Berbamine inhibits porcine epidemic diarrhea virus in vitro and in vivo.

Porcine epidemic diarrhea virus (PEDV) is a significant contributor to high mortality rates in piglets, posing a serious threat to the global pig industry. The absence of effective control measures and vaccines against circulating PEDV variants underscores the urgent need for new treatment strategies. In this study, we screened a compound library and identified Berbamine as a potential anti-PEDV drug through molecular docking techniques. In vitro experiments demonstrated that Berbamine significantly inhibits PEDV proliferation in Vero and IPEC-J2 cells in a dose-dependent manner, primarily targeting the replication phase of the PEDV life cycle. Furthermore, in vivo experiments revealed that Berbamine effectively alleviates intestinal damage caused by PEDV infection in piglets, leading to a reduction in viral load and cytokine levels, including IL-6, IL-8, IL-1ß, and TNF-α. Additionally, autodock predictions indicate that viral non-structural proteins 3 and 16 (Nsp3 and Nsp16) are potential targets for Berbamine. Consequently, Berbamine holds significant promise for application and development as an antiviral treatment against PEDV.

Integrating a multi-variable scenario with Attention-LSTM model to forecast long-term coastal beach erosion.

Beach erosion is an adverse impact of climate change and human development activities. Effective beach management necessitates integrating natural and anthropogenic factors to address future erosion trends, while most current prediction models focus only on natural factors, which may provide an incomplete and potentially inaccurate representation of erosion dynamics. This study enhances prediction methods by integrating both natural and anthropogenic factors, thereby enhancing the accuracy and reliability of erosion projections. By extracting historical shorelines through CoastSat model from 1986 to 2020, we develop multivariable scenarios with Attention-LSTM model to predict the regional impacts of natural and anthropogenic factors on erosion to sandy beaches along the typical shoreline of Shenzhen in China. Results reveal that Shenzhen's beaches experienced erosion up to 12 m over the past 35 years. Here we project a decrease in the mean erosion rate of the beaches, identifying population growth (21.0 %) as the main controlling factor before the mid-century in a range of scenarios. We find that Attention-LSTM multi-model ensemble approach can provide overall improved accuracy and reliability over a wide range of beach erosion compared to scenario prediction model of Attention-LSTM and statistical model of Digital Shoreline Analysis System (DSAS), yielding an average uncertainty of 10.99 compared to 13.29. These insights reveal policies to safeguard beaches because of the rising demand for beaches due to human factors, coupled with decreased impervious surfaces through ecological conservation, lead to mitigation for beach erosion. Accurate forecasts empower policymakers to implement effective coastal management strategies, safeguard resources, and mitigate erosion's adverse effects. Our study offers finely-tuned predictions of coastal erosion, providing crucial insights for future coastal conservation efforts and climate change adaptation along the shoreline, and serving as a foundation for further research aimed at understanding the evolving environmental impacts of beach erosion in Shenzhen.

High-sensitive sensory neurons exacerbate rosacea-like dermatitis in mice by activating γδ T cells directly.

Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd-/-) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea.

Assessing the potential spray drift of a six-rotor unmanned aerial vehicle sprayer using a test bench and airborne drift collectors under low wind velocities: impact of atomization characteristics and application parameters.

BACKGROUND: The unmanned aerial spraying systems (UASS) have gained widespread use for plant protection in recent years. However, spray drift from UASS is a major concern when controlling weeds over large areas and warrants a thorough investigation. This study examined the atomization characteristics of the herbicide florpyrauxifen-benzyl under downwash airflow using a UASS spray test platform. Potential spray drift was assessed using a test bench (TB) and airborne drift collectors (ADCs) in the field under low wind speeds (<1 m s-1). RESULTS: Atomization characteristics were significantly affected by the spray liquid, adjuvant, nozzle type and spray pressure. The addition of an adjuvant reduced the liquid sheet length, improved physicochemical properties and increased droplet size under the downwash airflow field. Drift evaluation in the field using the TB revealed that sediment spray drift predominantly occurred from the middle to the entire length of the device when fine-to-medium droplets were produced after the sprayer passed. ADC assessment found that higher flight altitudes and finer droplets resulted in higher drift values, whereas the addition of an adjuvant and the use of an air-induction nozzle reduced drift <3 m aboveground. CONCLUSION: The combination of using TB in the target area and ADCs in the off-target area as an alternative method to determine residual droplets in the current airflow provided valuable insights into airborne drift assessment for UASS. © 2024 Society of Chemical Industry.

