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As a new focal point for China's embrace of openness in this new era, the Pilot Free Trade Zone should play a more significant role as a testing ground and provide greater opportunities. The impact and mechanism of establishing free trade zones on the advancement of new quality productive forces in pilot regions based on theoretical analysis. Findings indicate formation can effectively promote improvements forces within pilot regions, with these conclusions remaining robust after conducting various tests. Mechanism analysis reveals that implementing Free Trade Zone policies can drive the advancement of new quality productive forces by promoting scientific and technological innovation, advancing industrial chain modernization processes, and enhancing international trade competitiveness. Furthermore, heterogeneity analysis demonstrates that pilot policies have a more pronounced enabling effect in eastern coastal regions. The research unveils the policy effects of \"free trade zones,\" which hold great significance for expanding high-level openness and accelerating advancements.  

KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter ( KRAS -G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS -G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS -G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS -G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a “quasi-triad plane” that stacks over the two external G-tetrads. The binding involves both π -stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS -G4 and is beneficial for the design of specific KRAS -G4-interactive drugs. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. Herein, the authors report the NMR solution structures of a bulge-containing KRAS-G4 that bound to two small molecules. The study provides molecular details of ligand interactions with KRAS-G4 and contributes insight into the design of specific KRAS-G4-interactive drugs.

With the widespread application of unmanned aerial vehicle technology in search and detection, express delivery and other fields, the requirements for unmanned aerial vehicle dynamic area coverage algorithms has become higher. For an unknown dynamic environment, an improved Dual-Attention Mechanism Double Deep Q-network area coverage algorithm is proposed in this paper. Firstly, a dual-channel attention mechanism is designed to deal with flight environment information. It can extract and fuse the features of the local obstacle information and full-area coverage information. Then, based on the traditional Double Deep Q-network algorithm, an adaptive exploration decay strategy and a coverage reward function are designed based on the real-time area coverage rate to meet the requirement of a low repeated coverage rate. The proposed algorithm can avoid dynamic obstacles and achieve global coverage under low repeated coverage rate conditions. Finally, with Python 3.12 and PyTorch 2.2.1 environment as the training platform, the simulation results show that, compared with the Soft Actor–Critic algorithm, the Double Deep Q-network algorithm, and the Attention Mechanism Double Deep Q-network algorithm, the proposed algorithm in this paper can complete the area coverage task in a dynamic and complex environment with a lower repeated coverage rate and higher coverage efficiency.

Herein, an ultra-sensitive and facile electrochemical biosensor for procalcitonin (PCT) detection was developed based on NiCoP/g-C3N4 nanocomposites. Firstly, NiCoP/g-C3N4 nanocomposites were synthesized using hydrothermal methods and then functionalized on the electrode surface by π-π stacking. Afterward, the monoclonal antibody that can specifically capture the PCT was successfully linked onto the surface of the nanocomposites with a 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-Hydroxysuccinimide (NHS) condensation reaction. Finally, the modified sensor was employed for the electrochemical analysis of PCT using differential Pulse Voltammetry(DPV). Notably, the larger surface area of g-C3N4 and the higher electron transfer capacity of NiCoP/g-C3N4 endow this sensor with a wider detection range (1 ag/mL to 10 ng/mL) and an ultra-low limit of detection (0.6 ag/mL, S/N = 3). In addition, this strategy was also successfully applied to the detection of PCT in the diluted human serum sample, demonstrating that the developed immunosensors have the potential for application in clinical testing.

Harvesting energy through water motion on solid surface is significantly important due to the energy generation intermittency of the usually used energy transducers. In this paper, n-type silicon thin film is fabricated through magnetron sputtering followed by rapid thermal processing under different temperatures. The influence of the annealing temperatures on film crystallinity, phase, conductivity and conductivity activation energy is systematically investigated. Moreover, the voltage outputs on different silicon films through the sliding of NaCl solution droplet are systematically discussed. With increasing the annealing temperature from 300 to 900 °C, the voltage value increases firstly and then decreases, achieving a highest value of 1060 mV on the sample annealed at 600 °C, which is much higher than that of the mostly reported carbon materials. Finally, a schematic model, which is based on the combined effect of contact potential change between NaCl solution droplet and silicon film accompanied with the variation of the film conductivity, is proposed to unveil the underlying mechanism behind voltage output on various silicon films. All the findings provide not only a platform for achieving a higher output voltage but also a mechanism for a better understanding of the water motion induced energy harvesting.

