrease in PM2.5 but did benefit the decrease in O3. The enhanced O3 control strategies obviously cause a higher decrease of O3 throughout Taiwan due to NOX and VOCS emission changes when they are implemented in the right places. Finally, three sets of short-term and long-term goals of controlling PM2.5 and O3 simultaneously are drawn from the comprehensive rankings for all simulated scenarios, depending on whether PM2.5 or O3 control is more urgent. In principle, the short-term scenarios could be ordinary or enhanced version of O3 decrease with lower NOX/VOCS emissions, while the long-term scenario is enhanced version of O3 decrease plus high emission reductions for all precursors.


Subject(s)
Air Pollutants , Air Pollution , Ozone , Volatile Organic Compounds , Air Pollutants/analysis , Air Pollution/analysis , Air Pollution/prevention & control , China , Environmental Monitoring , Ozone/analysis , Particulate Matter/analysis , Taiwan , Volatile Organic Compounds/analysis
13.
PLoS Pathog ; 15(8): e1007992, 2019 08.
Article in English | MEDLINE | ID: mdl-31381617

ABSTRACT

Genotype I (GI) virus has replaced genotype III (GIII) virus as the dominant Japanese encephalitis virus (JEV) in the epidemic area of Asia. The mechanism underlying the genotype replacement remains unclear. Therefore, we focused our current study on investigating the roles of mosquito vector and amplifying host(s) in JEV genotype replacement by comparing the replication ability of GI and GIII viruses. GI and GIII viruses had similar infection rates and replicated to similar viral titers after blood meal feedings in Culex tritaeniorhynchus. However, GI virus yielded a higher viral titer in amplifying host-derived cells, especially at an elevated temperature, and produced an earlier and higher viremia in experimentally inoculated pigs, ducklings, and young chickens. Subsequently we identified the amplification advantage of viral genetic determinants from GI viruses by utilizing chimeric and recombinant JEVs (rJEVs). Compared to the recombinant GIII virus (rGIII virus), we observed that both the recombinant GI virus and the chimeric rJEVs encoding GI virus-derived NS1-3 genes supported higher replication ability in amplifying hosts. The replication advantage of the chimeric rJEVs was lost after introduction of a single substitution from a GIII viral mutation (NS2B-L99V, NS3-S78A, or NS3-D177E). In addition, the gain-of-function assay further elucidated that rGIII virus encoding GI virus NS2B-V99L/NS3-A78S/E177E substitutions re-gained the enhanced replication ability. Thus, we conclude that the replication advantage of GI virus in pigs and poultry is the result of three critical NS2B/NS3 substitutions. This may lead to more efficient transmission of GI virus than GIII virus in the amplifying host-mosquito cycle.


Subject(s)
Encephalitis Virus, Japanese/genetics , Encephalitis, Japanese/virology , Mosquito Vectors , Mutation , Viral Nonstructural Proteins/genetics , Viremia/transmission , Animals , Chickens , Culex , Encephalitis Virus, Japanese/pathogenicity , Encephalitis, Japanese/epidemiology , Encephalitis, Japanese/genetics , Female , Genotype , RNA Helicases/genetics , Serine Endopeptidases/genetics , Swine , Virus Replication
14.
Neurochem Res ; 46(8): 2181-2191, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34032956

ABSTRACT

Application of chemotherapeutic oxaliplatin represses gene transcription through induction of DNA methylation, which may contribute to oxaliplatin-induced chronic pain. Here, Ddr1, which showed an increased methylation in the promoter, was screened from the SRA methylation database (PRJNA587622) after oxaliplatin treatment. qPCR and MeDIP assays verified that oxaliplatin treatment increased the methylation in Ddr1 promoter region and decreased the expression of DDR1 in the neurons of spinal dorsal horn. In addition, overexpression of DDR1 by intraspinal injection of AAV-hSyn-Ddr1 significantly alleviated the mechanical allodynia induced by oxaliplatin. Furthermore, we found that oxaliplatin treatment increased the expression of DNMT3b and ZEB1 in dorsal horn neurons, and promoted the interaction between DNMT3b and ZEB1. Intrathecal injection of ZEB1 siRNA inhibited the enhanced recruitment of DNMT3b and the hypermethylation in Ddr1 promoter induced by oxaliplatin. Finally, ZEB1 siRNA rescued the DDR1 downregulation and mechanical allodynia induced by oxaliplatin. In conclusion, these results suggested that the ZEB1 recruited DNMT3b to the Ddr1 promoter, which induced the DDR1 downregulation and contributed to the oxaliplatin-induced chronic pain.


