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Previous studies have shown that benzoylaconine (BAC), a representative monoester alkaloid, has a potential anti-inflammatory effect. This study investigated the underlying molecular mechanisms using the mode of LPS-activated RAW264.7 macrophage cells. Our findings showed that BAC significantly suppressed the release of pro-inflammatory cytokines and mediators, including IL-6, TNF-α, IL-1β, ROS, NO, and PGE2. BAC treatment also effectively downregulated the elevated protein levels of iNOS and COX-2 induced by LPS in a dose-dependent manner. In this study, we found that BAC inhibited LPS-induced NF-κB activation by reducing the phosphorylation and degradation of IκBα by western blotting and blocking the nuclear translocation of p65 using an immunofluorescence assay. The elevated protein levels of JNK, p38, and ERK phosphorylation after LPS stimulation were restored effectively by BAC treatment. The protein expression of Toll-like receptor 4 (TLR4) and LPS-induced phosphorylation of TAK1, which is a crucial upstream regulatory factor of TLR-induced MAPK and NF-κB signaling, were inhibited by BAC in activated RAW264.7 macrophages. Moreover, BAC decreased the levels of TAK1 phosphorylation and pro-inflammatory cytokines and mediators associated with MAPK and NF-κB activation, similar to TLR4 inhibitor TAK-242. These findings demonstrated that BAC exhibited an anti-inflammatory effect by the inhibition of TLR-induced MAPK and NF-κB pathways, indicating that it could potentially be used for treating inflammatory diseases.

The protective component of specific memory B cells (MBCs) response relative to serum antibody response in primary SARS-CoV-2 infection is not well understood. Using a relatively unbiased B-cell culture method with a limited number of MBCs in each well (100 cells/well), we characterized the fine specificity of MBC responses against SARS-CoV-2 infection. While serum spike antibody is predominantly against S2 domain, the memory B cells mainly recognize S1 domain. The 44.4–85.3% of S-binding MBCs are specific to S1 domain. High frequency of MBCs (30–62% of SARS-CoV-2 S-specific MBCs) cross-reacting with SARS-CoV S has also been demonstrated. 22–33% of S1-binding MBCs were cross-reactive with the SARS-CoV RBD. In addition, a panel of human monoclonal Ab was derived from S1-binding MBCs recognizing six group epitopes (groups 1–6). Among them, RBD-specific Ab (826) in group 4 and cross-reactive Ab (808) could resist the neutralizing escape of omicron. Herein, we demonstrated that a dominant S1-directed MBC response was generated during primary SARS-CoV-2 infection. More importantly, the cross-reactive RBD-directed MBCs against SARS-CoV may protect against emerging SARS-CoV-2 variants.

SARS-CoV-2 nucleocapsid (N) protein plays a key role in multiple stages of the viral life cycle such as viral replication and assembly. This protein is more conserved than the Spike protein of the virus and can induce both humoral and cell-mediated immune responses, thereby becoming a target for clinical diagnosis and vaccine development. However, the immunogenic characteristics of this protein during natural infection are still not completely understood. Patient-derived monoclonal antibodies (mAbs) against SARS-CoV-2 N protein were generated from memory B cells in the PBMCs using the antigen-specific B cell approach. For epitope mapping of the isolated hmAbs, a panel of series-truncated N proteins were used , which covered the N-terminal domain (NTD, aa 46-174 ) and C-terminal domain (CTD, aa 245-364 ), as well as the flanking regions of NTD and CTD. NTD- or CTD-specific Abs in the plasma from COVID-19 patients were also tested by ELISA method. Cross-binding of hmAbs or plasma Abs in COVID-19 patients to other human β-CoV N proteins was determined using the capture ELISA. We isolated five N-specific monoclonal antibodies (mAbs) from memory B cells in the peripheral blood of two convalescent COVID-19 patients. Epitope mapping revealed that three of the patient-derived mAbs (N3, N5 and N31) targeted the C-terminal domain (CTD), whereas two of the mAbs (N83 and 3B7) targeted the N-terminal domain (NTD) of SARS-CoV-2 N protein. All five patient-derived mAbs were cross-reactive to the N protein of SARS-CoV but showed little to no cross-reactivity to the N proteins of other human beta coronaviruses (β-CoVs). We also tested 52 plasma samples collected from convalescent COVID-19 patients for Abs against the N proteins of human β-CoVs and found that 78.8% of plasma samples showed detectable Abs against the N proteins of SARS-CoV-2 and SARS-CoV. No plasma sample had cross-reactive Abs to the N protein of MERS-CoV. Cross-reactive Abs to the N proteins of OC43 and HKU1 were detected in 36.5% (19/52) and 19.2% (10/52) of plasma samples, respectively. These results suggest that natural SARS-CoV-2 infection elicits cross-reactive Abs to the N protein of SARS-CoV and that the five patient-derived mAbs to SARS-CoV-2 N protein NTD and CTD cross-react with their counterparts of SARS-CoV, but not other human β-CoVs. Thus, these five patient-derived mAbs can potentially be used for developing the next generation of COVID-19 At-Home Test kits for rapid and specific screening of SARS-CoV-2 infection.