Cohort study of cardiovascular safety of different COVID-19 vaccination doses among 46 million adults in England.

The first dose of COVID-19 vaccines led to an overall reduction in cardiovascular events, and in rare cases, cardiovascular complications. There is less information about the effect of second and booster doses on cardiovascular diseases. Using longitudinal health records from 45.7 million adults in England between December 2020 and January 2022, our study compared the incidence of thrombotic and cardiovascular complications up to 26 weeks after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273). These findings support the wide uptake of future COVID-19 vaccination programs.

CFI-Net: A Choquet Fuzzy Integral Based Ensemble Network With PSO-Optimized Fuzzy Measures for Diagnosing Multiple Skin Diseases Including Mpox.

In the domain of medical diagnostics, precise identification of various skin and oral diseases is vital for effective patient care. In particular, Mpox is a potentially dangerous viral disease with zoonotic origins, capable of human-to-human transmission, underscoring the urgency of precise diagnostic methods for timely intervention. This paper introduces a novel approach named the Choquet Fuzzy Integral-based Ensemble (CFI-Net) for accurate classification of skin diseases, with a specific emphasis on detecting Mpox, foot ulcers, and various mouth and oral diseases. Our methodology begins with Transfer Learning, enhancing the classification capabilities of base classifiers (DenseNet169, MobileNetV1 and DenseNet201) by incorporating additional layers. Subsequently, we aggregate the prediction scores from each base classifier using the Choquet fuzzy integral (CFI) to derive the final predicted labels, thus ensuring dynamic and robust predictions. Fuzzy measures, a crucial component of this fuzzy integral-based ensemble method, are typically determined through manual experimentation in previous approaches. However, in our study, we have tackled the challenge of manual tuning by employing meta-heuristic optimization algorithm to precisely configure the fuzzy measures for optimal performance. A rigorous evaluation is conducted on four publicly available datasets, encompassing two Mpox datasets, a foot ulcer dataset, and a mouth and oral disease dataset. The experiments reveal the remarkable effectiveness of CFI-Net in significantly improving disease classification accuracy. Additionally, we employ Grad-CAM analysis to provide insights into the decision-making processes of our models. Our findings underscore the exceptional performance of CFI-Net, achieving accuracy rates of 98.06% and 94.81% for Mpox detection, 99.06% for foot ulcer detection, and an impressive 99.61% for mouth and oral disease classification. This research not only contributes to the advancement of disease diagnosis but also demonstrates the effectiveness of ensemble learning techniques coupled with fuzzy integral-based fusion in enhancing diagnostic accuracy.

A modified orthotopic left lung transplantation model in rats.

To enhance the operability of the rat orthotopic left lung transplantation model, we implemented several improvements and meticulously detailed the procedure. One hundred and thirty-one healthy male Sprague Dawley rats, weighing between 250 and 300 g, were utilized, with 64 serving as donors, 64 as recipients, and 3 as sham controls. We employed a modified three-cuff technique for the orthotopic left lung transplantation. Notably, our modified perfusion method could prevent donor lung edema, while waist-shaped cuffs minimized suture slippage during anastomosis. Additionally, positioning the recipient rat in a slightly left-elevated supine position during anastomosis reduced tension on the lung hilum, thus mitigating the risk of vascular laceration. The introduction of a unique two-person anastomosis technique significantly reduced operation time and substantially improved success rates. Furthermore, maximizing inflation of donor lungs both during preservation and surgery minimized the occurrence of postoperative atelectasis. Various other procedural refinements contributed to the enhanced operability of our model. Sixty-four rat orthotopic left lung transplantations were performed with only one surgical failure observed. The acquisition time for donor lungs averaged (19 ± 4) minutes, while (11 ± 1) minutes were allocated for donor lung hilum anatomy and cuff installation. Recipient thoracotomy and left lung hilar anatomy before anastomosis required (24 ± 8) minutes, with anastomosis itself taking (31 ± 6) minutes. Remarkably, the survival rate at the 4-h postoperative mark stood at 96.7 %. Even six months post-operation, transplanted left rat lungs continued to exhibit proper inflation and contraction rhythms, displaying signs of chronic pathological changes. In summary, our modified rat model of orthotopic left lung transplantation demonstrates robust operability, significantly reducing surgical duration, improving operation success rates, and enhancing postoperative survival rates. Furthermore, its long-term survival capacity enables the simulation of acute and chronic disease processes following lung transplantation.