Subject(s)
Chronic Pain/metabolism , DNA Methylation/physiology , Discoidin Domain Receptor 1/genetics , Oxaliplatin/adverse effects , Spinal Cord Dorsal Horn/metabolism , Zinc Finger E-box-Binding Homeobox 1/metabolism , Animals , Chronic Pain/chemically induced , DNA/metabolism , DNA (Cytosine-5-)-Methyltransferases/metabolism , DNA Methylation/drug effects , Down-Regulation/drug effects , Hyperalgesia/chemically induced , Hyperalgesia/metabolism , Male , Neuralgia/chemically induced , Neuralgia/metabolism , Promoter Regions, Genetic/physiology , RNA, Small Interfering/pharmacology , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn/drug effects , Up-Regulation/drug effects , DNA Methyltransferase 3B
15.
Bioorg Med Chem ; 40: 116163, 2021 06 15.
Article in English | MEDLINE | ID: mdl-33932711

ABSTRACT

Bruton's tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase member of the TEC family of tyrosine kinases. Pre-clinical and clinical data have shown that targeting BTK can be used for the treatment for B-cell disorders. Here we disclose the discovery of a novel imidazo[4,5-b]pyridine series of potent, selective reversible BTK inhibitors through a rational design approach. From a starting hit molecule 1, medicinal chemistry optimization led to the development of a lead compound 30, which exhibited 58 nM BTK inhibitory potency in human whole blood and high kinome selectivity. Additionally, the compound demonstrated favorable pharmacokinetics (PK), and showed potent dose-dependent efficacy in a rat CIA model.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Drug Discovery , Imidazoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Agammaglobulinaemia Tyrosine Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship
16.
BMC Public Health ; 21(1): 835, 2021 05 01.
Article in English | MEDLINE | ID: mdl-33933062

ABSTRACT

BACKGROUND: The coronavirus disease of 2019 (COVID-19) has quickly spread to all corners of the world since its emergence in Wuhan, China in December of 2019. The disease burden has been heterogeneous across regions of the world, with Americas leading in cumulative cases and deaths, followed by Europe, Southeast Asia, Eastern Mediterranean, Africa and Western Pacific. Initial responses to COVID-19 also varied between governments, ranging from proactive containment to delayed intervention. Understanding these variabilities allow high burden countries to learn from low burden countries on ways to create more sustainable response plans in the future. METHODS: This study used a mixed-methods approach to perform cross-country comparisons of pandemic responses in the United States (US), Brazil, Germany, Australia, South Korea, Thailand, New Zealand, Italy and China. These countries were selected based on their income level, relative COVID-19 burden and geographic location. To rationalize the epidemiological variability, a list of 14 indicators was established to assess the countries' preparedness, actual response, and socioeconomic and demographic profile in the context of COVID-19. RESULTS: As of 1 April 2021, the US had the highest cases per million out of the nine countries, followed by Brazil, Italy, Germany, South Korea, Australia, New Zealand, Thailand and China. Meanwhile, Italy ranked first out of the nine countries' total deaths per million, followed by the US, Brazil, Germany, Australia, South Korea, New Zealand, China and Thailand. The epidemiological differences between these countries could be explained by nine indicators, and they were 1) leadership, governance and coordination of response, 2) communication, 3) community engagement, 4) multisectoral actions, 5) public health capacity, 6) universal health coverage, 7) medical services and hospital capacity, 8) demography and 9) burden of non-communicable diseases. CONCLUSION: The COVID-19 pandemic manifests varied outcomes due to differences in countries' vulnerability, preparedness and response. Our study rationalizes why South Korea, New Zealand, Thailand, Australia and China performed better than the US, Italy and Brazil. By identifying the strengths of low burden countries and weaknesses of hotspot countries, we elucidate factors constituting an effective pandemic response that can be adopted by leaders in preparation for re-emerging public health threats.


Subject(s)
COVID-19 , Pandemics , Africa , Americas , Asia, Southeastern , Australia/epidemiology , Brazil , China/epidemiology , Europe , Germany , Humans , Italy , New Zealand/epidemiology , Republic of Korea , SARS-CoV-2 , Thailand , United States
17.
J Med Internet Res ; 22(6): e20586, 2020 06 23.
Article in English | MEDLINE | ID: mdl-32544072

