Epitope(s) involving amino acids of the fusion loop of Japanese encephalitis virus envelope protein is(are) important to elicit protective immunity.

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.

Author Correction: Trade-offs in using European forests to meet climate objectives.

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.

Corner-Sharing Tetrahedrally Coordinated W-V Dual Active Sites on Cu2 V2 O7 for Photoelectrochemical Water Oxidation.

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.

Trade-offs in using European forests to meet climate objectives.

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.

Low-temperature culture enhances production of flavivirus virus-like particles in mammalian cells.

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.

A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney dysfunction.

Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function. The whole data set consisted of 146 patients with 391 PMB concentrations. The prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. In the overall evaluation process, none of the models exhibited satisfactory predictive ability in both prediction- and simulation-based diagnostic simultaneously. However, the evaluation of the models in the subgroup of patients with normal liver and kidney function revealed improved predictive performance compared to those with liver and/or kidney dysfunction. Bayesian forecasting demonstrated enhanced predictability with the incorporation of two to three prior observations. The external evaluation highlighted a lack of consistency between the prediction results of published models and the external validation dataset. Nonetheless, Bayesian forecasting holds promise in improving the predictive performance of the models, and feedback from therapeutic drug monitoring is crucial in optimizing individual dosing regimens.

Mapping land-use and land-cover changes through the integration of satellite and airborne remote sensing data.

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.

Population pharmacokinetics of polymyxin B in patients with liver dysfunction.

AIMS: Polymyxin B (PMB) is widely used to treat infections caused by multidrug-resistant Gram-negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics. METHODS: We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions. RESULTS: PMB pharmacokinetic analyses included 401 steady-state concentrations in 136 adult patients. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child-Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose-normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5 mg/L, the appropriate dose was 40-75 mg/12-h. When the dose exceeded 100 mg/12-h, the risk of nephrotoxicity increased significantly. CONCLUSIONS: This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK-guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window.

Effects of Cathepsin K Inhibitors on Dentin Erosion: An in vitro Study.

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.

The impact of metabolic diseases and their comorbidities for stroke in a middle-income area of China: a case-control study.

BACKGROUND: There are few studies on the comorbidity of hypertension (HTN), diabetes mellitus (DM) and dyslipidemia (DLP) associated with stroke. We aimed to explore the relationship between the number of metabolic diseases and stroke and its different subtypes, and to reveal whether metabolic diseases alone or coexist can significantly increase the risk of stroke. METHODS: We completed a multi-center case-control study in Jiangxi Province, China. Neuroimaging examination was done in all cases. Controls were stroke-free adults recruited from the community in the case concentration area and matched with the cases in 1:1 ratio by age and sex. Odds ratios (OR) were calculated by conditional logistic regression. RESULTS: We enrolled 11,729 case-control pairs. The estimated ORs among patients with 1, 2 and 3 metabolic diseases were 3.16 (2.78-3.60), 7.11 (6.16-8.20), 12.22 (9.73-15.36), respectively after adjusting age, body mass index, urban-rural areas, cardiac disease, smoking, alcohol intake, physically active, high intake of salt, meat-biased diet, high homocysteine. The coexistence of HTN and DM (OR: 7.67), the coexistence of HTN and DLP (OR:7.58), and the coexistence of DM and DLP (OR:3.64) can all significantly increase the risk of stroke. HTN alone or combined other metabolic diseases were significantly more strongly associated with intracerebral haemorrhage than ischemic stroke. CONCLUSIONS: The risk of stroke increased with the number of chronic metabolic diseases. It is necessary to regularly monitor blood pressure, blood sugar and blood lipids and strengthen lifestyle management and take appropriate drug interventions to prevent exposure to multiple metabolic diseases based on existing conditions.

The activity, distribution, and colocalization of cathepsin K and matrix metalloproteases in intact and eroded dentin.

OBJECTIVES: This study aimed to assess the activity, distribution, and colocalization of cathepsin K (catK) and matrix metalloproteases (MMPs) in both intact and eroded dentin in vitro. MATERIALS AND METHODS: Eroded dentin was obtained by consecutive treatment with 5% citric acid (pH = 2.3) for 7 days, while intact dentin remained untreated. Pulverized dentin powder (1.0 g) was extracted from both intact and eroded dentin using 5 mL of 50 mM Tris-HCl buffer (0.2 g/1 mL, pH = 7.4) for 60 h to measure the activity of catK and MMPs spectrofluorometrically. In addition, three 200-µm-thick dentin slices were prepared from intact and eroded dentin for double-labeling immunofluorescence to evaluate the distribution and colocalization of catK and MMPs (MMP-2 and MMP-9). The distribution and colocalization of enzymes were analyzed using inverted confocal laser scanning microscopy (CLSM), with colocalization rates quantified using Leica Application Suite Advanced Fluorescent (LAS AF) software. One-way analysis of variance (ANOVA) was used to analyze the fluorescence data related to enzyme activity (α = 0.05). RESULTS: The activity of catK and MMPs was significantly increased in eroded dentin compared with intact dentin. After erosive attacks, catK, MMP-2, and MMP-9 were prominently localized in the eroded regions. The colocalization rates of catK with MMP-2 and MMP-9 were 13- and 26-fold higher in eroded dentin, respectively, than in intact dentin. CONCLUSIONS: Erosive attacks amplified the activity of catK and MMPs in dentin while also altering their distribution patterns. Colocalization between catK and MMPs increased following erosive attacks. CLINICAL RELEVANCE: CatK, MMP-2, and MMP-9 likely play synergistic roles in the pathophysiology of dentin erosion.