The Tandem Nitrate and CO2 Reduction for Urea Electrosynthesis: Role of Surface N-Intermediates in CO2 Capture and Activation.

Electrochemical reduction of CO2 and nitrate offers a promising avenue to produce valuable chemicals through the using of greenhouse gas and nitrogen-containing wastewater. However, the generally proposed reaction pathway of concurrent CO2 and nitrate reduction for urea synthesis requires the catalysts to be both efficient in both CO2 and nitrate reduction, thus narrowing the selection range of suitable catalysts. Herein, we demonstrate a distinct mechanism in urea synthesis, a tandem NO3 - and CO2 reduction, in which the surface amino species generated by nitrate reduction play the role to capture free CO2 and subsequent initiate its activation. When using the TiO2 electrocatalyst derived from MIL-125-NH2, it intrinsically exhibits low activity in aqueous CO2 reduction, however, in the presence of both nitrate and CO2, this catalyst achieves an excellent urea yield rate of 43.37 mmol ⋅ g-1 ⋅ h-1 and a Faradaic efficiency of 48.88 % at -0.9 V vs. RHE in a flow cell. Even at a low CO2 level of 15 %, the Faradaic efficiency of urea synthesis remains robust at 42.33 %. The tandem reduction procedure was further confirmed by in situ spectroscopies and theoretical calculations. This research provides new insights into the selection and design of electrocatalysts for urea synthesis.

Tank-mix adjuvants improved spray performance and biological efficacy in rice insecticide application with unmanned aerial vehicle sprayer.

BACKGROUND: The use of unmanned aerial vehicles (UAVs) for the application of plant protection products (PPPs) in paddy fields is becoming increasingly prevalent worldwide. Despite its growing usage, UAV spraying for rice pest control faces practical challenges, including limited canopy penetration, uneven deposition, and significant spray drift. This study investigated the impact of two tank-mix adjuvants, Wonderful Rosin (Adjuvant-1) and Tiandun (Adjuvant-2), at six volume concentrations, on the spray liquid's physicochemical properties, spray drift, plant deposition, and the biological efficacy of rice insecticides using a quadrotor UAV sprayer. RESULTS: The physicochemical characteristics of the spray liquid influenced spray performance and biological efficacy. Incorporating Adjuvant-1 and Adjuvant-2 led to a decrease in surface tension and contact angle while increasing the viscosity of the spray solution. These alterations in surface tension and viscosity contributed to an optimized droplet size distribution, reduced spray drift, enhanced deposition uniformity and penetration, and improved control efficacy against the rice planthopper in UAV applications. The highest control efficacy was observed at a concentration of 0.5%, showing an improvement of 35.12% (Adjuvant-1) and 20.23% (Adjuvant-2) over applications without tank-mix adjuvant 7 days after treatment. CONCLUSION: The judicious selection of tank-mix adjuvants for UAV PPP applications can significantly enhance spray performance and biological efficacy in controlling rice insects. This study's findings offer valuable insights for integrating tank-mix adjuvants into UAV spraying applications. © 2024 Society of Chemical Industry.

Quercetin attenuates inflammation in rosacea by directly targeting p65 and ICAM-1.

