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Abstract The Porcine epidemic diarrhea virus (PEDV) presents a substantial risk to the domestic pig industry, resulting in extensive and fatal viral diarrhea among piglets. Recognizing the mucosal stimulation triggered by PEDV and harnessing the regulatory impact of lactobacilli on intestinal function, we have developed a lactobacillus-based vaccine that is carefully designed to elicit a strong mucosal immune response. Through bioinformatics analysis, we examined PEDV S proteins to identify B-cell linear epitopes that meet the criteria of being non-toxic, soluble, antigenic, and capable of neutralizing the virus. In this study, a genetically modified strain of Lactobacillus mucosae G01 (L.mucosae G01) was created by utilizing the S layer protein (SLP) as a scaffold for surface presentation. Chimeric immunodominant epitopes with neutralizing activity were incorporated at various sites on SLP. The successful expression of SLP chimeric immunodominant epitope 1 on the surface of L.mucosae G01 was confirmed through indirect immunofluorescence and transmission electron microscopy, revealing the formation of a transparent membrane. The findings demonstrate that the oral administration of L.mucosae G01, which expresses the SLP chimeric immunodominant gene epitope1, induces the production of secreted IgA in the intestine and feces of mice. Additionally, there is an elevation in IgG levels in the serum. Moreover, the levels of cytokines IL-2, IL-4, IFN-γ, and IL-17 are significantly increased compared to the negative control group. These results suggest that L. mucosae G01 has the ability to deliver exogenous antigens and elicit a specific mucosal immune response against PEDV. This investigation presents new possibilities for immunoprophylaxis against PEDV-induced diarrhea.

Abstract Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children’s brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3–10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

PurposePositive attitudes toward physical activity have been consistently linked to health Behaviors. This study aims to validate the effectiveness of attitude change in the domain of exercise and identify the mechanisms through which this change occurs in the context of sports and promote exercise behavior.Methods103 university students (20.7 ± 1.97 years, 40 males, and 63 females) completed the implicit and explicit attitude tests. Based on their exercise levels assessed using the Physical Activity Rating Scale (PARS-3), participants were categorized into low and high exercise level groups. From this sample, 66 university students (19 males and 47 females) with low exercise levels completed a self-generated information task. Subsequently, physical activity was assessed through a skipping rope task.ResultsThe implementation of the self-generated information task resulted in notable alterations in implicit attitudes (ηi2 = 0.07) toward physical activity during subsequent Implicit Attitude Test (IAT) evaluations. Additionally, significant changes were observed in explicit attitudes (ηe2 = 0.12) toward physical activity among university students. Moreover, the use of self-generated information positively influenced immediate exercise behavior.DiscussionThis study provides valuable insights into the impact of attitudes on behaviors among university students. It suggests that attitudes toward physical activity can be effectively changed through the use of self-generated information methodology, leading to an enhancement in immediate exercise behavior. Such attitude change has the potential to promote healthier behaviors and reduce the risk of diseases. These findings hold implications for interventions aimed at enhancing physical activity levels among university students.

Porcine epidemic diarrhea virus (PEDV) is responsible for causing fatal watery diarrhea in piglets, resulting in significant economic losses within the pig farming industry. Although vaccination is currently employed as a preventive measure, certain vaccines do not provide complete protection against PEDV field strains. Probiotics present a promising alternative due to their ability to regulate intestinal flora, enhance host immunity, and improve resistance against pathogenic microorganisms. We isolated six lactic acid bacteria (LAB) from the fecal microorganisms of Bama pigs, compared to Limosilactobacillus mucosae DSM13345 of the same genus in which Limosilactobacillus mucosae G01 (L. mucosae G01) proved to have a potent anti-PEDV effect. In a comprehensive manner, L. mucosae G01 significantly augmented the phosphorylation of IRF3 in IPEC-J2 cells, resulting in the induction of interferons (IFN α, IFN β, IFN λ1, and IFN λ3) and subsequent upregulation of interferon-stimulated genes (ISGs) (MX1, MX2, OAS1, and ZAP) in a dose-dependent fashion, consequently leading to the mitigation of PEDV replication. These findings underscore the promising prospects of L. mucosae G01 as a naturally derived substitute for combating PEDV and other enteric coronavirus infections.