Background Cerebral small vessel disease (CSVD) is a major contributor to cognitive decline and gait abnormalities in the elderly population. Understanding the relationship between these impairments can aid in early detection and intervention. This study investigated the association between gait performance and cognitive decline in patients with CSVD, focusing on specific gait parameters as potential clinical markers of cognitive impairment. Methods This cross-sectional study included 95 elderly patients with confirmed atherosclerotic CSVD at Guangzhou Geriatric Hospital. Participants underwent comprehensive gait assessments using the Timed Up and Go (TUG) test, Berg Balance Scale (BBS), and Short Physical Performance Battery (SPPB). Cognitive function was evaluated using the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Imaging markers, including total magnetic resonance imaging (MRI) CSVD burden and Fazekas scale score, were analyzed. Results Participants with cognitive decline performed significantly worse on the TUG test, BBS, and SPPB, particularly on the SPPB sit-to-stand component. The total MRI CSVD burden and Fazekas scale scores were significantly higher in the cognitive decline group. Deep cerebral microbleeds and enlarged perivascular spaces in the basal ganglia were more prevalent in individuals with cognitive decline. The association between the SPPB sit-to-stand score and cognitive decline remained significant after adjusting for confounders (OR 0.44; 95% confidence interval (CI) 0.21 to 0.94; p  = 0.034). Conclusion This study highlighted the significant relationship between gait performance and cognitive decline in elderly patients with CSVD. In particular, the sit-to-stand component emerged as a robust predictor of cognitive impairment, suggesting its potential as a valuable clinical marker for early detection. The incorporation of gait assessments into routine clinical evaluations can enhance early intervention efforts, improve patient outcomes, and inform healthcare policies. Further longitudinal and multicenter studies are warranted to validate these findings and to explore the underlying mechanisms.

The phenomenon of extensive erosion of silty submarine slopes in the Yellow River delta has been well documented in numerous studies. Due to poor drainage and high compressibility, silty sediments are particularly prone to pore pressure buildup and accumulated seepage under wave and current action, which can influence sediment erodibility (e.g., the critical bed shear stress and the erosion rate under various bed shear stresses). To date, there remains a lack of parametric formulation to quantitatively characterize the erodibility of silty sediments with the coupled effects of the hydraulic gradient of upward seepage and the slope gradient. In this study, a series of laboratory experiments were conducted to explore the erodibility of silt sediments from the Yellow River delta under varying hydraulic gradients of upward seepage and slope gradients. The results reveal that both upward seepage and increased slope gradients can enhance the erodibility of silty sediments. Specifically, as the seepage gradient increases from 0.1 to 0.8, the critical Shields parameter required for initiating silty particle motion decreases linearly, with a reduction rate of 0.01 per 0.1 increase in the seepage gradient, independently of changes in slope gradient. Additionally, the erosion coefficient of silty sediments grows exponentially with rising seepage gradients, with its average growth rate accelerating with increasing slope inclination. For flat sediment beds, the erosion coefficient influenced by upward seepage can be up to five times that in the absence of seepage. An empirical formula for calculating the critical Shields parameter and an erosion model incorporating upward seepage gradient and slope effects were developed through multiple regression analysis, providing an experimental basis for numerical simulations of scour in silty submarine slopes under combined waves and currents.