AIMS: Rosacea is an inflammatory skin disease with immune and vascular dysfunction. Although there are multiple treatment strategies for rosacea, the clinical outcomes are unsatisfactory. MAIN METHODS: Combining transcriptome data and the Connectivity Map database quercetin was identified as a novel candidate for rosacea. Next, the therapeutic efficacy of quercetin was substantiated through proteomic analyses, in vivo experiments, and in vitro assays. Additionally, the utilization of DARTS, molecular docking and experimental verification revealed the therapeutic mechanisms of quercetin. KEY FINDINGS: Treatment with quercetin resulted in the following effects: (i) it effectively ameliorated rosacea-like features by reducing immune infiltration and angiogenesis; (ii) it suppressed the expression of inflammatory mediators in HaCaT cells and HDMECs; (iii) it interacted with p65 and ICAM-1 directly, and this interaction resulted in the repression of NF-κB signal and ICAM-1 expression in rosacea. SIGNIFICANCE: We show for the first time that quercetin interacted with p65 and ICAM-1 directly to alleviated inflammatory and vascular dysfunction, suggesting quercetin is a novel, promising therapeutic candidate for rosacea.

Implementation and external validation of the Cambridge Multimorbidity Score in the UK Biobank cohort.

BACKGROUND: Patients with multiple conditions present a growing challenge for healthcare provision. Measures of multimorbidity may support clinical management, healthcare resource allocation and accounting for the health of participants in purpose-designed cohorts. The recently developed Cambridge Multimorbidity scores (CMS) have the potential to achieve these aims using primary care records, however, they have not yet been validated outside of their development cohort. METHODS: The CMS, developed in the Clinical Research Practice Dataset (CPRD), were validated in UK Biobank participants whose data is not available in CPRD (the cohort used for CMS development) with available primary care records (n = 111,898). This required mapping of the 37 pre-existing conditions used in the CMS to the coding frameworks used by UK Biobank data providers. We used calibration plots and measures of discrimination to validate the CMS for two of the three outcomes used in the development study (death and primary care consultation rate) and explored variation by age and sex. We also examined the predictive ability of the CMS for the outcome of cancer diagnosis. The results were compared to an unweighted count score of the 37 pre-existing conditions. RESULTS: For all three outcomes considered, the CMS were poorly calibrated in UK Biobank. We observed a similar discriminative ability for the outcome of primary care consultation rate to that reported in the development study (C-index: 0.67 (95%CI:0.66-0.68) for both, 5-year follow-up); however, we report lower discrimination for the outcome of death than the development study (0.69 (0.68-0.70) and 0.89 (0.88-0.90) respectively). Discrimination for cancer diagnosis was adequate (0.64 (0.63-0.65)). The CMS performs favourably to the unweighted count score for death, but not for the outcomes of primary care consultation rate or cancer diagnosis. CONCLUSIONS: In the UK Biobank, CMS discriminates reasonably for the outcomes of death, primary care consultation rate and cancer diagnosis and may be a valuable resource for clinicians, public health professionals and data scientists. However, recalibration will be required to make accurate predictions when cohort composition and risk levels differ substantially from the development cohort. The generated resources (including codelists for the conditions and code for CMS implementation in UK Biobank) are available online.

Pathways for achieving conservation targets under metacoupled anthropogenic disturbances.

Enhancing connectivity between protected areas stands as a paramount objective in advancing global conservation goals, particularly in coastal regions grappling with escalating human disruptions. However, little attention has been given to quantitative assessment of human-nature interactions within and among protected areas. Here, we endeavored to model the connectivity between protected areas in rapidly urbanizing regions in China, drawing on insights from the framework of metacoupling based on connected corridors at short and long distances. In alignment with the overarching global conservation aim of increasing the overall coverage of protected areas, we found that adding new site to the protected area system yields superior connectivity gains compared to merely expanding the boundaries of the existing sites. Within the connectivity network between protected areas, we discerned specific sites acting as stepping stones, pivotal in enhancing connectivity among the chosen protected areas. Our study propounds a pragmatic methodology for prioritizing local protection initiatives and underscores the criticality of incorporating connectivity conservation strategies. This approach is vital for attaining regional biodiversity targets, given the dual perspective encompassing both human activities and the natural environment, particularly in the face of mounting anthropogenic disturbances.

