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Plant pathogenic fungi seriously threaten agricultural production. There is an urgent need to develop novel fungicides with low toxicity and high efficiency. In this study, we designed and synthesized 44 pyrazolo[3,4-d]pyrimidin-4-one derivatives and evaluated them for their fungicidal activities. The bioassay data revealed that most of the target compounds possessed moderate to high in vitro antifungal activities. Especially compound g22 exhibited remarkable antifungal activity against Sclerotinia sclerotiorum with an EC50 value of 1.25 mg/L, close to that of commercial fungicide boscalid (EC50 = 0.96 mg/L) and fluopyram (EC50 = 1.91 mg/L). Moreover, compound g22 possessed prominent protective activity against S. sclerotiorum in vivo for 24 h (95.23%) and 48 h (93.78%), comparable to positive control boscalid (24 h (96.63%); 48 h (93.23%)). Subsequent studies indicated that compound g22 may impede the growth and reproduction of S. sclerotiorum by affecting the morphology of mycelium, destroying cell membrane integrity, and increasing cell membrane permeability. In addition, the application of compound g22 did not injure the growth or reproduction of Italian bees. This study revealed that compound g22 is expected to be developed for efficient and safe agricultural fungicides.

Inspired by commercially established fluxapyroxad as the lead compound of novel efficient antifungal ingredients, novel pyrazole carboxylate derivatives containing a flexible thiazole backbone were successfully designed, synthesized, and detected for their in vitro and in vivo biological activities against eight agricultural fungi. The antifungal bioassay results showed that compound 24 revealed excellent bioactivities against Botrytis cinerea and Sclerotinia sclerotiorum, with median effective concentrations (EC50) of 0.40 and 3.54 mg/L, respectively. Compound 15 revealed remarkable antifungal activity against Valsa mali, with an EC50 value of 0.32 mg/L. For in vivo fungicide control against B. cinerea and V. mali, compounds 3 and 24 at 25 mg/L, respectively, displayed prominent efficacy on cherry tomatoes and apple branches. Molecular docking results demonstrated that compound 15 could form an interaction with several crucial residues of succinate dehydrogenase (SDH), and the in vitro enzyme assay indicated that the target compound 15 displayed an inhibitory effect toward SDH, with an IC50 value of 82.26 μM. The experimental results indicated that phenyl pyrazole carboxylate derivatives displayed a weak antifungal property and low activity compared to the other title substituent pyrazole carboxylate derivatives. Compounds 3, 15, and 24 are promising antifungal candidates worthy of further fungicide development due to their prominent effectiveness.

BACKGROUND Liver cancer is one of the most common malignant tumors, and ranks as the fourth leading cause of cancer death worldwide. Microvascular invasion (MVI) is considered one of the most important factors for recurrence and poor prognosis of liver cancer. Thus, accurately identifying MVI before surgery is of great importance in making treatment strategies and predicting the prognosis of patients with hepatocellular carcinoma (HCC). Radiomics as an emerging field, aims to utilize artificial intelligence software to develop methods that may contribute to cancer diagnosis, treatment improvement and evaluation, and better prediction. AIM To investigate the predictive value of computed tomography radiomics for MVI in solitary HCC ≤ 5 cm. METHODS A total of 185 HCC patients, including 122 MVI negative and 63 MVI positive patients, were retrospectively analyzed. All patients were randomly assigned to the training group (n = 124) and validation group (n = 61). A total of 1351 radiomic features were extracted based on three-dimensional images. The diagnostic performance of the radiomics model was verified in the validation group, and the Delong test was applied to compare the radiomics and MVI-related imaging features (two-trait predictor of venous invasion and radiogenomic invasion). RESULTS A total of ten radiomics features were finally obtained after screening 1531 features. According to the weighting coefficient that corresponded to the features, the radiomics score (RS) calculation formula was obtained, and the RS score of each patient was calculated. The radiomics model exhibited a better correction and identification ability in the training and validation groups [area under the curve: 0.72 (95% confidence interval: 0.58-0.86) and 0.74 (95% confidence interval: 0.66-0.83), respectively]. Its prediction performance was significantly higher than that of the image features (P < 0.05). CONCLUSION Computed tomography radiomics has certain predictive value for MVI in solitary HCC ≤ 5 cm, and the predictive ability is higher than that of image features.

