Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression.

Acylphosphatase 1 (ACYP1), a protein located in the mammalian cell cytoplasm, has been shown to be associated with tumor initiation and progression by functioning as a metabolism-related gene. Here we explored the potential mechanisms by which ACYP1 regulates the development of HCC and participates in the resistance to lenvatinib. ACYP1 can promote the proliferation, invasion, and migration capacities of HCC cells in vitro and in vivo. RNA sequencing reveals that ACYP1 markedly enhances the expression of genes related to aerobic glycolysis, and LDHA is identified as the downstream gene of ACYP1. Overexpression of ACYP1 upregulates LDHA levels, which then increases the malignancy potential of HCC cells. GSEA data analysis reveals the enrichment of differentially expressed genes in the MYC pathway, indicating a positive correlation between MYC and ACYP1 levels. Mechanistically, ACYP1 exerts its tumor-promoting roles by regulating the Warburg effect through activating the MYC/LDHA axis. Mass spectrometry analysis and Co-IP assays confirm that ACYP1 can bind to HSP90. The regulation of c-Myc protein expression and stability by ACYP1 is HSP90 dependent. Importantly, lenvatinib resistance is associated with ACYP1, and targeting ACYP1 remarkably decreases lenvatinib resistance and inhibits progression of HCC tumors with high ACYP1 expression when combined with lenvatinib in vitro and in vivo. These results illustrate that ACYP1 has a direct regulatory role in glycolysis and drives lenvatinib resistance and HCC progression via the ACYP1/HSP90/MYC/LDHA axis. Targeting ACYP1 could synergize with lenvatinib to treat HCC more effectively.

What is the Role of Hierarchical Interventions? Insights from the Evolution of Water Collaborative Governance in China.

Collaborative governance has been viewed as an effective approach to solve the problem of environmental pollution. Recently, while some scholars have advanced the integral role of hierarchical interventions in collaborative processes and outcomes, less attention has been paid to the long-term evolution of hierarchical interventions through the lifecycle of collaboration. Based on the case study of water collaborations along the Maxi River in the Yangtze Delta region since 2001, this paper investigates the empirical evolution and influencing mechanisms of hierarchical interventions, primarily hands-off and hands-on interventions, at different collaboration development stages. The results show that collaborations along the Maxi River have experienced stages of activation, collectivity and institutionalization in the past twenty years, wherein the quality and extent of the collaborative dynamics have gradually enhanced. Hierarchical interventions are found to be context-specific, though both hands-off and hands-on intervention tools have potential to exert positive influence on the three collaborative dynamics (principled engagement, shared motivation and capacity building). Hands-on strategies, namely the superiors' direct participation or support, are of great importance in the initial stage when stakeholders have conflicts of interests/values or failed past experiences. As the collaborative process matures, the superordinate governments would usually adopt hands-off tools to provide an institutional framework and a legitimate basis, thereby fostering participants' interdependence and self-initiated motivations. Additionally, in Chinese context, hands-off tools tend to take more powerful effects than hands-on tools in the long term.

Mangasese doped polypyrole nanoparticels for photothermal/chemodynamic therapy and immune activation.

Photothermal therapy (PTT) is a promising treatment that efficiently suppresses local cancer, but fails to induce a robust antitumor immune response against tumor metastasis and recurrence. In this study, a NIR responsive nano-immunostimulant (Mn/A-HP NI) is fabricated by entrapping manganese and azo-initiator (AIPH) into hyaluronic acid-based polypyrrole nanoparticle. The as-prepared Mn/A-HP NIs with a high photothermal conversion efficiencey of 20.17% dramatically induced the imunogenic cell death of tumor cells and triggered the release ATP and HMGB1. Meanwhile, the hyperthermia induced AIPH decomposition to produce alkyl radicals which further destroyed cancer cells. Furthermore, the Mn/A-HP NIs were capable of promoting the maturation and antigen cross-presentation ability of dendritic cells. Consequently, the multifunctional Mn/A-HP NIs provided a combined treatment via integrating PTT/chemo-dynamic therapy and immune activation for tumor therapy.

Protective effects of SND1 in retinal photoreceptor cell damage induced by ionizing radiation.