CGO-ensemble: Chaos game optimization algorithm-based fusion of deep neural networks for accurate Mpox detection.

The rising global incidence of human Mpox cases necessitates prompt and accurate identification for effective disease control. Previous studies have predominantly delved into traditional ensemble methods for detection, we introduce a novel approach by leveraging a metaheuristic-based ensemble framework. In this research, we present an innovative CGO-Ensemble framework designed to elevate the accuracy of detecting Mpox infection in patients. Initially, we employ five transfer learning base models that integrate feature integration layers and residual blocks. These components play a crucial role in capturing significant features from the skin images, thereby enhancing the models' efficacy. In the next step, we employ a weighted averaging scheme to consolidate predictions generated by distinct models. To achieve the optimal allocation of weights for each base model in the ensemble process, we leverage the Chaos Game Optimization (CGO) algorithm. This strategic weight assignment enhances classification outcomes considerably, surpassing the performance of randomly assigned weights. Implementing this approach yields notably enhanced prediction accuracy compared to using individual models. We evaluate the effectiveness of our proposed approach through comprehensive experiments conducted on two widely recognized benchmark datasets: the Mpox Skin Lesion Dataset (MSLD) and the Mpox Skin Image Dataset (MSID). To gain insights into the decision-making process of the base models, we have performed Gradient Class Activation Mapping (Grad-CAM) analysis. The experimental results showcase the outstanding performance of the CGO-ensemble, achieving an impressive accuracy of 100% on MSLD and 94.16% on MSID. Our approach significantly outperforms other state-of-the-art optimization algorithms, traditional ensemble methods, and existing techniques in the context of Mpox detection on these datasets. These findings underscore the effectiveness and superiority of the CGO-Ensemble in accurately identifying Mpox cases, highlighting its potential in disease detection and classification.

Stronger increases but greater variability in global mangrove productivity compared to that of adjacent terrestrial forests.

Mangrove forests are a highly productive ecosystem with important potential to offset anthropogenic greenhouse gas emissions. Mangroves are expected to respond differently to climate change compared to terrestrial forests owing to their location in the tidal environment and unique ecophysiological characteristics, but the magnitude of difference remains uncertain at the global scale. Here we use satellite observations to examine mean trends and interannual variability in the productivity of global mangrove forests and nearby terrestrial evergreen broadleaf forests from 2001 to 2020. Although both types of ecosystem experienced significant recent increases in productivity, mangroves exhibited a stronger increasing trend and greater interannual variability in productivity than evergreen broadleaf forests on three-quarters of their co-occurring coasts. The difference in productivity trends is attributed to the stronger CO2 fertilization effect on mangrove photosynthesis, while the discrepancy in interannual variability is attributed to the higher sensitivities to variations in precipitation and sea level. Our results indicate that mangroves will have a faster increase in productivity than terrestrial forests in a CO2-rich future but may suffer more from deficits in water availability, highlighting a key difference between terrestrial and tidal ecosystems in their responses to climate change.

China's conservation and restoration of coastal wetlands offset much of the reclamation-induced blue carbon losses.

China's coastal wetlands have experienced large losses and gains with rapid coastal reclamation and restoration since the end of the 20th century. However, owing to the difficulties in mapping soil organic carbon (SOC) in blue carbon stocks of coastal wetlands on a national scale, little is known about the spatial pattern of SOC stock in China's coastal wetlands and the loss and gain of SOC stock following coastal reclamation, conservation, and restoration over the past decades. Here, we developed a SOC stock map in China's coastal wetlands at 30 m spatial resolution, analyzed the spatial variability and driving factors of SOC stocks, and finally estimated SOC losses and gains due to coastal reclamation and wetland management from 1990 to 2020. We found that the total SOC stocks in China's coastal wetlands were 77.8 Tg C by 2020 with 3.6 Tg C in mangroves, 8.8 Tg C in salt marshes, and 65.4 Tg C in mudflats. Temperature, rainfall, and seawater salinity exerted the highest relative contributions to SOC spatial variability. The spatial trend of SOC density gradually decreased from south to north except for Liaoning province, with the lowest density in Shandong province. About 24.9% (19.4 Tg C) of SOC stocks in China's coastal wetlands were lost due to high-intensity reclamation, but SOC stock gained from conservation and restoration offset the reclamation-induced losses by 58.2% (11.3 Tg C) over the past three decades. These findings demonstrated the great potential of conservation and restoration of coastal wetlands in reversing the loss trend of blue carbon and contributing to the mitigation of climate change toward carbon neutrality. Our study provides significant spatial insights into the stocks, sequestration, and recovery capacity of blue carbon following rapid urbanization and management actions, which benefit the progress of global blue carbon management.

