ENO2-derived phosphoenolpyruvate functions as an endogenous inhibitor of HDAC1 and confers resistance to antiangiogenic therapy.

Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of ß-catenin and activates the ß-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.

An Inductor-Loaded Single-Port Planar Dual-Broadband Antenna with Stable Gains.

A single-port dual-wideband base-station antenna is reported here for mobile communication systems. Loop and stair-shaped structures with lumped inductors are adopted for dual-wideband operation. The low and high bands share the same radiation structure to accomplish a compact design. The operation principle of the proposed antenna is analyzed, and the effects of the lumped inductors are studied. The measured operation bands are from 0.64 GHz to 1 GHz and from 1.59 GHz to 2.82 GHz, with relative bandwidths of 43.9% and 55.8%, respectively. Broadside radiation patterns and stable gain with a variation of less than 2.2 dB are achieved for both bands. The inductor-loading technology is proven to be an effective way for dual-band antenna design with wide bandwidth and stable gain performance.

Exploring the mechanism of Cassiae semen in regulating lipid metabolism through network pharmacology and experimental validation.

BACKGROUND: Multiple studies have assessed the role of Cassiae semen (CS) in regulating lipid metabolism. However, the mechanism of action of CS on non-alcoholic fatty liver disease (NAFLD) has seen rare scrutiny. OBJECTIVE: The objective of this study was to explore the regulatory mechanism of CS on lipid metabolism in NAFLD. METHODS: Components of CS ethanol extract (CSEE) were analyzed and identified using UPLC-Q-Orbirap HRMS. The candidate compounds of CS and its relative targets were extracted from the Traditional Chinese Medicine Systems Pharmacology, Swiss-Target-Prediction, and TargetNet web server. The Therapeutic Target Database, Genecards, Online Mendelian Inheritance in Man, and DisGeNET were searched for NAFLD targets. Binding affinity between potential core components and key targets was established employing molecular docking simulations. After that, free fatty acid (FFA)-induced HepG2 cells were used to further validate part of the network pharmacology results. RESULTS: Six genes, including Caspase 3 (CASP3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA), epidermal growth factor receptor (EGFR), and amyloid ß (A4) precursor protein (APP) were identified as key targets. The mitogen-activated protein kinase (MAPK) signaling pathway was found to associate closely with CS's effect on NAFLD. Per molecular docking findings, toralactone and quinizarin formed the most stable combinations with hub genes. About 0.1 (vs. FFA, P<0.01) and 0.2 (vs. FFA, P<0.05) mg/ml CSEE decreased lipid accumulation in vitro by reversing the up-regulation of CASP3, EGFR, and APP and the down-regulation of PIK3CA. CONCLUSION: CSEE can significantly reduce intracellular lipid accumulation by modulating the MAPK signaling pathway to decrease CASP3 and EGFR expression.

Event-Triggered Cluster Consensus of Multi-Agent Systems via a Modified Genetic Algorithm.

This article is concerned with the event-triggered output feedback cluster consensus of leader-following multi-agent systems (MASs) under limited communication resources. Specifically, the distributed agents are divided into several clusters to accomplish different collective tasks under diverse intracluster and intercluster communications. First, to alleviate excessive communication resource consumption, two sampled-data-based event-triggered schemes are developed to distinguish agent-to-agent communications within clusters and between clusters. Based on these schemes, an event-based cluster consensus control protocol is proposed to solve the problem. Then, sufficient criteria on asymptotic stability of the resulting closed-loop system are derived and expressed in terms of matrix inequalities. It is noteworthy that the derived criteria for controller design are nonlinear and nonconvex with respect to the output feedback control gains and triggering parameters. To handle this issue, a modified genetic algorithm (MGA) with multiple subpopulations is proposed, where the subpopulations are independent of each other. The key feature of the designed MGA lies in that the fitness value is described as an accumulation of initial value and weighing value of each matrix inequality. Finally, an application of satellite formation flying is exemplified to demonstrate the effectiveness of the derived theoretical results.

Refined Dynamic Event-Triggering Cluster Consensus of Multiagent Systems With Fixed/Switching Topology.

This article is concerned with cluster consensus control of multiagent systems (MASs) with the fixed/switching topology under a dynamic event-trigger (DET) mechanism. A refined sampled-data-based DET scheme is proposed by introducing two dynamically adjusting threshold parameters to distinguish the different transmission requirements for neighboring agents intra and outer cluster. Faced with the difficulties of acquiring full state information among spatially distributed agents, output feedback is employed to construct cooperative control protocols. Both fixed and switching topologies are considered to execute the designed DET-based cooperative cluster consensus control protocols. By constructing appropriate Lyapunov-Krasovskii functionals (LKFs), some sufficient criteria in terms of matrix inequalities for the cluster consensus of MASs are derived, which can ensure that the error system with the proposed DET-based control strategy is asymptotically stable. Facing the nonconvex issue induced by output feedback, a particle swarm optimization (PSO)-based control design algorithm is novelly developed to calculate the control gains and event-triggering parameters jointly based on the derived stability criteria. The elements of the matrix variables are valued stochastically in certain ranges and the fitness function is designed as the accumulation of the weighting value of each matrix inequality. Finally, an application of multiple satellites formation flying is applied to numerically illustrate the effectiveness of the cluster consensus control strategy with the designed DET mechanism.