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RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.

The Ili River Basin (IRB) is located in the northwest of China. With its large-scale zone and abundant resources, it is believed to be a "wet island" and a biotic resource storehouse in the dry regions of Eurasia. The IRB has stable ecological conditions and abundant water resources, providing natural conditions for agricultural production and human settlements. With the population increasing and economic development advancing, the competition for land resources is becoming fierce, leading to some ecological problems in this region. Therefore, understanding the spatiotemporal changes and driving mechanisms of the "three-zone space" (TZS) in the IRB is of significant practical importance for promoting sustainable development and optimizing the territorial spatial pattern. This study first analyzes the characteristics and intensity of the TZS changes from 2000 to 2020. Then, it utilizes the optimized parameter Geodetector (OPGD) to analyze the driving mechanisms behind these changes. The results show the following. Firstly, the agricultural space (AS) increased by a total of 837.5 km2, the urban space (US) increased by 519.64 km2, and other ecological space (OES) increased by 1518.83 km2. Green ecological space (GES) decreased by 2875.97 km2. Secondly, intensity analysis indicated that the total TZS change in IRB was 11.07%. At the spatial-type level, the increased intensities of OES, US, and AS were active. In spatial transformation intensity, US and OES tended to transform into AS; AS tended to transform into US; and OES and GES had a mutual transformation tendency. Thirdly, AS converted into US around emerging cities like Khorgas and Cocodala. The conversion towards GES was scattered. The mutual conversion between OES and GES showed spatial distribution consistency, mainly occurring in the Borohoro ranges and the Halik ranges. Lastly, regarding the driving mechanisms, the evolution of US in the IRB was driven by social and economic factors. Location and climate factors accelerated agricultural development, facilitating the transformation of GES and OES into AS. Climate and economic factors played a crucial role in the scale of conversions between OES and GES. The findings can provide a basis for the governance and protection of the IRB, help to form a rational territorial spatial pattern, and offer scientific guidance for sustainable land management. [ABSTRACT FROM AUTHOR]

Ecological source areas play a pivotal role in nature preservation and soil conservation. These areas are critical in optimizing land-use patterns and fostering the establishment facilitating the establishment of protected ecological source areas. In this study, two types of state layers of ecological source area change were extracted based on land cover data and integrated with an intelligent algorithm to analyze the role of ecological factors contributing to land change. Recommendations are proposed to enhance the optimization of the ecological spatial pattern within the Yellow River Basin. The results indicate key findings: (1) The ecological source areas in the Daxia River Basin experienced Fluctuations between 1990 and 2020 due to the interconversion of grassland and unused land. The change was relatively smooth during 1990–2000, with the ecological source areas increasing slightly by 16.016 km2. From 2000 to 2010, the proportion of unutilized land transferred to grassland was 6.3%, which is significantly higher than the annual transfer average of 1.6%. This is mainly due to the ecological protection measures in the cities of Linxia and Hezuo. Between 2010 and 2020, economic construction resulted in the loss of grassland, and the percentage of grassland turned out was 7.3%, which was significantly higher than the annual average of 1.8%. (2) In the Daxia River Basin, rainfall, sunlight intensity, temperature, and elevation had a greater impact on land change during the period from 1990 to 2020, with contributions of −0.4, 0.09, 0.08, and −0.26, respectively. [ABSTRACT FROM AUTHOR]

Objective: Oral squamous cell carcinoma (OSCC) is the most common malignant tumour in the oral cavity. OSCC is aggressive and prone to metastasis; it is associated with high mortality and short survival. In this study, we investigated the function of the long non‐coding RNA LINC00525 in OSCC progression and the molecular mechanisms through in vitro and in vivo experiments. Materials and Methods: CCK8 assay was used to detect the effect of LINC00525 on cell viability; transwell migration and invasion assays and scratch assay were used to examine the role of LINC00525 in cell migration and invasion. Flow cytometry, RT‐PCR and western blot were used to detect apoptosis indexes. Tumorigenic effects were investigated using mouse xenograft tumour models. Results: LINC00525 was associated with OSCC survival and prognosis. LINC00525 knockdown decreased cell viability and epithelial‐mesenchymal transition (EMT) properties and increased apoptosis and also shortened the cell cycle of OSCC cells in vitro. The downregulation of LINC00525 reduced the growth of OSCC tumour in vivo. LINC00525 can regulate OSCC cells via the apoptotic signalling pathway. Conclusion: Our results indicate that LINC00525 exhibits oncogenic functions in OSCC. LINC00525 may be a new promising and potential target for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Recently, the vascular protective effect of anti-diabetic agents has been receiving much attention. Sodium glucose cotransporter 2 (SGLT2) inhibitors had demonstrated reductions in cardiovascular (CV) events. However, the therapeutic effect of dapagliflozin on angiogenesis in peripheral arterial disease was unclear. This study aimed to explore the effect and mechanism of dapagliflozin on angiogenesis after hindlimb ischemia. We first evaluated the effect of dapagliflozin on post-ischemic angiogenesis in the hindlimbs of rats. Laser doppler imaging was used to detect the hindlimb blood perfusion. In addition, we used immunohistochemistry to detect the density of new capillaries after ischemia. The relevant signaling pathways of dapagliflozin affecting post-ischemic angiogenesis were screened through phosphoproteomic detection, and then the mechanism of dapagliflozin affecting post-ischemic angiogenesis was verified at the level of human umbilical vein endothelial cells (HUVECs). After subjection to excision of the left femoral artery, all rats were randomly distributed into two groups: the dapagliflozin group (left femoral artery resection, receiving intragastric feeding with dapagliflozin (1 mg/kg/d), for 21 consecutive days) and the model group, that is, the positive control group (left femoral artery resection, receiving intragastric feeding with citric acid–sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days). In addition, the control group, that is the negative control group (without left femoral artery resection, receiving intragastric feeding with citric acid–sodium citrate buffer solution (1 mg/kg/d), for 21 consecutive days) was added. At day 21 post-surgery, the dapagliflozin-treatment group had the greatest blood perfusion, accompanied by elevated capillary density. The results showed that dapagliflozin could promote angiogenesis after hindlimb ischemia. Then, the ischemic hindlimb adductor-muscle tissue samples from three rats of model group and dapagliflozin group were taken for phosphoproteomic testing. The results showed that the PI3K-Akt-eNOS signaling pathway was closely related to the effect of dapagliflozin on post-ischemic angiogenesis. Our study intended to verify this mechanism from the perspective of endothelial cells. In vitro, dapagliflozin enhanced the tube formation, migration, and proliferation of HUVECs under ischemic and hypoxic conditions. Additionally, the dapagliflozin administration upregulated the expression of angiogenic factors phosphorylated Akt (p-Akt) and phosphorylated endothelial nitric oxide synthase (p-eNOS), as well as vascular endothelial growth factor A (VEGFA), both in vivo and in vitro. These benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. dapagliflozin could promote angiogenesis after ischemia. This effect might be achieved by promoting the activation of the PI3K-Akt-eNOS signaling pathway. This study provided a new perspective, new ideas, and a theoretical basis for the treatment of peripheral arterial disease. [ABSTRACT FROM AUTHOR]