Smart meters are one of the crucial terminals in the construction of smart grids, and it is necessary to assess their health status to prevent failures. Based on a hierarchical evaluation index system, this study improved the entropy method and adopted a combined weighting method to integrate subjective and objective weights. The authors constructed an index cloud matter‐element model to develop the extensibility of the matter element and used the correlation between the level and index clouds to evaluate the health status of smart meters. Here, the level cloud model and the index cloud model reflected the fuzziness of the boundary of the health level and the uncertainty of the sampling data of indexes, respectively. Based on the theory of constant weight decision and variable weight, the weight was adjusted dynamically by combining the real‐time operation data of the entropy method, and the evaluation results were corrected in real time to elucidate the effect of extreme changes and unhealthy conditions on smart meters. Verification of the calculation example demonstrated accurate evaluation using the method in this study, and the maintenance schedule could be adjusted reasonably.

Background The recurrent aphthous stomatitis (RAS) frequently affects patient quality of life as a result of long lasting and recurrent episodes of burning pain. However, there were temporarily few available effective medical therapies currently. Drug target identification was the first step in drug discovery, was usually finding the best interaction mode between the potential target candidates and probe small molecules. Therefore, elucidating the molecular mechanism of RAS pathogenesis and exploring the potential molecular targets of medical therapies for RAS was of vital importance. Methods Bioinformatics data mining techniques were applied to explore potential novel targets, weighted gene co-expression network analysis (WGCNA) was used to construct a co-expression module of the gene chip data from GSE37265, and the hub genes were identified by the Molecular Complex Detection (MCODE) plugin. Results A total of 16 co-expression modules were identified, and 30 hub genes in the turquoise module were identified. In addition, functional analysis of Hub genes in modules of interest was performed, which indicated that such hub genes were mainly involved in pathways related to immune response, virus infection, epithelial cell, signal transduction. Two clusters (highly interconnected regions) were determined in the network, with score = 17.647 and 10, respectively, cluster 1 and cluster 2 are linked by STAT1 and ICAM1, it is speculated that STAT1 may be a primary gene of RAS. Finally, genistein, daidzein, kaempferol, resveratrol, rosmarinic acid, triptolide, quercetin and (-)-epigallocatechin-3-gallate were selected from the TCMSP database, and both of them is the STAT-1 inhibitor. The results of reverse molecular docking suggest that in addition to triptolide, (-)-Epigallocatechin-3-gallate and resveratrol, the other 5 compounds (flavonoids) with similar structures may bind to the same position of STAT1 protein with different docking score. Conclusions Our study identified STAT1 as the potential biomarkers that might contribute to the diagnosis and potential therapeutic target of RAS, and we can also screen RAS therapeutic drugs from STAT-1 inhibitors.