ABSTRACT

BACKGROUND: Frontline health care workers, including physicians, are at high risk of contracting coronavirus disease (COVID-19) owing to their exposure to patients suspected of having COVID-19. OBJECTIVE: The aim of this study was to evaluate the benefits and feasibility of a double triage and telemedicine protocol in improving infection control in the emergency department (ED). METHODS: In this retrospective study, we recruited patients aged ≥20 years referred to the ED of the National Taiwan University Hospital between March 1 and April 30, 2020. A double triage and telemedicine protocol was developed to triage suggested COVID-19 cases and minimize health workers' exposure to this disease. We categorized patients attending video interviews into a telemedicine group and patients experiencing face-to-face interviews into a conventional group. A questionnaire was used to assess how patients perceived the quality of the interviews and their communication with physicians as well as perceptions of stress, discrimination, and privacy. Each question was evaluated using a 5-point Likert scale. Physicians' total exposure time and total evaluation time were treated as primary outcomes, and the mean scores of the questions were treated as secondary outcomes. RESULTS: The final sample included 198 patients, including 93 cases (47.0%) in the telemedicine group and 105 cases (53.0%) in the conventional group. The total exposure time in the telemedicine group was significantly shorter than that in the conventional group (4.7 minutes vs 8.9 minutes, P<.001), whereas the total evaluation time in the telemedicine group was significantly longer than that in the conventional group (12.2 minutes vs 8.9 minutes, P<.001). After controlling for potential confounders, the total exposure time in the telemedicine group was 4.6 minutes shorter than that in the conventional group (95% CI -5.7 to -3.5, P<.001), whereas the total evaluation time in the telemedicine group was 2.8 minutes longer than that in the conventional group (95% CI -1.6 to -4.0, P<.001). The mean scores of the patient questionnaire were high in both groups (4.5/5 to 4.7/5 points). CONCLUSIONS: The implementation of the double triage and telemedicine protocol in the ED during the COVID-19 pandemic has high potential to improve infection control.


Subject(s)
Coronavirus Infections/diagnosis , Coronavirus Infections/prevention & control , Emergency Service, Hospital , Infection Control/methods , Pandemics/prevention & control , Pneumonia, Viral/diagnosis , Pneumonia, Viral/prevention & control , Telemedicine/methods , Triage/methods , Adult , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Feasibility Studies , Female , Health Personnel , Humans , Infection Control/standards , Male , Pneumonia, Viral/epidemiology , Pneumonia, Viral/transmission , Retrospective Studies , SARS-CoV-2 , Taiwan/epidemiology
18.
J Manipulative Physiol Ther ; 41(8): 680-690, 2018 10.
Article in English | MEDLINE | ID: mdl-30594332

ABSTRACT

OBJECTIVE: The purpose of this study was to compare the thickness of the oblique cervical inferior (OCI) and the error of the head reposition test between the painful and nonpainful sides of patients with cervicogenic headache (CeH) and between the patients and the asymptomatic group. METHODS: Thirteen patients (24.5 ± 4.8 years) and 14 asymptomatic participants (23.9 ± 2.7 years) were included. The head reposition test was recorded by a 3-dimensional motion analysis system. The thickness of the OCI was recorded by ultrasonography. The measured outcomes were compared between the painful and nonpainful sides and with the asymptomatic participants. RESULTS: The thickness of the OCI in the rest condition on the painful side (9.92 ± 2.31 mm) was smaller than that of the nonpainful side (10.56 ± 2.24 mm). The constant error of the head-to-target test toward the nonpainful side was smaller in the patients with CeH (-1.6 ± 4.3°) than in the asymptomatic group (3.3 ± 3.7°, P = 0.005). CONCLUSION: Asymmetric OCI and cervical proprioception were demonstrated in patients with CeH.


Subject(s)
Head Movements/physiology , Kinesthesis/physiology , Neck Muscles/physiopathology , Post-Traumatic Headache/physiopathology , Adult , Female , Humans , Male , Middle Aged , Neck Muscles/diagnostic imaging , Post-Traumatic Headache/diagnostic imaging , Psychomotor Performance , Ultrasonography
19.
Emerg Infect Dis ; 23(11): 1883-1886, 2017 11.
Article in English | MEDLINE | ID: mdl-29048288

ABSTRACT

The virulence of genotype I (GI) Japanese encephalitis virus (JEV) is under debate. We investigated differences in the virulence of GI and GIII JEV by calculating asymptomatic ratios based on serologic studies during GI- and GIII-JEV endemic periods. The results suggested equal virulence of GI and GIII JEV among humans.


Subject(s)
Encephalitis Virus, Japanese/pathogenicity , Encephalitis, Japanese/virology , Adult , Encephalitis Virus, Japanese/genetics , Encephalitis Virus, Japanese/isolation & purification , Encephalitis, Japanese/epidemiology , Female , Genotype , Humans , Male , Middle Aged , Taiwan/epidemiology , Virulence
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