The treatment of non-small cell lung cancer (NSCLC) is challenging due to immune tolerance and evasion. Salidroside (SAL) is an extract in traditional Chinese medicine and has a potential antitumor ...effect. However, the mechanism of SAL in regulating the immunological microenvironment of NSCLC is yet to be clarified.
The mouse model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established. And then, the percentage of tumor-infiltrating T cell subsets including Treg was detected in tumor-bearing mice with or without SAL treatment. In vitro, the effect of SAL on the expression of IL-10, Foxp3 and Stub1 and the function of Treg were detected by flow cytometry. Network pharmacology prediction and molecular docking software were used to predict the target of SAL and intermolecular interaction. Furthermore, the effect of SAL on the expression of Hsp70 and the co-localization of Stub1-Foxp3 in Treg was confirmed by flow cytometry and confocal laser microscopy. Finally, Hsp70 inhibitor was used to verify the above molecular expression.
We discovered that SAL treatment inhibits the growth of tumor cells by decreasing the percentage of tumor-infiltrated CD4
Foxp3
T cells. SAL treatment downregulates the expression of Foxp3 in Tregs, but increases the expression of Stub1, an E3 ubiquitination ligase upstream of Foxp3, and the expression of Hsp70. Inhibiting the expression of Hsp70 reverses the inhibition of SAL on Foxp3 and disrupts the colocalization of Stub1 and Foxp3 in the nucleus of Tregs.
SAL inhibits tumor growth by regulating the Hsp70/stub1/Foxp3 pathway in Treg to suppress the function of Treg. It is a new mechanism of SAL for antitumor therapy.
In the current study, a comparative molecular field analysis (CoMFA) model with the combined activity of polybrominated biphenyls (PBBs) bioconcentration, long-range transport, and the highest ...infrared signal intensity (weight ratio of 5:4:1) was constructed based on the threshold method and was further evaluated and analyzed. PBB-153 derivatives with improved combined activity values of bioconcentration, long-range transport, and the highest infrared signals intensity were designed based on contour maps of the CoMFA model. The environmental stability and functionality of the derivatives were also evaluated. The constructed model showed good prediction ability, fitting ability, stability, and external prediction ability. The contribution rates of electrostatic and steric fields to the combined activity of PBBs were 53.4% and 46.6%, respectively. Four PBB-153 derivatives with significantly improved bioconcentration, long-range transport and the highest infrared signal intensity (the combined activity value of these three parameters decreased) were screened with good environmental stability and functionality. Results validated the accuracy and reliability, and ability of the generated model to realize the simultaneous modification of the three activities of the target molecule. The binding ability of the designed derivatives to food chain biodegradation enzymes increased, thereby verifying the improvement in the bioconcentration. The half-lives of the derivatives in air and their ability to be absorbed by the plants significantly improved compared to the target molecule, further showing that the long-range transport of derivatives was reduced. In addition, the introduction of the -NO group caused the N =O stretching vibration of the derivatives to increase the infrared signal intensity. The present model provides a theoretical design method for the molecular modification of environmentally friendly PBBs.
A straightforward access to tricyclic indoles bearing 3,4-fused seven-membered rings has been established by using 4-aminoindoles as 1,4-bisnucleophiles in three-component reactions. ...1H-Azepino4,3,2-cdindoles, 4,6-dihydro-1H-azepino4,3,2-cdindoles and 1,3,4,6-tetrahydro-5H-azepino4,3,2-cdindol-5-ones could thus be synthesized in one pot in moderate to good yields. Beyond opening access to 3,4-fused tricyclic indoles, the use of easily accessible 4-aminoindoles as C,N-1,4-bisnucleophiles also provides a new platform to be used in a diversity-oriented synthesis strategy, fully displaying its benefits of maximizing molecular complexity and reaction diversity.
The evaluation of the capability of network-based systems of systems has replaced the simple method that considers return on investment, becoming a new paradigm for planning national defence ...capabilities. However, the dual uncertainty of the key system attributes of scenes and weapons has brought great challenges for decision-making. Based on this, we developed a multiobjective optimization model with multiple stages and scenarios under uncertainty to determine plans. In this study, we consider planning risk and planning cost as the two objectives. To solve this problem, we propose a hybrid solution for a network-based optimization method integrated with fuzzy set theory. The network-based optimization method combines the NSGA-II-DE and complex network theory. We use the characteristics of the network to evaluate the capabilities of the WSoS, and the NSGA-II-DE is used to generate a development plan and finally output a set of Pareto optimal solutions. We use fuzzy sets to determine the fuzzy membership of each plan on the Pareto front and determine a satisfactory solution. Finally, we conduct simulation experiments to verify the rationality of the methods proposed in this article. The results can provide a set of efficient solutions for military planners, helping generate a variety of planning solutions and trade-offs according to their preferences.
Graphical Abstract
TonB-dependent siderophore receptors play a critical transport role for Flavobacterium columnare virulence formation and growth, and have become valuable targets for the development of novel ...antimicrobial agents. Traditional Chinese medicine has demonstrated notable efficacy in the treatment of fish diseases and includes potential antibacterial agents. Herein, we performed molecular docking-based virtual screening to discover novel TonB-dependent siderophore receptor inhibitors from traditional Chinese medicine and provide information for developing novel antibacterial agents. Firstly, we efficiently obtained 11 potential inhibitors with desirable drug-like characteristics from thousands of compounds in the TCM library based on virtual screening and property prediction. The antibacterial activity of Enoxolone, along with its interaction characteristics, were determined via an MIC assay and molecular dynamic simulation. Transcriptional profiling, along with validation experiments, subsequently revealed that an insufficient uptake of iron ions by bacteria upon binding to the TonB-dependent siderophore receptors is the antibacterial mechanism of Enoxolone. Finally, Enoxolone's acceptable toxicity was illustrated through immersion experiments. In summary, we have used virtual screening techniques for the first time in the development of antimicrobial agents in aquaculture. Through this process, we have identified Enoxolone as a promising compound targeting the TonB-dependent siderophore receptor of F. columnare . In addition, our findings will provide new ideas for the advancement of innovative antimicrobial medications in aquaculture.