Integrative conjugative elements mediate the high prevalence of tmexCD3-toprJ1b in Proteus spp. of animal source.

IMPORTANCE: The emergence and spread of tmexCD-toprJ have greatly weakened the function of tigecycline. Although studies have demonstrated the significance of Proteus as carriers for tmexCD-toprJ, the epidemic mechanism and characteristics of tmexCD-toprJ in Proteus remain unclear. Herein, we deciphered that the umuC gene in VRIII of SXT/R391 ICEs was a hotspot for the integration of tmexCD3-toprJ1b-bearing mobile genetic elements by genomic analysis. The mobilization and dissemination of tmexCD3-toprJ1b in Proteus were mediated by highly prevalent ICEs. Furthermore, the co-occurrence of tmexCD3-toprJ1b-bearing ICEs with other chromosomally encoded multidrug resistance gene islands warned that the chromosomes of Proteus are significant reservoirs of ARGs. Overall, our results provide significant insights for the prevention and control of tmexCD3-toprJ1b in Proteus.

Natural Sesquiterpene Lactone as Source of Discovery of Novel Fungicidal Candidates: Structural Modification and Antifungal Activity Evaluation of Xanthatin Derived from Xanthium strumarium L.

As part of our ongoing efforts to discover novel agricultural fungicidal candidates from natural sesquiterpene lactones, in the present work, sixty-three xanthatin-based derivatives containing a arylpyrazole, arylimine, thio-acylamino, oxime, oxime ether, or oxime ester moiety were synthesized. Their structures were well characterized by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry, while the absolute configurations of compounds 5' and 6a were further determined by single-crystal X-ray diffraction. Meanwhile, the antifungal activities of the prepared compounds against several phytopathogenic fungi were investigated using the spore germination method and the mycelium growth rate method in vitro. The bioassay results illustrated that compounds 5, 5', and 15 exhibited excellent inhibitory activity against the tested fungal spores and displayed remarkable inhibitory effects on fungal mycelia. Compounds 5 and 5' exhibited more potent inhibitory activity (IC50 = 1.1 and 24.8 µg/mL, respectively) against the spore of Botrytis cinerea than their precursor xanthatin (IC50 = 37.6 µg/mL), wherein the antifungal activity of compound 5 was 34-fold higher than that of xanthatin and 71-fold higher than that of the positive control, difenoconazole (IC50 = 78.5 µg/mL). Notably, compound 6'a also demonstrated broad-spectrum inhibitory activity against the four tested fungal spores. Meanwhile, compounds 2, 5, 8, and 15 showed prominent inhibitory activity against the mycelia of Cytospora mandshurica with the EC50 values of 2.3, 11.7, 11.1, and 3.0 µg/mL, respectively, whereas the EC50 value of xanthatin was 14.8 µg/mL. Additionally, compounds 5' and 15 exhibited good in vivo therapeutic and protective effects against B. cinerea with values of 55.4 and 62.8%, respectively. The preliminary structure-activity relationship analysis revealed that the introduction of oxime, oxime ether, or oxime ester structural fragment at the C-4 position of xanthatin or the introduction of a chlorine atom at the C-3 position of xanthatin might be significantly beneficial to antifungal activity. In conclusion, the comprehensive investigation indicated that partial xanthatin-based derivatives from this study could be considered for further exploration as potential lead structures toward developing novel fungicidal candidates for crop protection.