Indolizine derivatives are a class of compounds with excellent biological activity. In this study, a series of indolizine derivatives, compound 1 (C1), compound 2 (C2), compound 3 (C3), and compound 4 (C4), were synthesized. 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) assay was used to evaluate their cytotoxicity against HepG2 (p53-wild), A549, and HeLa cell lines. HepG2 cells apoptosis induced by C3 was determined using Hoechst staining and acridine orange/ethidium bromide staining. Cells' apoptotic ratio was measured by Annexin V-FITC/PI double staining. Changes in mitochondrial membrane potential and intracellular reactive oxygen species (ROS) in HepG2 cells after C3 treatment were determined. Immunofluorescence staining and Western blot analysis were carried out to detect p53 levels and analyze the apoptosis-associated proteins, respectively. Moreover, the cytotoxic activity of C3 was examined in two other hepatocellular carcinoma (HCC) cell lines with different p53 status including Huh-7 cells (p53-mutant) and Hep3B cells (p53-null). The results indicated that C3 showed stronger inhibition towards HepG2 cells than other cell lines. Fluorescent staining and flow cytometry analysis confirmed that C3 induced apoptosis of HepG2 cells. C3 could also increase intracellular ROS and cause a decrease in the mitochondrial membrane potential. C3 promoted p53 activation and increased p53 accumulation in nuclei. The expression of p53 and Bax was increased with the down-regulation of Bcl-2, which promoted the release of cytochrome c and caspase-3 activation. Collectively, the study demonstrated that C3 caused HepG2 cell apoptosis the mitochondria p53 pathway. These results inspired us to further develop indolizine derivatives as potential potent inhibitors against liver cancer.

The mechanism behind spontaneous growth of metal whiskers is essential to develop lead-free whisker mitigation strategy for the sake of long-term reliability of electronics, and has been sought for several decades. However, a consensus about it still lacks, and a host of factors influencing the phenomenon have been investigated, but the role of interface energy has not been paid adequate attention. In this study, the whisker growth propensities of ball-milled Ti 2 InC/In and non-MAX phase TiC/In and SiC/In are comparatively studied in the terms of the wettability, thermal behavior and crystal structures. The wetting angles of indium with Ti 2 InC, TiC, and SiC (144.4°, 155.7°, and 142.2°, respectively) are large and quite close, indicating the poor wettability between liquid indium and the three ceramics. The thermal behaviors of all the three systems have obvious changes after ball milling. The number density of indium whiskers on ball-milled Ti 2 InC is significantly greater than those on the TiC and SiC substrates, which is explained based on interface energy and the crystal structure difference of the ceramic substrates.

Background Altered adipokine secretion in dysfunctional adipose tissue facilitates the development of atherosclerotic diseases including lower extremity peripheral artery disease (PAD). Asprosin is a recently identified adipokine and displays potent regulatory role in metabolism, but the relationship between asprosin and lower extremity PAD remains uninvestigated. Methods 33 type 2 diabetes mellitus (T2DM) patients (DM), 51 T2DM patients with PAD (DM + PAD) and 30 healthy normal control (NC) volunteers were recruited and the blood samples were collected for detecting the circulatory asprosin level and metabolomic screening. RNA sequencing was performed using the aorta tissues from the type 2 diabetic db/db mice and human umbilical vein endothelial cells (HUVECs) were treated with asprosin to determine its impact on the endothelial-to-mesenchymal transition (EndMT). Results The circulating levels of asprosin in DM + PAD group were significantly higher than that of NC group and the DM group. Circulating asprosin level was remarkably negatively correlated with ankle-brachial index (ABI), even after adjusting for age, sex, body mass index (BMI) and other traditional risk factors of PAD. Logistic regression analysis revealed that asprosin is an independent risk factor for PAD and receiver-operator characteristic (ROC) curve determined a good sensitivity (74.5%) and specificity (74.6%) of asprosin to distinguish PAD. Data from metabolomics displayed a typical characteristics of de novo amino acid synthesis in collagen protein production by myofibroblasts in patients with PAD and activation of TGF-β signaling pathway appeared in the aortic tissue of db/db mice. Asprosin directly induces EndMT in HUVECs in a TGF-β-dependent manner as TGF-β signaling pathway inhibitor SB431542 erased the promotional effect of asprosin on EndMT. Conclusions Elevated circulatory asprosin level is an independent risk factor of lower extremity PAD and might serve as a diagnostic marker. Mechanistically, asprosin directly induces EndMT that participates in vascular injury via activation of TGF-β signaling pathway. Trial registration This trial was registered at clinicaltrials.gov as NCT05068895