Polyurethane - Dispersed Diazo Black GNN Polymer dye (PU-DDB GNN) was synthesized by incorporation of DDB GNN into polyurethane chains. The expected structure of polyurethane-dispersed diazo black GNN polymer dye was confirmed by FT-IR and UV-vis spectra. The photochromic phenomenon of polyurethane-dispersed diazo-black GNN dyes was investigated. And through the thermogravimetric analysis and differential calorimetry analysis, it is confirmed to be an amorphous structure with good thermal stability. Through the test of its mechanical properties, the results show that the elongation at break is quite high.

Corticosteroid resistance (CR) is a serious disadvantage in treating many chronic inflammatory conditions. Eosinophils are the main inflammation cells in allergic reactions. Environmental pollution, such as PM2.5, is associated with the pathogenesis of allergic disorders. The objective of this study is to elucidate the mechanism by which the exposure to PM2.5 confers eosinophil CR status.Patients with allergic rhinitis were recruited and assigned to corticosteroid sensitive (CS) and CR groups. Eosinophils were purified from nasal lavage fluids collected from patients with allergic rhinitis. A murine AR mouse model was developed with dust mite allergens and PM2.5 as the sensitization reagents.CR status was detected in about 60% eosinophil collected in patients with AR. Upon exposure to eosinophil activators, CS eosinophils released a large quantity of mediators, which was suppressed by the presence of steroids in the culture. CR eosinophils demonstrated resistance to steroidal therapy. RAS activation levels in eosinophils were higher in CR eosinophils than in CS eosinophils. Higher expression of the Son of sevenless-1 (Sos1) was detected in CR eosinophils, which formed a complex with RAS and glucocorticoidreceptor-α in CR eosinophils to prevent the binding between steroids and glucocorticoidreceptor-α. The presence of an Sos1 inhibitor dissociated glucocorticoid receptor-α from RAS/Sos1 complex, that restored the sensitivity to steroids in eosinophils. Administering the Sos1 inhibitor effectively attenuated the experimental allergic rhinitis.CR status was detected in approximately 1/3 eosinophils sampled from patients with allergic rhinitis. Sos1 was instrumental in the development and perseverance of CR in eosinophils. Sos1 inhibition restored sensitivity to steroids in CR eosinophils, which effectively reduced experimental allergic rhinitis.

Aim The prediction model of postoperative survival for single large and huge hepatocellular carcinoma (SLH-HCC, diameter > 5.0 cm) without portal vein tumour thrombus has not been well established. This study aimed to develop novel nomograms to predict postoperative recurrence and survival of these patients. Methods Data from 2469 patients with SLH-HCC who underwent curative resection from January 2005 to December 2015 in China were retrospectively collected. Specifically, nomograms of recurrence-free survival (RFS) and overall survival (OS) using data from a training cohort were developed with the Cox regression model (n = 1012). The modes were verified in an internal validation cohort (n = 338) and an external cohort comprising four tertiary institutions (n = 1119). Results The nomograms of RFS and OS based on tumour clinicopathologic features (diameter, differentiation, microvascular invasion, α-fetoprotein), operative factors (preoperative transcatheter arterial chemoembolisation therapy, scope of liver resection and intraoperative blood transfusion), underlying liver function (albumin-bilirubin grade) and systemic inflammatory or immune status (neutrophil-to-lymphocyte ratio) achieved high C-indexes of 0.85 (95% confidence interval [CI], 0.79–0.91) and 0.86 (95% CI, 0.79–0.93) in the training cohort, respectively, which were significantly higher than those of the five conventional HCC staging systems (0.62–0.73 for RFS, 0.63–0.75 for OS). The nomograms were validated in the internal cohort (0.83 for RFS, 0.84 for OS) and external cohort (0.87 for RFS, 0.88 for OS) and had well-fitted calibration curves. Our nomograms accurately stratified patients with SLH-HCC into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. Conclusions The two nomograms achieved optimal prediction for postsurgical recurrence and OS for patients with SLH-HCC after curative resection.