As a broad-spectrum antiviral, and especially as a popular drug for treating coronavirus disease 2019 (COVID‐19) today, arbidol often involves drug–drug interactions (DDI) when treating critical patients. This study established a rapid and effective ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method to detect arbidol and its metabolite arbidol sulfoxide (M6-1) levels in vivo and in vitro. In this study, a 200 μL incubation system was used to study the inhibitory effect of the antitumor drug napabucasin on arbidol in vitro, with IC50 values of 2.25, 3.91, and 67.79 μM in rat liver microsomes (RLMs), human liver microsomes (HLMs), and CYP3A4.1, respectively. In addition, we found that the mechanism of inhibition was non-competitive inhibition in RLM and mixed inhibition in HLM. In pharmacokinetic experiments, it was observed that after gavage administration of 48 mg/kg napabucasin and 20 mg/kg arbidol, napabucasin inhibited the metabolism of arbidol in vivo and significantly changed the pharmacokinetic parameters of arbidol, such as AUC(0-t) and AUC(0-∞), in rats. We also found that napabucasin increased the AUC(0-t) and AUC(0-∞) of M6-1, the main metabolite of arbidol. This study provides a reference for the combined use of napabucasin and arbidol in clinical practice.

Vortioxetine is a novel anti-major depression disorder drug with a high safety profile compared with other similar drugs. However, little research has been done on drug-drug interactions (DDI) about vortioxetine. In this paper, the inhibitory effect of vortioxetine on cytochrome P450 (CYP450) and the type of inhibitory mechanism were investigated in human and rat liver microsomes. We set up an in vitro incubation system of 200 μL to measure the metabolism of probe substrates at the present of vortioxetine at 37°C. The concentrations of the metabolites of probe substrates were all measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. It was found no time-dependent inhibition (TDI) of vortioxetine through determination of half-maximal inhibitory concentration (IC50) shift values. The enzymes and metabolites involved in this experiment in human and rats were as follows: CYP3A4/CYP3A (midazolam); CYP2B6/CYP2B (bupropion); CYP2D6/CYP2D (dextromethorphan); CYP2C8/CYP2C-1 (amodiaquine); CYP2C9/CYP2C-2 (losartan); and CYP2C19/CYP2C-3 (mephenytoin). We found that vortioxetine competitively inhibited CYP2C19 and CYP2D6 in human liver microsomes (HLMs) with inhibition constant (Ki) values of 2.17 μM and 9.37 μM, respectively. It was noncompetitive inhibition for CYP3A4 and CYP2C8, and its Ki values were 7.26 μM and 6.96 μM, respectively. For CYP2B6 and CYP2C9, vortioxetine exhibited the mixed inhibition with Ki values were 8.55 μM and 4.17 μM, respectively. In RLMs, the type of vortioxetine inhibition was uncompetitive for CYP3A and CYP2D (Ki = 4.41 and 100.9 μM). The inhibition type was competitive inhibition, including CYP2B and CYP2C-2 (Ki = 2.87 and 0.12 μM). The inhibition types of CYP2C-1 and CYP2C-3 (Ki = 39.91 and 4.23 μM) were mixed inhibition and noncompetitive inhibition, respectively. The study of the above mechanism will provide guidance for the safe clinical use of vortioxetine so that the occurrence of DDI can be avoided.