The emergence of various SARS-CoV-2 variants presents challenges for antibody therapeutics, emphasizing the need for more potent and broadly neutralizing antibodies. Here, we employed an unbiased screening approach and successfully isolated two antibodies from individuals with only exposure to ancestral SARS-CoV-2. One of these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum of SARS-CoV-2 variants, including the latest KP.2, KP.3 and XEC, with consistent IC 50 values ranging from ~1 to 5 ng/mL. It also displayed broad neutralization activity against SARS-CoV and related sarbecoviruses. Structural analysis revealed that these antibodies target shared hotspot but mutation-resistant epitopes, with their Fabs locking receptor binding domains (RBDs) in the “down” conformation through interactions with adjacent Fabs and RBDs, and cross-linking Spike trimers into di-trimers. In vivo studies conducted in a JN.1-infected hamster model validated the protective efficacy of CYFN1006-1. These findings suggest that antibodies with cross-neutralization activities can be identified from individuals with exclusively ancestral virus exposure. Functional and structural studies of two potent antibodies isolated from individuals exposed only to ancestral SARS-CoV-2, demonstrating broad neutralization against the latest SARS-CoV-2 variants and related sarbecoviruses.

Scalability refers to the capability of a system or network being expanded or upgraded easily to satisfy ever-increasing growing demand, the development of smart grid is anticipated to be highly desirable in realizing the scalability. In this paper, scalability of smart infrastructure system composed of smart power electricity, smart information as well as smart communication was emphasized, which may provide basis and foundation for all other systems. All scalability aspects in smart grid was taken into consideration and particular focus was directed on the three major parts of smart infrastructure system. Finally, issues regarding to future challenges and opportunities of scalability architectures together with protocols and algorithms in smart grid were also addressed.

The rising global incidence of central nervous system (CNS) diseases, exacerbated by the formidable blood-brain barrier (BBB) hindering effective drug delivery, necessitates novel therapeutic strategies. Nasal administration has emerged as a promising non-invasive route, bypassing the BBB via direct neural pathways (olfactory/trigeminal), systemic absorption, or lymphatic drainage. However, inherent nasal barriers like the mucus layer and epithelium limit its efficacy. This review distinguishes itself by integrating mechanistic insights into nasal transport pathways with the rational design of advanced nano-delivery systems. We first outline the challenges in CNS drug delivery and detail the nasal anatomy and transport pathways facilitating nose-to-brain delivery. Subsequently, we emphasize the critical properties required of advanced nano-carriers to improve mucosal penetration, prolong retention, and promote drug accumulation at cerebral injury sites. Following a detailed analysis of the advantages and limitations associated with nose-to-brain delivery, we consolidate recent advances in nasal nano-delivery systems for treating CNS disorders, emphasizing their capacity to improve brain-targeting efficiency, enhance therapeutic efficacy, reduce systemic toxicity, and enable previously undruggable CNS targets. Finally, we expand the discussion to encompass current challenges impeding clinical translation, including safety concerns, manufacturing scalability, and regulatory hurdles, while highlighting emerging trends such as artificial intelligence-driven formulation design. This comprehensive analysis aims to deepen the understanding of nasal-to-brain transport mechanisms and inform the future development of effective nasal formulations for improved neurological therapeutics.

The noninvasive diagnosis of pancreatic lesions is a critical clinical challenge. This study aims to create machine learning (ML) radiomic models for differentiating pancreatic lesions and an integrated model for pancreatic ductal adenocarcinoma (PDAC) detection. 640 patients with pathologically confirmed malignant (  = 450), borderline (  = 108), or benign (  = 82) lesions were enrolled and divided into training (70%) and validation (30%) cohorts. Radiomic features were extracted from regions of interest on arterial and venous phase CT scans. LASSO logistic regression was used to select 36 features for building ML models, including random forest, logistic regression, support vector machine, and artificial neural networks. An integrated nomogram combining radiomic features and CA19-9 levels was developed to distinguish PDAC from borderline tumors. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. All ML models effectively differentiated the three tumor types. The random forest algorithm showed the best performance, achieving an area under the curve (AUC) of 0.99 and 0.95 in the training and validation sets, respectively. CA19-9 was identified as an independent diagnostic factor for PDAC. The nomogram integrating radiomics and CA19-9 achieved an AUC of 0.89 and accuracy of 0.85 in the training set, with corresponding values of 0.85 and 0.82 in the validation set. Radiomics-based ML models effectively differentiated benign, borderline, and malignant pancreatic tumors. The nomogram combining radiomic features with CA19-9 demonstrated robust performance, showing considerable potential to streamline the diagnostic process and facilitate timely care planning for patients with suspected pancreatic cancer.