With the large-scale development of electric vehicles, in order to reduce the potential safety hazards in the charging process of electric vehicles, this paper analyzes the charging safety characteristics of electric batteries, charge and discharge equipment, and power supply equipment of electric vehicles, studies the fault correlation between multi-level equipment, and establishes an integrated fault priority comprehensive evaluation model based on comprehensive fuzzy analytic hierarchy process. The data on the interconnected data platform can be used to obtain a quantitative evaluation result of the actual demonstration effect, and the actual effect of the integrated security early warning system. It can effectively improve the charging safety of electric vehicles and promote the healthy development of electric vehicles.

BACKGROUND To promote the discovery and development of new fungicide with novel scaffolds or modes of action, a series of novel 5-(2-chloroethyl)-1-phenyl-6-(pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized, and evaluated for their antifungal activities. RESULTS The bioassay data showed that compound 8IIId (EC50 = 1.93 mg L-1 ) is superior to boscalid (EC50 = 6.71 mg L-1 ) against Valsa mali. We introduced chiral groups on the structure of 8IIId, and two chiral configurations were respectively synthesized, which are 8Vc and 8Vd. Surprisingly, 8Vc showed significant antifungal activities against Valsa mali and Physalospora piricola with EC50 values of 0.22 and 0.55 mg L-1 . Physiological and biochemical studies showed that the primary action mechanism of compound 8Vc on Valsa mali may involve changing mycelial morphology and increasing cell membrane permeability. CONCLUSION These results demonstrated that 8Vc could be further modified as fungicide and provided a valuable reference for antifungal agents with pyrazolo[3,4-d]pyrimidin-4-one skeleton. © 2021 Society of Chemical Industry.

Additional file 1: Table S1. Primers used for RT-qPCR. Figure S1. Enzyme activity of MNNG mutagenesis re-screening. a diameter ratio (hydrolysis circle diameter/strain diameter) of TA and its mutants, b FPase activities of TA and its mutants, c CMCase activities of TA and its mutants. Figure S2. Enzyme activity of EMS mutagenesis re-screening. a FPase activities of M-84 and its mutants, b CMCase activities of M-84 and its mutants, c pNPCase activities of M-84 and its mutants, d pNPGase activities of M-84 and its mutants. Figure S3. Enzyme activity of ARTP mutagenesis re-screening. a FPase activities of ME-10 and its mutants, b CMCase activities of ME-10 and its mutants, c pNPCase activities of ME-10 and its mutants, d pNPGase activities of ME-10 and its mutants. Figure S4. Common biomasses after pretreatment for hydrolysis.

In ground-based microwave radiometer remote sensing, low-elevation-angle (-3&deg, ~3&deg, ) radiation data are often discarded because they are considered to be of little value and are often difficult to model due to the complicated mechanism. Based on the observed X-band horizontal polarization low elevation angle microwave radiation data and the meteorological data at the same time, this study investigated the generation mechanism of low elevation angle brightness temperature (LEATB) and its relationship with meteorological data, i.e., temperature, humidity, and wind speed, under low sea state. As a result, one could find that the LEATB was sensitive to the atmosphere at the elevation angle between 1&deg, to 3&deg, and a diurnal variation of the LEATB reached up to 10 K. This study also found a linear relationship between the LEATB and sea surface wind speed under low sea state at an elevation range from &minus, 3&deg, to 0&deg, i.e., the brightness temperature decreased as the wind speed increased, which was inconsistent with the observations at the elevation angle from &minus, 10&deg, to &minus, 5&deg, The variation of the LEATB difference according to the change in the over-the-horizon detection capability (OTHDC) of the shipborne microwave radar was examined to identify the reason for this phenomenon theoretically. The results showed that the LEATB difference was significantly influenced by a change in the OTHDC. Further, this study examined a remote sensing method to extract the sea surface wind speed data from experimental LEATB data under low sea state. The results demonstrated that the X-band horizontal polarization LEATBs were useful to retrieve the sea surface wind speed data at a reasonable accuracy&mdash, the root mean square error of 0.02408 m/s. Overall, this study proved the promising potential of the LEATB data for retrieving temperature profiles, humidity profiles, sea surface winds, and the OTHDC.

