Design, Synthesis, Antibacterial Activity, and Mechanisms of Novel Benzofuran Derivatives Containing Disulfide Moieties.

The unsatisfactory effects of conventional bactericides and antimicrobial resistance have increased the challenges in managing plant diseases caused by bacterial pests. Here, we report the successful design and synthesis of benzofuran derivatives using benzofuran as the core skeleton and splicing the disulfide moieties commonly seen in natural substances with antibacterial properties. Most of our developed benzofurans displayed remarkable antibacterial activities to frequently encountered pathogens, including Xanthomonas oryzae pv oryzae (Xoo), Xanthomonas oryzae pv oryzicola (Xoc), and Xanthomonas axonopodis pv citri (Xac). With the assistance of the three-dimensional quantitative constitutive relationship (3D-QSAR) model, the optimal compound V40 was obtained, which has better in vitro antibacterial activity with EC50 values of 0.28, 0.56, and 10.43 µg/mL against Xoo, Xoc, and Xac, respectively, than those of positive control, TC (66.41, 78.49, and 120.36 µg/mL) and allicin (8.40, 28.22, and 88.04 µg/mL). Combining the results of proteomic analysis and enzyme activity assay allows the antibacterial mechanism of V40 to be preliminarily revealed, suggesting its potential as a versatile bactericide in combating bacterial pests in the future.

Synthesis, Bioactivities, and Antibacterial Mechanism of 5-(Thioether)-N-phenyl/benzyl-1,3,4-oxadiazole-2-carboxamide/amine Derivatives.

1,3,4-Oxadiazole thioethers have shown exciting antibacterial activities; however, the current mechanism of action involving such substances against bacteria is limited to proteomics-mediated protein pathways and differentially expressed gene analysis. Herein, we report a series of novel 1,3,4-oxadiazole thioethers containing a carboxamide/amine moiety, most of which show good in vitro and in vivo bacteriostatic activities. Compounds A10 and A18 were screened through CoMFA models as optimums against Xanthomonas oryzae pv. oryzae (Xoo, EC50 values of 5.32 and 4.63 mg/L, respectively) and Xanthomonas oryzae pv. oryzicola (Xoc, EC50 values of 7.58 and 7.65 mg/L, respectively). Compound A10 was implemented in proteomic techniques and activity-based protein profiling (ABPP) analysis to elucidate the antibacterial mechanism and biochemical targets. The results indicate that A10 disrupts the growth and pathogenicity of Xoc by interfering with pathways associated with bacterial virulence, including the two-component regulation system, flagellar assembly, bacterial secretion system, quorum sensing, ABC transporters, and bacterial chemotaxis. Specifically, the translational regulator (CsrA) and the virulence regulator (Xoc3530) are two effective target proteins of A10. Knocking out the CsrA or Xoc3530 gene in Xoc results in a significant reduction in the motility and pathogenicity of the mutant strains. This study contributes available molecular entities, effective targets, and mechanism basis for the management of rice bacterial diseases.

Development and Mechanism Investigation of Novel Thioacetalized Indoles as Antiphytoviral Agents.

Potato virus Y (PVY) is a highly destructive pathogen that infects Solanum tuberosumvL., commonly known as potato, a crop that produces one of the most crucial food staples of the world. The PVY viral infection can considerably reduce the yield and quality of potatoes, thereby causing significant economic ramifications. Given the unsatisfactory performance of commercially available antiviral agents against PVY, we synthesized a series of novel indole-derived compounds followed by their bioevaluation and investigation of the mechanisms governing their anti-PVY activity. These indole-based derivatives contain dithioacetal as a key chemical moiety, and most of them exhibit promising anti-PVY activities. In particular, compound B2 displays remarkable in vivo protective and inactivating properties, with half-maximal effective concentration (EC50) values of 209.3 and 113.0 µg/mL, respectively, in stark contrast to commercial agents such as ningnanmycin (EC50 = 281.4 and 136.3 µg/mL, respectively) and ribavirin (EC50 = 744.8 and 655.4 µg/mL, respectively). The mechanism using which B2 enhances plant immune response to protect plants from PVY is elucidated using enzyme activity tests, real-time quantitative polymerase chain reaction (RT-qPCR), and proteomics techniques. This study aims to pave the way for developing candidate pesticides and related molecules using antiphytoviral activity.