Objective. A case-control study was conducted to explore the effect of acupuncture combined with rehabilitation training on limb function and nerve injury rehabilitation in elderly patients with stroke. Methods. A total of 72 elderly patients with stroke treated from March 2019 to June 2021 in our hospital were enrolled as the object of study. The clinical data were collected and divided into two groups according to their different treatment methods. The patients cured with routine treatment combined with rehabilitation training were taken as the control group and the patients cured with acupuncture combined with rehabilitation training as the study group. The clinical efficacy was recorded, and the cognition and activities of daily living were evaluated by Terrell Cognitive Assessment scale, limb motor function score, and activities of daily living scale. The National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) were employed to compare the neurological function before and after treatment. Glasgow Outcome Scale (GOS) and Disability Rating Scale (DRS) were adopted to evaluate the functional prognosis. The simplified Fugl-Meyer assessment of motor recovery score was employed to evaluate the limb function of the patients. The Wolf Motor Function Test (WMFT) score was adopted to evaluate the functional rehabilitation effect of the patients. Enzyme-linked immunosorbent assay (ELISA) was adopted to determine the serum neurological function indexes such as nerve growth factor, Smur100B protein, and glial fibrillary acidic protein. The cerebral blood flow (CBF), peak time, average transit time, and cerebral blood volume were measured by CT perfusion imaging, and the incidence of side effects during treatment was recorded. Results. Regarding the recovery of cognitive function and daily function after treatment, after treatment, the MoCA and ADL scores were increased, and the comparison indicated that the MoCA and ADL scores of the study group were remarkably higher compared to the control group (P<0.05). With regard to the FMA-UE scores after treatment, the Fugl-Meyer scores were gradually increased, and the Fugl-Meyer scores in the study group were remarkably higher compared to the control group (P<0.05) in the next two months. After 2 weeks, 4 weeks, 6 weeks, and 6 weeks of treatment, the WMFT scores gradually increased, and the WMFT score of the study group was remarkably higher compared to the control group. After treatment, the levels of nerve growth factor and S-100B protein were decreased, and the level of glial fibrillary acidic protein was increased. Comparison between the two groups, it indicated the improvement degree of each neurological function index in the study group was remarkably better (P<0.05). With regard to cerebral hemodynamic indexes after treatment, 1 week after treatment, the CBF and average transit time of the observation group were remarkably higher compared to the control group, and the levels of cerebral blood volume and peak time were remarkably lower compared to the control group (P<0.05). After 4 weeks of treatment, the cerebral hemodynamic indexes of the observation group did not change remarkably, and they were all lower than 1 week after the treatment. In the terms of side effects, 1 case of limb dysfunction, 1 case of swallowing dysfunction, 1 case of electrolyte disturbance, and none of infection in the study group, the incidence of adverse reactions was 8.33%. In the control group, there were 3 cases of limb dysfunction, 2 cases of swallowing dysfunction, 2 cases of electrolyte disturbance, and 3 cases of infection, and the incidence of adverse reactions was 27.78%. Compared between groups, the incidence of adverse reactions in the study group was lower (P<0.05). Conclusion. Early use of acupuncture combined with rehabilitation training has a remarkable therapeutic effect on elderly stroke patients. It can remarkably promote the recovery of the patient’s condition, remarkably enhance their neurological function, cognitive function, motor function, and daily life function, and effectively strengthen the patient’s prognosis score. It has important clinical application value to reduce the incidence of adverse reactions.