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0−t), AUC(0−∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of tenacissoside G, tenacissoside H, and tenacissoside I in rat plasma. The rat plasma was treated with liquid-liquid extraction using ethyl acetate. The determination was performed on the UPLC HSS T3 column (50 mm × 2.1 mm, 1.8 μm) with a mobile phase consisting of acetonitrile-water (containing 0.1% formic acid) and gradient elution at a flow rate of 0.4 mL/min. Electrospray (ESI) positive ion mode detection and multireaction monitoring (MRM) quantitative analysis were performed. A total of 36 rats were given tenacissoside G, tenacissoside H, and tenacissoside I, respectively, orally (5 mg/kg) and intravenously (1 mg/kg), with 6 rats in each group, to evaluate the pharmacokinetic difference of tenacissoside G, tenacissoside H, and tenacissoside I in rats. The calibration curves showed good linearity in the range of 5–2000 ng/mL, where r was greater than 0.99. The results of precision, accuracy, recovery, matrix effect, and stability met the requirements of biological sample detection methods. The established UPLC-MS/MS method was successfully applied to pharmacokinetic studies of tenacissoside G, tenacissoside H, and tenacissoside I, and the bioavailability was 22.9%, 89.8%, and 9.4%, respectively.

Ponazuril is a triazine anticoccidial drug which is the main metabolite of toltrazuril in animals, it has excellent activity against many protozoa, including Cystoisospora suis, and has broad application prospects in the control of swine coccidiosis. To evaluate the pharmacokinetic and excretion characteristics of ponazuril, 12 healthy piglets aged 10–14 days were divided into 2 groups for pharmacokinetic studies, which were given 20 mg/kg body weight ponazuril orally and intravenously, respectively. And 6 other piglets were housed individually in metabolic cages and given the same oral dose of ponazuril. After administration, the concentration of ponazuril in plasma, fecal, and urine samples collected was determined using high-performance liquid chromatography (HPLC). The plasma concentration profiles of ponazuril obtained after intravenous and oral administration were analyzed simultaneously by the nonlinear mixed-effects (NLME) model. Following the results, the pharmacokinetics of ponazuril exhibited a Michaelis-Menten elimination with Michaelis-Menten constant Km and maximum metabolic rate Vm of 10.8 μg/mL and 0.083 mg/kg/h. The apparent volume of distribution was calculated to be 735 mL/kg, and the final estimated oral bioavailability was 81%. Besides, cumulatively 86.42 ± 2.96% of ponazuril was recovered from feces and 0.31% ± 0.08% from urine during 0–1,020 h after oral administration. These findings indicated a good oral absorption of ponazuril in piglets with nonlinear disposition and slow excretion largely via feces, implying sustained drug concentration in vivo and long-lasting anticoccidial effects.

In order to improve the accuracy and robustness of existing automated crack detection methods, a fully convolutional neural network for pixel-level detection based on densely connected and deeply supervised network is proposed. First, the densely connected layers are applied for enhancing the propagation and reuse of crack features. Then, the deeply supervised modules are designed to make network extract more significant features through multi-scale levels. Finally, the feature maps from different scales are fused to achieve complementarity at different levels. In addition, a class-balanced cross-entropy loss function is designed to balance backgrounds and cracks by increasing the weight of crack pixel loss. The proposed method is tested on three public datasets, and the experiments show that our method is superior to state-of-the-art methods in accuracy, speed and robustness.

Objective: To investigate the molecular mechanism of enriched rehabilitation training in improving cognitive dysfunction of ischemic stroke.Material and method: We established a rat model of cerebral ischemia with cognitive impairment and then carried out them to 4 groups according to different treatments. The all groups were performed Water maze training and cognitive function assessment. Western blot and Immunofluorescence were used to analyze the expression of synaptic plasticity-related proteins, regulatory proteins, and PKMζ in hippocampus. The patch clamp technique was used to record the field potential changes in the hippocampus and analyze the induction of LTP, and to observe the changes in field potential and LTP after the addition of PKMζ inhibitors.Results: The results showed that enriched rehabilitation training improved cognitive function in stroke rats, increased the PKMζ and SYN protein levels, and enhanced LTP in the ischemia hippocampus. The enhanced LTP for the rats after enriched rehabilitation training was attenuated by ZIP.Conclusion: We discuss this enriched rehabilitation training adaptive response to stroke as a potential underlying mechanism, which may play a role in improving synaptic plasticity and cognitive dysfunction.