Association between independent practice time and patient outcomes in the emergency department: a retrospective study of residents in three urban hospitals in Taiwan.

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.

[Energy and nutrients intake from complementary foods of children aged 6-23 months in China in 2019-2021].

OBJECTIVE: To describe the energy and nutrients intake from complementary foods of children aged 6-23 months in different areas of China. METHODS: The data was from the National Special Program for Science & Technology Basic Resources Investigation-China Children's Nutrition and Health System Survey and Application of 0-18 Years Old Children. Children aged 6-23 months(n=546) were included in the current study. Demographic characteristics, socioeconomic status and birth status were collected through questionnaire survey. We used 24-hour weighted dietary record method to collect the intake of complementary foods. Energy, protein, fat, carbohydrate, calcium, iron, zinc, selenium, potassium, vitamin A, vitamin B_1, vitamin B_2 and vitamin C intakes were calculated by using Chinese Food Composition Database. RESULTS: For children aged 6-8 months, 9-11 months, 12-17 months and 18-23 months, the energy intake from complementary foods was 156.1, 258.0, 388.7 and 581.1 kcal, respectively. The protein intake was 5.1, 10.1, 15.0 and 21.7 g, respectively. The fat intake was 3.3, 6.7, 9.5 and 15.9 g, respectively. The calcium intake was 38.7, 54.8, 78.6 and 106.9 mg, respectively. The iron intake was 1.3, 2.2, 3.5 and 5.3 mg, respectively. The zinc intake was 0.7, 1.4, 2.0 and 2.9 mg, respectively. The vitamin A intake was 83.7, 100.3, 157.4 and 180.4 µgRAE, respectively. The vitamin B_1 intake was 0.1, 0.2, 0.2 and 0.3 mg, respectively. The vitamin B_2 intake was 0.1, 0.1, 0.2 and 0.3 mg, respectively. The vitamin C intake was 1.8, 6.3, 9.5 and 19.2 mg, respectively. Compared with the World Health Organization recommended value of nutrients density, the density of protein from complementary foods for children aged 6-23 months was higher(2.6-3.8 mg/100 kcal vs.0.9-1.0 mg/100 kcal). The density of iron(1.0, 0.9 mg/100 kcal vs.4.5, 3.0 mg/100 kcal) and zinc(0.5, 0.5 mg/100 kcal vs.1.6, 1.1 mg/100 kcal) was lower for children aged 6-8 months and 9-11 months, respectively. CONCLUSION: The main issues of complementary food for children in China were high protein for children aged 6-23 months and low iron and zinc for infants aged 6-11 months.

Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach.

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.

A Novel κ-Carrageenase from Marine Bacterium Rhodopirellula sallentina SM41: Heterologous Expression, Biochemical Characterization and Salt-Tolerance Mechanism Investigation.

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.

The Prevalence and Impact of Fake News on COVID-19 Vaccination in Taiwan: Retrospective Study of Digital Media.

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.

A numerical study of reducing the concentration of O3 and PM2.5 simultaneously in Taiwan.

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.

Steroid receptor coactivator-1 enhances the stemness of glioblastoma by activating long noncoding RNA XIST/miR-152/KLF4 pathway.

Glioblastoma (GBM) recurrence is attributed to the presence of therapy-resistant glioblastoma stem cells. Steroid receptor coactivator-1 (SRC-1) acts as an oncogenic regulator in many human tumors. The relationship between SRC-1 and GBM has not yet been studied. Herein, we investigate the role of SRC-1 in GBM. In this study, we found that SRC-1 expression is positively correlated with grades of glioma and inversely correlated with glioma patient's prognosis. Steroid receptor coactivator-1 promotes the proliferation, migration, and tumor growth of GBM cells. Notably, SRC-1 knockdown suppresses the stemness of GBM cells. Mechanistically, long noncoding RNA X-inactive specific transcript (XIST) is regulated by SRC-1 at the posttranscriptional level and mediates the function of SRC-1 in promoting stemness-like properties of GBM. Steroid receptor coactivator-1 can promote the expression of Kruppel-like factor 4 (KLF4) through the XIST/microRNA (miR)-152 axis. Additionally, arenobufagin and bufalin, SRC small molecule inhibitors, can reduce the proliferation and stemness of GBM cells. This study reveals SRC-1 promotes the stemness of GBM by activating the long noncoding RNA XIST/miR-152/KLF4 pathway and provides novel markers for diagnosis and therapy of GBM.

NS2B/NS3 mutations enhance the infectivity of genotype I Japanese encephalitis virus in amplifying hosts.

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.

ZEB1 Induces Ddr1 Promoter Hypermethylation and Contributes to the Chronic Pain in Spinal Cord in Rats Following Oxaliplatin Treatment.

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.