Crocin is a unique water-soluble carotenoid found in crocus and gardenia flowers. Crocin has been shown to have a variety of pharmacological activities, such as antioxidant, anti-cancer, memory improvement, antidepressant, anti-ischemia, blood pressure lowering and aphrodisiac, gene protection and detoxification activities. Due to their amphiphilicity, crocin molecules form concentration-dependent self-associates (micelles) in a water solution. In the present study, using various NMR techniques (T2 relaxation and selective gradient NOESY), we have demonstrated that crocin forms mixed micelles with water-soluble drug delivery system glycyrrhizin and linoleic acid molecules. Note, that the spin–spin T2 relaxation time and NOESY spectroscopy are very sensitive to intermolecular interactions and molecular diffusion mobility. The second purpose of this work was the elucidation of the interaction of crocin with a model lipid membrane using NMR techniques and a molecular dynamics simulation and its effects on lipid oxidation. It was shown that the crocin molecule is located near the surface of the lipid bilayer and effectively protects lipids from oxidation by peroxyl radicals. The role of glycyrrhizin and vitamin C in metal-induced lipid oxidation was also elucidated. The results of this study may be useful for expanding the field of application of crocin in medicine and in the food industry. [ABSTRACT FROM AUTHOR]

Gastric cancer is becoming the second biggest cause of death from cancer. Treatment and prognosis of different types of gastric cancer vary greatly. However, the routine pathological examination is limited to the tissue level and is easily affected by subjective factors. In our study, we examined gastric mucosal samples from 50 normal tissue and 90 cancer tissues. Hyperspectral imaging technology was used to obtain spectral information. A two‐classification model for normal tissue and cancer tissue identification and a four‐classification model for cancer type identification are constructed based on the improved deep residual network (IDRN). The accuracy of the two‐classification model and four‐classification model are 0.947 and 0.965. Hyperspectral imaging technology was used to extract molecular information to realize real‐time diagnosis and accurate typing. The results show that hyperspectral imaging technique has good effect on diagnosis and type differentiation of gastric cancer, which is expected to be used in auxiliary diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Natural bioactive compounds have recently emerged as a current strategy for Alzheimer's disease treatment. Carotenoids, including astaxanthin, lycopene, lutein, fucoxanthin, crocin and others are natural pigments and antioxidants, and can be used to treat a variety of diseases, including Alzheimer's disease. However, carotenoids, as oil-soluble substances with additional unsaturated groups, suffer from low solubility, poor stability and poor bioavailability. Therefore, the preparation of various nano-drug delivery systems from carotenoids is a current measure to achieve efficient application of carotenoids. Different carotenoid delivery systems can improve the solubility, stability, permeability and bioavailability of carotenoids to a certain extent to achieve Alzheimer's disease efficacy. This review summarizes recent data on different carotenoid nano-drug delivery systems for the treatment of Alzheimer's disease, including polymer, lipid, inorganic and hybrid nano-drug delivery systems. These drug delivery systems have been shown to have a beneficial therapeutic effect on Alzheimer's disease to a certain extent. [ABSTRACT FROM AUTHOR]

We experimentally investigate trap-loss spectra of the cesium 6S1/2(F = 4) → 71P3/2 Rydberg transition by combining the cesium atomic magneto-optical trap with the narrow-linewidth, continuously tunable 318.6 nm ultraviolet laser. Specifically, the atoms in the magneto-optical trap are excited to the Rydberg state due to the ultraviolet laser single-step Rydberg excitation, which leads to the reduction of atomic fluorescence. Based on the trap-loss spectroscopy technology, the Autler–Townes (AT) splitting due to a strong cooling laser is observed, and the parameter dependence of the AT splitting interval of trap-loss spectroscopy is investigated. The effective temperature of cold atoms is measured by using simplified time-of-flight fluorescence imaging. In addition, closed-loop feedback power stabilization of 318.6 nm ultraviolet laser is carried out. This lays the foundation for further experimental research related to the Rydberg atoms using ultraviolet lasers, which is of great significance for the development of quantum computing and quantum information. [ABSTRACT FROM AUTHOR]