Objective: To explore the relationship between miR-7-5p and brain edema after intracerebral hemorrhage and the role of butylphthalide (NBP) in brain edema after intracerebral hemorrhage.Method: Routine blood testing, C-reactive protein results, and computed tomography data were collected 1, 7, and 14 days after intracerebral hemorrhage in six patients. Levels of MMP-9, ZO-1, occludin, IL-6, TNF-α, and miR-7-5p were detected in each patient's serum. Sixty male Sprague–Dawley rats were randomly divided into sham operation, intracerebral hemorrhage, and NBP treatment groups. Dry–wet weight was used to assess brain edema, and Evans blue staining was used to assess the permeability of the blood–brain barrier. Expression levels of IL-6, TNF-α, ZO-1 and occludin, PI3K, AKT, p-AKT, AQP4, and miR-7-5p were analyzed in the rat brains.Result: The blood neutrophil–lymphocyte ratio (NLR) on day 1 was associated with the area of brain edema on day 7. The expression of miR-7-5p decreased after intracerebral hemorrhage, and as a result, the inhibition of the PI3K/AKT pathway was weakened. The decreased inhibition of the PI3K/AKT pathway resulted in an increase in AQP4 expression, which further aggravated brain edema. NBP can upregulate the expression of miR-7-5p, affecting these pathways to reduce brain edema.Conclusion: After intracerebral hemorrhage, miR-7-5p expression in brain tissue is reduced, which may increase the expression of AQP4 by activating the PI3K/AKT pathway. NBP can inhibit this process and reduce brain edema.

A highly selective and sensitive optical sensor was developed to colorimetric detect trace Fe3+ ions in aqueous solution. The sensor was the sulfasalazine (SSZ) functionalized microgels (SSZ-MGs), which were fabricated via in-situ quaternization reaction. The obtained SSZ-MGs had hydrodynamic radius of about 259 ± 24 nm with uniform size distribution at 25 °C. The SSZ-MG aqueous suspensions can selectively and sensitively response to Fe3+ ions in aqueous solution at 25 °C and pH of 5.6, which can be quantified by UV-visible spectroscopy and also easily distinguished by the naked eye. Job’s plot indicated that the molar binding ratio of SSZ moiety in SSZ-MGs to Fe3+ was close to 1:1 with an apparent association constant of 1.72 × 104 M−1. A linear range of 0−12 μM with the detection limit of 0.110 μM (0.006 mg/L) was found. The obtained detection limit was much lower than the maximum allowance level of Fe3+ ions in drinking water (0.3 mg/L) regulated by the Environmental Protection Agency (EPA) of the United States. The existence of 19 other species of metal ions, namely, Ag+, Li+, Na+, K+, Ca2+, Ba2+, Cu2+, Ni2+, Mn2+, Pb2+, Zn2+, Cd2+, Co2+, Cr3+, Yb3+, La3+, Gd3+, Ce3+, and Bi3+, did not interfere with the detection of Fe3+ ions.

The Internet of Medical Things (IoMT) is an application of the Internet of Things (IoT) in the medical field. It is a cutting-edge technique that connects medical sensors and their applications to healthcare systems, which is essential in smart healthcare. However, Personal Health Records (PHRs) are normally kept in public cloud servers controlled by IoMT service providers, so privacy and security incidents may be frequent. Fortunately, Searchable Encryption (SE), which can be used to execute queries on encrypted data, can address the issue above. Nevertheless, most existing SE schemes cannot solve the vector dominance threshold problem. In response to this, we present a SE scheme called Vector Dominance with Threshold Searchable Encryption (VDTSE) in this study. We use a Lagrangian polynomial technique and convert the vector dominance threshold problem into a constraint that the number of two equal-length vectors' corresponding bits excluding wildcards is not less than a threshold t. Then, we solve the problem using the proposed technique modified in Hidden Vector Encryption (HVE). This technique makes the trapdoor size linear to the number of attributes and thus much smaller than that of other similar SE schemes. A rigorous experimental analysis of a specific application for privacy-preserving diabetes demonstrates the feasibility of the proposed VDTSE scheme. [ABSTRACT FROM AUTHOR]