Therapeutic responses to chemotherapy or immunotherapy by molecular subtype in bladder cancer patients: A meta-analysis and systematic review.

To systematically evaluate the differences in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of bladder cancer (BC). A comprehensive literature search was performed up to December 2021. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were used to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response by fix-effect modeling. Eight studies involving 1,463 patients were included. For immunotherapy, CC3 showed the highest response rate (CC1 vs. CC3: OR=0.52, 95% CI=0.34-0.78, p=0.002; CC2 vs. CC3: OR=0.42, 95% CI=0.28-0.62, p<0.001), which was mainly reflected in the highest response rate to atezolizumab (CC1 vs. CC3: OR=0.47, 95% CI=0.29-0.75, p=0.002; CC2 vs. CC3: OR=0.38, 95% CI=0.24-0.59, p<0.001). For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC1 vs. CC3: OR=2.05, 95% CI=1.23-3.41, p=0.006; CC2 vs. CC3: OR=2.48, 95% CI=1.50-4.10, p<0.001). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR=1.93, 95% CI=1.09-3.41, p=0.020) and chemoradiation therapy (CRT) (OR=6.07, 95% CI=1.87-19.71, p<0.001). Compared with CC1, CC3 only showed a poorer response to CRT (OR=4.53, 95% CI=1.26-16.27, p=0.020), and no difference in NAC. Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.

Splicing Indoles and 4,5-Dihydro-1H-pyrazoline Structure Gave Birth to Novel Antiviral Agents: Design, Synthesis, and Mechanism Study.

The specific conation of our research is to invent a series of indole derivatives containing a 4,5-dihydro-1H-pyrazoline motif with effective antiviral activity. The anti-potato virus Y (PVY) activities of target compounds were systematically investigated. Most target compounds exhibited good PVY activities. Compound D40, which exhibited outstanding anti-PVY activities, was sieved using a three-dimensional quantitative structure-activity relationship. Based on the anti-PVY activity assessments, the curative and protective activities of D40 were found to be 64.9 and 60.8%, respectively, which were superior to those of the commercial drug Ningnanmycin (50.2 and 50.7%, respectively). In addition, defensive enzyme activities and proteomics results indicate that D40 can increase the three crucial defense-related enzyme activities and regulate the carbon fixation pathway in photosynthetic organisms to intensify the resistance of plants to PVY. Therefore, our study suggests that compound D40 might be used as a suitable crop protection pesticide.

NUF2 is correlated with a poor prognosis and immune infiltration in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies. Recently, immunotherapy has been considered a promising treatment for metastatic ccRCC. NUF2 is a crucial component of the Ndc80 complex. NUF2 can stabilize microtubule attachment and is closely related to cell apoptosis and proliferation. This research is dedicated to investigating the role of NUF2 in ccRCC and the possible mechanisms. METHODS: First, analysis of NUF2 mRNA expression levels in ccRCC and normal tissues by The Cancer Genome Atlas (TCGA) database and further verified by analysis of independent multiple microarray data sets in the Gene Expression Omnibus (GEO) database. Moreover, we evaluated and identified correlations between NUF2 expression, clinicopathologic variable, and overall survival (OS) in ccRCC by various methods. We investigated the relationship between NUF2 and tumor immune infiltration and the expression of corresponding immune cell markers via the Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER) databases. Then, we performed functional enrichment analysis of NUF2 co-expressed genes using R software and protein-protein interactions (PPIs) using the search tool used to retrieve interacting genes/proteins (STRING) databases. RESULTS: We discovered that NUF2 mRNA expression was upregulated in ccRCC tissues and was associated with sex, grade, pathological stage, lymph node metastasis, and worse prognosis. In addition, NUF2 was positively linked to tumor immune cells in ccRCC. Moreover, NUF2 was closely related to genetic markers of different immune cells. Finally, functional enrichment and protein-protein interaction (PPI) analysis suggested that NUF2 and its closely related genes may be involved in the regulation of the cell cycle and mitosis. Our results suggested that NUF2 is correlated with a poor prognosis and immune infiltration in ccRCC.

