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A series of dipicolyl amine pyrimidines (DPPs) were previously identified as potential α7 agonists by means of a calcium influx assay in the presence of the positive allosteric modulator (PAM) 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596). The compounds lack the quaternary or strongly basic nitrogens of typical nicotinic agonists. Although differing in structure from typical nicotinic agonists, based on crystallographic data with the acetylcholine binding protein, they appeared to engage the site shared by such typical orthosteric agonists. Using oocytes expressing human α7 receptors, we found that the DPPs were efficacious activators of the receptor, with currents showing rapid desensitization characteristic of α7 receptors. However, we note that the rate of recovery from this desensitization depends strongly on structural features within the DPP family. Although the activation of receptors by DPP was blocked by the competitive antagonist methyllycaconitine (MLA), MLA had no effect on the DPP-induced desensitization, suggesting multiple modes of DPP binding. As expected, the desensitized conformational states could be reactivated by PAMs. Mutants made insensitive to acetylcholine by the C190A mutation in the agonist binding site were weakly activated by DPPs. The observation that activation of C190A mutants by the DPP compounds was resistant to the allosteric antagonist (-)cis-trans-4-(2,3,5,6-tetramethylphenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide supports the hypothesis that the activity of these noncanonical agonists in the orthosteric binding sites was not entirely dependent on the classic epitopes controlling activation by typical agonists and that perhaps they may access alternative modes for promoting the conformational changes associated with activation and desensitization. SIGNIFICANCE STATEMENT: This study reports a family of nicotinic acetylcholine receptor agonists that break the rules about what the structure of a nicotinic acetylcholine receptor agonist should be. It shows that the activity of these noncanonical agonists in the orthosteric binding sites is not dependent on the classical epitopes controlling activation by typical agonists and that through different binding poses, they promote unique conformational changes associated with receptor activation and desensitization.

The design optimization of a direct-drive permanent magnet synchronous generator (DDPMSG) is of great significance for wind turbines because of its unique advantages. This paper proposes a two-stage model to realize multi-objective design optimization for a 6 MW DDPMSG. In the first stage, a surrogate optimized response surface model based on an improved sparrow search algorithm (ISSA) was established for modeling the cogging torque and generator efficiency. In the second-stage model, a multi-objective optimization model is proposed to optimize the cogging torque and generator efficiency of the DDPMSG. Finally, the proposed two-stage model was used for a 6 MW DDPMSG design optimization, and the simulation results demonstrated the superiority and rationality of the proposed model. In the first-stage model, the proposed surrogate model based on the ISSA had a better modeling accuracy and lower errors. Compared with traditional response surface models and correlation analysis models, the proposed optimized surrogate model reduced errors in the cogging torque by 34.63% and 42.97%, respectively, while the errors in the efficiency models were reduced by 12.92% and 60.78%, respectively, which indicates the superiority of the first-stage model. In the second stage, compared with the single-objective optimization model, the multi-objective optimization model achieved a trade-off optimization between the cogging torque and the efficiency. Compared with the cogging torque optimization model, the proposed model optimized the efficiency by 101.41%. Compared with the efficiency optimization model, the proposed model reduced the cogging torque by 16.67%. These results verified the superiority and rationality of the second-stage model. [ABSTRACT FROM AUTHOR]

Lithium-ion batteries, as the main energy storage component of electric vehicles (EVs), play a crucial role in ensuring the safe and reliable operation of the battery systems through monitoring their state of health (SOH). However, temperature variations and battery aging have significant impacts on the internal parameters of lithium-ion batteries, and these changes directly correlate with the accuracy of battery SOH estimation. To address these issues, this paper proposes an estimation method for lithium-ion battery SOH that considers the impact of temperature. The method begins with reconstructing a second-order hybrid equivalent circuit model for lithium-ion batteries, through which an adaptive update rate for battery model parameters is designed. On this basis, a nonlinear observer for battery states is introduced by integrating filters to estimate SOH. The proposed method considers the impact of capacity in the design of the parameter adaptive update rate, enabling the capacity to be dynamically adjusted based on the actual state of the batteries. This reduces the cumulative error in the SOC observer and improves the modeling accuracy of battery models. Experimental results demonstrate that the method proposed in this paper exhibits exceptional performance in SOH estimation under different temperature conditions. The mean absolute error for SOH estimation does not exceed 0.5%, and the root mean square error does not exceed 0.2%. This method can significantly improve the estimation accuracy of SOH, providing a more efficient and accurate solution for battery management systems in EVs. [ABSTRACT FROM AUTHOR]