Discovery of Natural Sesquiterpene Lactone 1-O-Acetylbritannilactone Analogues Bearing Oxadiazole, Triazole, or Imidazole Scaffolds for the Development of New Fungicidal Candidates.

In recent decades, natural products have been considered important resources for developing of new agrochemicals because of their novel architectures and multibioactivities. Consequently, herein, 1-O-acetylbritannilactone (ABL), a natural sesquiterpene lactone from Inula britannica L., was used as a lead for further modification to discover fungicidal candidates. Six series of ABL-based derivatives containing an oxadiazole, triazole, or imidazole moiety were designed and synthesized, and their antifungal activities were also evaluated in vitro and in vivo. Bioassay results revealed that compounds 8d, 8h, and 8j (EC50 = 61.4, 30.9, and 12.4 µg/mL, respectively) exhibited more pronounced inhibitory activity against Fusarium oxysporum than their precursor ABL (EC50 > 500 µg/mL) and positive control hymexazol (EC50 = 77.2 µg/mL). Derivatives 8d and 11j (EC50 = 19.6 and 41.5 µg/mL, respectively) exhibited more potent antifungal activity toward Cytospora mandshurica than ABL (EC50 = 68.3 µg/mL). Compound 10 exhibited excellent and broad-spectrum antifungal activity against seven phytopathogenic fungal mycelia. Particularly, the inhibitory activity of compound 10 against the mycelium of Botrytis cinerea was more than 10.8- and 2.3-fold those of ABL and hymexazol, respectively. Meanwhile, derivative 10 (IC50 = 47.7 µg/mL) displayed more pronounced inhibitory activity against the spore of B. cinerea than ABL (IC50 > 500 µg/mL) and difenoconazole (IC50 = 80.8 µg/mL). Additionally, the in vivo control efficacy of compound 10 against B. cinerea was further studied using infected tomatoes (protective effect = 58.4%; therapeutic effect = 48.7%). The preliminary structure-activity relationship analysis suggested that the introduction of the 1,3,4-oxadiazole moiety (especially the 1,3,4-oxadiazole heterocycle containing the 4-chlorophenyl, 2-furyl, or 2-pyridinyl group) on the skeleton of ABL was more likely to produce potential antifungal compounds. These findings pave the way for further design and development of ABL-based derivatives as potential antifungal agents.

Renal-friendly Li+-doped carbonized polymer dots activate Schwann cell autophagy for promoting peripheral nerve regeneration.

Activation of autophagy in Schwann cells (SCs) has emerged as a powerful trigger for peripheral nerve injury (PNI) repair. Lithium ion (Li+) is a classical autophagy activator that plays an important role in promoting axonal extension and remyelination. However, the therapeutic window of existing lithium drugs is extremely narrow, and the adverse side effects, especially nephrotoxicity, severely limit their therapeutic value. Herein, Li+-doped carbonized polymer dots (Li-CPDs) was synthesized for the first time to change the pharmacokinetics of Li+ from occupying epithelial sodium channels to lipid raft-mediated endocytosis. The in-vivo results confirmed that Li-CPDs could accelerate the removal of myelin debris and promote nerve regeneration via activating autophagy of SCs. Moreover, Li-CPDs exhibited almost no renal toxicity compared to that of raw lithium drugs. Thus, Li-CPDs could serve as a promising Li+-based nanomedicine for PNI regeneration with improved biosafety. STATEMENT OF SIGNIFICANCE: Regardless of the fact that lithium drugs have been used in treatment of mental illness such as manic depression, the systemic side effects and renal metabolic toxicity still seriously restrict their clinical application. Since Li+ and Na+ compete for ion channels of cell membrane, the cell entry efficiency is extremely low and easily affected by body fluctuations, which seems to be an unsolvable problem. Herein, we rationally exploited the endocytotic features of CPDs to develop Li-CPDs. The Li-CPDs improved the entry pathway, greatly reduced nephrotoxicity, and inherited the biological function of Li+ to activate autophagy for promoting peripheral nerve regeneration. Due to the BBB-crossing property of Li-CPDs, it also showed application prospects in future research on central nervous system diseases.