Background In this study, we developed a nomogram and a Bayesian network (BN) model for prediction of survival in gallbladder carcinoma (GBC) patients following surgery and compared the performance of the two models. Methods Survival prediction models were established and validated using data from 698 patients with GBC who underwent curative-intent resection between 2008 and 2017 at one of six Chinese tertiary hospitals. Model construction and internal validation were performed using data from 381 patients at one hepatobiliary center, and external validation was then performed using data from 317 patients at the other five centers. A BN model and a nomogram model were constructed based on the independent prognostic variables. Performance of the BN and nomogram models was compared based on area under receiver operating characteristic curves (AUC), model accuracy, and a confusion matrix. Results Independent prognostic variables included age, pathological grade, liver infiltration, T stage, N stage, and margin. In internal validation, AUC was 84.14% and 78.22% for the BN and nomogram, respectively, and model accuracy was 75.65% and 72.17%, respectively. In external validation, AUC was 76.46% and 70.19% for the BN and nomogram, respectively, with model accuracy of 66.88% and 60.25%, respectively. Based on the confusion matrix, the nomogram had a higher true positive rate but a substantially lower true negative rate compared to the BN. Conclusion A BN model was more accurate than a Cox regression-based nomogram for prediction of survival in GBC patients undergoing curative-intent resection.

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05 μg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4 μg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC50 values of 0.13 μM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

The design and synthesis of novel multi-substituted benzo-indole pyrazole Schiff base derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activities against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella. In addition, we selected 20 compounds for the in vitro antibacterial activities assay of 6 drug-resistant bacteria strains. The result revealed compound 8I-w exhibited excellent antibacterial activity against 4 drug-resistant E. coli bacteria strains with IC50 values of 7.0, 17.0, 13.5, and 1.0 μM, respectively. In vitro enzyme inhibitory assay showed that compound 8I-w displayed potent inhibition against DNA gyrase with IC50 values of 0.10 μM. The molecular docking model indicated that compounds 8I-w can bind well to the DNA gyrase by interacting with various amino acid residues. This study demonstrated that the compound 8I-w can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

Background T-helper 2 (Th2) polarization plays a critical role in the pathogenesis of chronic rhinosinusitis (CRS) with accompanying nasal allergy. Recent studies indicate that B cell lymphoma-2-like protein-12 (Bcl2L12) is associated with immune dysregulation. The purpose of this study was to elucidate the role of Bcl2L12 in the pathogenesis of Th2 polarization of CRS patients. Methods CRS patients with nasal allergy (CRSa) and without nasal allergy (CRSna) were recruited into this study. CD4+ T cells were isolated from the blood samples of human subjects. A variety of immunologic molecular strategies were used to assess Th2 polarization and Bcl2L12 expression. Results Twenty CRSa patients, 20 CRSna patients, and 20 healthy subjects were recruited into this study. High levels of immunoglobulin E (IgE), interleukin 4 (IL-4), IL-5, IL-13, and Bcl2L12 were detected in nasal extracts of CRSa patients, but not in CRSna patients. The levels of Bcl2L12 were positively correlated with Th2 cytokines. CD4+ T cells from CRSa patients were prone to differentiate into Th2 cells, in which Bcl2L12 was required. Conclusion Bcl2L12 is positively correlated with Th2 cytokine levels in the nasal mucosa of CRSa patients. Bcl2L12 contributes to the Th2 polarization, which may be a novel therapeutic target in the treatment of CRSa.

Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon-pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 μM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.

According to the theory of traditional Chinese medicine, based on the four properties and five flavors of traditional Chinese medicines, the lifting and lowering theory and channel tropism, Professor Chen combined with the theory of traditional Chinese medicine and constitution identification to prescribe for patients and used herb pairs to treat many kinds of pulmonary diseases. And he has achieved good clinical effect by "treatment methods selection according to syndromes". His experience in medication and compatibility mechanism are worthy of further exploration and promotion by scholars.