Based on the panel data (2005-2019) of cities (prefectures) in the Chengdu-Chongqing Economic Circle, we have developed an evaluation system for agricultural modernization and new-type urbanization that measures the development level of each city and applies the coupling and coordination model to calculate their coupling and combination levels. The results indicate that the level of comprehensive order parameters of agricultural modernization in various cities (prefectures) in the Chengdu-Chongqing Economic Circle generally displays an upward trend. The areas with high-degree agricultural modernization were mainly distributed in Chengdu from 2005 to 2010, and the center of agricultural modernization was shifted to western areas after 2010, with a stable upward trend in the level of comprehensive order parameters of new-type urbanization. In terms of coupling degree, there was an overall upward trend. Except for Nanchong and Dazhou, other cities (prefectures) progressed from “Undeveloped Coordination” to “Intermediate Coordination.” The imbalanced development of agricultural modernization and new-type urbanization continually improved, with the combination level increasing from “Low-Low” to “Medium-Medium.”

According to the requirements of energy supply of lunar exploration engineering spacecraft， a novel adjustable solar panel with three degrees of freedom is proposed. The 2UU-UPU parallel mechanism is adopted as the prototype of adjustable solar panel mechanism. The constraint equation and positional relationship of the adjustable solar panel mechanism are analyzed， the degree of freedom of parallel robot is solved by the theory of spiral， and the positional anti-solution equation is introduced by the modified Kutzbach-Grübler formula. On this basis， the system is simulated by using Adams software， and the simulation results are compared with theoretical numerical calculations to verify the correctness of mathematical modeling of the adjustable solar panel mechanical and the rationality of the three-dimensional solid model.

Immunotherapy, which aims to enhance the function of T cells, has emerged as a novel therapeutic approach for hepatocellular carcinoma (HCC). Nevertheless, the clinical utility of using flow cytometry to assess immune cell infiltration (ICI) is hindered by its cumbersome procedures, prompting the need for more accessible methods. Here, we acquired gene expression profiles and survival data of HCC from TCGA and GSE10186 datasets. The patients were categorized into two clusters of ICI, and a set of 11 characteristic genes responsible for the differentiation performance of these ICI clusters were identified. Subsequently, we successfully developed a modified ICI score (mICIS) by utilizing the expression levels of these genes. The efficacy of our mICIS was confirmed via mass cytometry, flow cytometry, and immunohistochemistry. Our research indicated that the favorable overall survival (OS) rate could be attributed to the improved function of anti-tumor leukocytes rather than their infiltration. Furthermore, we observed that the low score group exhibited lower expression levels of T-cell exhaustion-associated genes, which was confirmed in both HCC tissues from patients and mice, which demonstrated that the benefits of the low scores were due to enhanced active/cytotoxic CD8+ T cells and reduced exhausted CD8+ T cells. Additionally, our mICIS stratified the benefits derived from immunotherapies. Lastly, we observed a misalignment between CD8+ T-cell infiltration and function in HCC. In summary, our mICIS demonstrated proficiency in assessing the OS rate of HCC and offering significant stratified data pertaining to distinct responses to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: TGF-β is related to the function of T cells in the tumor microenvironment. However, the characteristics of TGF-β affecting the function of CD8+ T cells in hepatocellular carcinoma (HCC) have not been clearly resolved. Methods: In this study, flow cytometry, mass cytometry, immunohistochemistry, RNA-seq, single-cell RNA-seq, assay for transposase-accessible chromatin with high throughput sequencing, chromatin immunoprecipitation, and dual-luciferase reporter gene assay were used to study the regulatory effect and molecular mechanism of TGF-β on HCC infiltrating CD8+ T cells. Results: Here, we demonstrated that the overall effect of TGF-β on CD8+ T cells in HCC was to activate p-p38 to induce exhaustion, but it also initiated cell-intrinsic resistance mechanisms: 1) TGF-β upregulated the levels of p-STAT1 (S727) and promoted LAIR2 secretion; 2) the TGF-β-p-STAT1-LAIR2 axis relieved CD8+ T cells from exhaustion, which we called "self-rescue"; 3) this "self-rescue" behavior showed time and dose limitations on TGF-β stimulation, which was easily masked by stronger inhibitory signals; 4) the function of CD8+ T cells was improved by using TAK-981 to amplify "self-rescue" signal. Conclusion: Our study describes a "self-rescue" mechanism of CD8+ T cells in HCC against exhaustion and the good effects from amplifying this signal. [ABSTRACT FROM AUTHOR]