RESUMEN
BACKGROUND: An important stage in controlling gene expression is RNA alternative splicing (AS), and aberrant AS can trigger the development and spread of malignancies, including hepatocellular carcinoma (HCC). A crucial component of AS is cleavage and polyadenylation-specific factor 4 (CPSF4), a component of the CPSF complex, but it is unclear how CPSF4-related AS molecules describe immune cell infiltration in the total tumor microenvironment (TME). METHODS: Using RNA-sequencing data and clinical data from TCGA-LIHC from the Cancer Genome Atlas (TCGA) database, the AS genes with differential expression were found. The univariate Cox analysis, KM analysis, and Spearman analysis were used to identify the AS genes related to prognosis. Screening of key AS genes that are highly correlated with CPSF4. Key genes were screened using Cox regression analysis and stepwise regression analysis, and prognosis prediction models and the topography of TME cell infiltration were thoroughly analyzed. RESULTS: A model consisting of seven AS genes (STMN1, CLSPN, MDK, RNFT2, PRR11, RNF157, GHR) was constructed that was aimed to predict prognostic condition. The outcomes of the HCC samples in the high-risk group were considerably worse than those in the lower risk group (p < 0.0001), and different risk patient groups were formed. According to the calibration curves and the area under the ROC curve (AUC) values for survival at 1, 2, and 3 years, the clinical nomogram performs well in predicting survival in HCC patients. These values were 0.76, 0.70, and 0.69, respectively. Moreover, prognostic signature was markedly related to immune infiltration and immune checkpoint genes expression. CONCLUSION: By shedding light on the function of CPSF4 and the seven AS genes in the formation and progression of HCC, this research analysis contributes to the development of more useful prognostic, diagnostic, and possibly therapeutic biomarkers.
RESUMEN
Hypercoordinated carbon-centered organometallic clusters extensively exist in polymetallic and metal surface catalysis. The investigation on their electronic structures and transformations is crucial for mechanistic studies. Herein, we try to clarify the reactivity difference between a hypercoordinated tetrametalated species [PA-C-Au4]+ and a classical trimetalated one [(PA-C-Au3) + H]+ based on experimental and theoretical studies. Under a protonolysis condition, the hypercoordinated carbon species [PA-C-Au4]+ experiences a sequential cleavage process of carbon-polymetal bonding through the trinuclear [(PA-C-Au3) + H]+ intermediate to end up with a methyl group. Theoretical studies indicate that the high symmetry of five-center bonding in [PA-C-Au4]+ promotes the delocalization of negative charges, finally resulting in less nucleophilicity of the central hypercarbon atom. In contrast, the low C3V triangular arrangement of gold atoms in the [(PA-C-Au3) + H]+ structure causes the decrease in orbital interaction between the Aun moiety and the central carbon atom and the increase in the negative charge on the central carbon atom. Along with the gradual cleavage of the carbon-polymetal bonding, the accumulation of negative charges and the reduction of steric hindrance around the central carbon atom jointly contribute to the synergistic multi-step protodeauration process. This work not only illustrates the reactivity difference of RC-Mn species in different degrees of metalation but also provides an essential structural basis for the design of synergistic polymetallic catalysts.
RESUMEN
Synergistic effect extensively exists in multimetal-involved catalytic or mediated processes of group 11 metals due to their remarkable metallophilic interactions. Herein, we present a multiple synergism model for alkynyl substrates and conduct theoretical investigations on various multimetallic bonding modes and the corresponding synergistic activations. We computationally screen nine alkynyl multisilver coordination modes and sequence their reactivity shown in an intramolecular nucleophilic addition reaction by the trend of active µ4-η1η1η2η2 and µ3-η1η1η2 to the relatively inert µ2-η1η2. The transition-state (TS) stabilization of the high-nuclearity mode mainly comes from the significant negative interaction energies between Agn and the substrate based on the distortion/interaction analysis. Energy decomposition analysis-natural orbitals for chemical valence (EDA-NOCV) analysis further reveals the charge-accepting reservoir effect of the polysilver moiety and the orbital match between the alkynyl group and specific spatial arrangement of silver atoms to account for this efficient activation. In addition, tests on different ligands coordinated to silver atoms show a correlation of the ligand conformation adjustability with the reactivity of the alkynyl unit, and the accommodable η2 activation unit embodies a lower deformation energy than the other homonuclear synergistic modes. Privileged multiple synergistic models have been further evidenced based on on-bench experiments by isolating trisilver and tetrasilver alkynyl complexes. This study not only systematically evaluates the multimetallic synergism of different coordination modes in alkyne activation but also provides a guidance for the future design of multimetallic catalysts.
RESUMEN
The green economy is essential in supporting sustainable economic development and relies on talents and technologies. From the perspective of traditional economic theory, this study explores the impact of high-speed rail and innovation on the green economy from the perspectives of talent and technology. Using the data of 281 prefecture-level cities in China from 2008 to 2018, this study constructs empirical models to discuss the driving factors of the green economy. Empirical results show that high-speed rail and innovation can promote the development of a green economy, and the opening of high-speed rail can strengthen the positive association between innovation and a green economy. The accessibility of high-speed rail improves the flow of talent between different cities and greatly stimulates the positive impact of innovation on green economic activities. In the further test, this study explores the impact of high-speed rail and innovation on the green economy from different dimensions, including government policy, economic strength, and administrative level. During China's 12th Five-Year Plan, high-speed rail and innovation had a positive impact on the green economy, but the impact of innovation can still be significant after this period. Moreover, the opening of high-speed rail may motivate the migration of talents from developed cities to developing ones, while developed cities can rely on technological advantages to support green economic activities. Furthermore, low-administrative level cities will rely on attracting more talents to promote a green economy due to technological disadvantages. Innovation can play a critical role in enhancing the green economy of cities with high administrative levels. Talents and technology are both important to green economic activities, and the construction of high-speed rail changes the impact of technology on the green economy through the flow of talent. Our findings can explain why the opening of high-speed rail can promote the development of a green economy and effectively help governments achieve the goal of sustainable development.
RESUMEN
Medicinal applications of gold complexes have recently attracted attention due to their innovative antitumor mechanisms. In this work, two hypercoordinated carbon-centered gold clusters PAA4 and PAA5 are quantitatively synthesized by an intramolecular 6-exo-dig cyclization of polymetalated precursors. The on-bench and in vitro experimental studies demonstrate that the characteristic hypercarbon-tetragold(I) multi-center bonding in PAA4 and PAA5 not only guarantees their stability under common physiological conditions, but also facilitates a glutathione (GSH)-triggered prompt and synergetic release of active Au(I) ions in the GSH-overexpressed and acidic microenvironment of human bladder cancer EJ cells. The instantly massive release of coordination unsaturated Au(I) ions causes the efficient inhibition of thioredoxin reductases and then induces a rapid pro-oxidant response, consequently causing the occurrence of accelerated ferroptosis of EJ cells. As a result, these hypercarbon-centered gold(I) cluster prodrugs show high cytotoxicity to bladder cancer cell lines and thus exhibit a significant inhibition effect towards bladder tumors in vivo. Correlation of the synergetic domino dissociation of carbon-polymetal multi-center bonding in metal clusters with the accelerated ferroptosis of cancer cells provides a strategy for metallo-prodrugs and opens a broader prospect for the biological application of metal cluster compounds.