Distributed generation (DG) has not only electricity value, but also capacity value. The capacity value can be represented by the credible capacity (CC) based on the equal power supply reliability ...criterion. The evaluation of reliability on distribution network (DN) is the core of CC calculation. Under a fault state, DGs can continue to supply power to some load by the island operating mode, and the DN reliability can be improved. Therefore, it is necessary to utilize the power supply restoration potential of DG and formulate an island partition scheme accurately in the reliability calculation of DN. A DG CC evaluation method based on island partition is proposed in the paper. The power supply reliability of an active distribution network is evaluated based on an island partition model, to realize the accurate evaluation of DG CC. The main work is as follows: First, an island partition model under a random fault state of DN is established. The fluctuation of DGs and load, interconnection switch, load priority, secondary outage constraint and other factors are fully considered in reliability assessment. A heuristic prospective greedy algorithm and the Prim algorithm are used to solve the island partition model accurately. Second, a reliability evaluation method of DN based on sequential Monte Carlo simulation (SMCS) is proposed. The system reliability level can be accurately analyzed under a fault state. Then, a CC evaluation method based on hypothesis testing is proposed. The convergence of the CC searching process can be scientifically judged by checking the conspicuousness of the reliability indices distribution obtained by the SMCS. Finally, a case study of the PG&E 69-bus system is analyzed. The topology of the DN, permeability of the DG and island partition strategy are known to have a significant impact on the DG CC.
•Distributed generation is with capacity value represented by credible capacity.•Island partition is firstly used into the DG credible capacity evaluation.•The island partition model can be solved by prospective greedy algorithm quickly.•Credible capacity searching is realized based on hypothesis test theory.•The island partition strategy has a significant impact on credible capacity.
With the rapid development of MEMS, the demand for metal microstructure is increasing. Micro electrochemical milling technology (MECM) is capable of manufacturing micro metallic devices or components ...based on the principle of electrochemical anode dissolution. To improve the capacity of MECM, this paper presents a compound method named ultrasonic vibration-assisted micro electrochemical milling technology (UA-MECM). Firstly, the simulation and mathematical model of UA-MECM process is established to explain the mechanism of ultrasonic vibration on micro electrochemical milling. Then, the effects of ultrasonic parameters, electrical parameters and feedrate on machining localization and surface quality are discussed considering sets of experiments. The surface roughness was effectively reduced from Ra 0.83 to Ra 0.26 µm with the addition of ultrasonic vibration. It turns out that ultrasonic vibration can obviously improve machining precision, efficiency and quality. Finally, two- and three-dimensional microstructures with good surface quality were successful fabricated. It shows that ultrasonic vibration-assisted electrochemical milling technology has excellent machining performance, which has potential and broad industrial application prospects.
Highlights
A composite electrode strategy to fabricate the perovskite solar cells (PSCs) with excellent comprehensive stabilities, particularly reverse-bias stability.
A record efficiency of 23.7% ...(certified 23.2%) for
n-i-p
PSCs using Cu as the electrode.
The strategy can be extended to the combinations of different transparent conducting oxides and low-cost metals.
Perovskite solar cells (PSCs) have become the representatives of next generation of photovoltaics; nevertheless, their stability is insufficient for large scale deployment, particularly the reverse bias stability. Here, we propose a transparent conducting oxide (TCO) and low-cost metal composite electrode to improve the stability of PSCs without sacrificing the efficiency. The TCO can block ion migrations and chemical reactions between the metal and perovskite, while the metal greatly enhances the conductivity of the composite electrode. As a result, composite electrode-PSCs achieved a power conversion efficiency (PCE) of 23.7% (certified 23.2%) and exhibited excellent stability, maintaining 95% of the initial PCE when applying a reverse bias of 4.0 V for 60 s and over 92% of the initial PCE after 1000 h continuous light soaking. This composite electrode strategy can be extended to different combinations of TCOs and metals. It opens a new avenue for improving the stability of PSCs.
Best Practices, including Best Available Techniques (BAT) and Best Environmental Practices (BEP), are typically included to provide for or promote particular practices, methods, measures, or ...standards in respect of the efficient recovery of a resource and the level of environmental protection. Deep seabed mining (DSM) is an activity to obtain mineral resources from the deep sea, which may have certain adverse impacts on the marine environment. International Seabed Authority (ISA), the regulator of DSM activities in the Area authorized by the United Nations Convention on the Law of the Sea (UNCLOS), has introduced those terms in its Mining Code as critical tools for the reduction in environmental risks arising from DSM. Terms that are not included by the UNCLOS, such as BAT and BEP, are commonly invoked, yet often without specification in the regulatory discourse for DSM. In the absence of precise definitions and operational details, the terms BAT and BEP may not be able to function as anticipated in the DSM domain. Against this backdrop, this paper attempts to explore possible means by which the ISA might enable the contractor to operationalize the BAT and BEP, including providing definitions, their placement in the exploitation regulations, and the criteria for its operationalization in the Standards and Guidelines. This paper cites the existing international instruments that incorporate the terms BAT and BEP and takes particular note of DSM into account to highlight specific considerations for their practical implementation for DSM.
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