Immune Mechanism of Ethylicin-Induced Resistance to Xanthomonas oryzae pv. oryzae in Rice.

Ethylicin (ET) was reported to be promising in the control of rice bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo). The detailed mechanism for this process remains unknown. Disclosed here is an in-depth study on the action mode of ET to Xoo. Through plant physiological and biochemical analysis, it was found that ET could inhibit the proliferation of Xoo by increasing the content of defense enzymes and chlorophyll in rice (Oryza sativa ssp. Japonica cv. Nipponbare). Label-free quantitative proteomic analysis showed that ET affected the rice abscisic acid (ABA) signal pathway and made the critical differential calcium-dependent protein kinase 24 (OsCPK24) more active. In addition, the biological function of OsCPK24 as a mediator for rice resistance to Xoo was determined through the anti-Xoo phenotypic test of OsCPK24 transgenic rice and the affinity analysis of the OsCPK24 recombinant protein in vitro and ET. This study revealed the molecular mechanism of ET-induced resistance to Xoo in rice via OsCPK24, which provided a basis for the development of new bactericides based on the OsCPK24 protein.

Compressive Strength Evaluation of Ultra-High-Strength Concrete by Machine Learning.

In civil engineering, ultra-high-strength concrete (UHSC) is a useful and efficient building material. To save money and time in the construction sector, soft computing approaches have been used to estimate concrete properties. As a result, the current work used sophisticated soft computing techniques to estimate the compressive strength of UHSC. In this study, XGBoost, AdaBoost, and Bagging were the employed soft computing techniques. The variables taken into account included cement content, fly ash, silica fume and silicate content, sand and water content, superplasticizer content, steel fiber, steel fiber aspect ratio, and curing time. The algorithm performance was evaluated using statistical metrics, such as the mean absolute error (MAE), root mean square error (RMSE), and coefficient of determination (R2). The model's performance was then evaluated statistically. The XGBoost soft computing technique, with a higher R2 (0.90) and low errors, was more accurate than the other algorithms, which had a lower R2. The compressive strength of UHSC can be predicted using the XGBoost soft computing technique. The SHapley Additive exPlanations (SHAP) analysis showed that curing time had the highest positive influence on UHSC compressive strength. Thus, scholars will be able to quickly and effectively determine the compressive strength of UHSC using this study's findings.

LMD method and multi-class RWSVM of fault diagnosis for rotating machinery using condition monitoring information.

Timely and accurate condition monitoring and fault diagnosis of rotating machinery are very important to maintain a high degree of availability, reliability and operational safety. This paper presents a novel intelligent method based on local mean decomposition (LMD) and multi-class reproducing wavelet support vector machines (RWSVM), which is applied to diagnose rotating machinery faults. First, the sensor-based vibration signals measured from the rotating machinery are preprocessed by the LMD method and product functions (PFs) are produced. Second, statistic features are extracted to acquire more fault characteristic information from the sensitive PF. Finally, these features are fed into a multi-class RWSVM to identify the rotating machinery health conditions. The experimental results validate the effectiveness of the proposed RWSVM method in identifying rotating machinery fault patterns accurately and effectively and its superiority over that based on the general SVM.

A monotonic degradation assessment index of rolling bearings using fuzzy support vector data description and running time.

Performance degradation assessment based on condition monitoring plays an important role in ensuring reliable operation of equipment, reducing production downtime and saving maintenance costs, yet performance degradation has strong fuzziness, and the dynamic information is random and fuzzy, making it a challenge how to assess the fuzzy bearing performance degradation. This study proposes a monotonic degradation assessment index of rolling bearings using fuzzy support vector data description (FSVDD) and running time. FSVDD constructs the fuzzy-monitoring coefficient ε⁻ which is sensitive to the initial defect and stably increases as faults develop. Moreover, the parameter ε⁻ describes the accelerating relationships between the damage development and running time. However, the index ε⁻ with an oscillating trend disagrees with the irreversible damage development. The running time is introduced to form a monotonic index, namely damage severity index (DSI). DSI inherits all advantages of ε⁻ and overcomes its disadvantage. A run-to-failure test is carried out to validate the performance of the proposed method. The results show that DSI reflects the growth of the damages with running time perfectly.