Staphylococcal nuclease and tudor domain containing 1 (SND1) has multiple functions in a variety of cellular processes. Here, we assessed the effects of SND1 in cellular DNA damage after ionizing radiation (IR). Knocking down SND1 in the mouse-derived photoreceptor 661 W cell line markedly inhibited cell proliferation and increased apoptosis after IR treatment. After DNA damage, SND1 induced Ataxia telangiectasia mutated kinase (ATM) signaling to launch DNA repair. Defects of SND1 were associated with missing response to DNA damage signal to cell cycle checkpoints or DNA repair. The current findings reveal SND1 as a new regulatory factor in DNA damage response.

Transcriptomic analysis reveals the functions of H2S as a gasotransmitter independently of Cys in Arabidopsis.

Numerous studies have revealed the gasotransmitter functions of hydrogen sulfide (H2S) in various biological processes. However, the involvement of H2S in sulfur metabolism and/or Cys synthesis makes its role as a signaling molecule ambiguous. The generation of endogenous H2S in plants is closely related to the metabolism of Cys, which play roles in a variety of signaling pathway occurring in various cellular processes. Here, we found that exogenous H2S fumigation and Cys treatment modulated the production rate and content of endogenous H2S and Cys to various degrees. Furthermore, we provided comprehensive transcriptomic analysis to support the gasotransmitter role of H2S besides as a substrate for Cys synthesis. Comparison of the differentially expressed genes (DEGs) between H2S and Cys treated seedlings indicated that H2S fumigation and Cys treatment caused different influences on gene profiles during seedlings development. A total of 261 genes were identified to respond to H2S fumigation, among which 72 genes were co-regulated by Cys treatment. GO and KEGG enrichment analysis of the 189 genes, H2S but not Cys regulated DEGs, indicated that these genes mainly involved in plant hormone signal transduction, plant-pathogen interaction, phenylpropanoid biosynthesis, and MAPK signaling pathway. Most of these genes encoded proteins having DNA binding and transcription factor activities that play roles in a variety of plant developmental and environmental responses. Many stress-responsive genes and some Ca2+ signal associated genes were also included. Consequently, H2S regulated gene expression through its role as a gasotransmitter, rather than just as a substrate for Cys biogenesis, and these 189 genes were far more likely to function in H2S signal transduction independently of Cys. Our data will provide insights for revealing and enriching H2S signaling networks.

What is policy content and how is the public's policy support? A policy cognition study based on natural language processing and social psychology.

Public policy plays a critical role in coordinating social resources, providing public services, and promoting public value. However, few studies have systematically investigated the public's policy cognition from the objective aspect of policy content and the subjective aspect of target audience's policy support. To fill this gap, we explore the policy content via natural language processing and also policy support from the perspective of social psychology. Specifically, regarding the policy content analysis, we collect over one thousand policy documents and design an annotation system by analyzing the policy content, basic structure and text features, and then utilize text classification and information retrieval models based on the Chinese large-scale pre-trained models. Moreover, according to the policy tools identified in the content analysis, our paper investigates the audience's policy support for these tools and its influential factors. Based on a sample of 476 respondents from the whole country, we adopt the ordinary least square method to explore the key factors of policy support for supply, demand and environmental tools from three variables: political trust, policy effectiveness and knowledge of policies. This study contributes to existing literature by forming a structured understanding of policies and exploring public support for policy tools, which could benefit the practitioners during the policy-making process and also enhance successfully policy implementation.

ACYP1 Is a Pancancer Prognostic Indicator and Affects the Immune Microenvironment in LIHC.

Background: ACYP1 plays important physiological and metabolic roles in glycolysis and membrane ion pump activity by catalyzing acyl phosphate hydrolysis. ACYP1 is related to tumorigenesis and progression and poor prognosis in gastrointestinal cancer. However, its pancancer roles and mechanisms are unclear. Our study aimed to understand the ACYP1 expression signature and prognostic value across cancers and investigate immune infiltration patterns in liver hepatocellular carcinoma (LIHC) and verify them in LIHC samples. Methods: Transcriptional expression profiles of ACYP1 across cancers were analyzed using Oncomine and TIMER. The prognostic value of ACYP1 was assessed across PrognoScan, Kaplan-Meier Plotter, and GEPIA. Significant pathways associated with ACYP1 in LIHC were obtained via Gene Set Enrichment Analysis. The correlation between ACYP1 expression and immune infiltration in LIHC was investigated using TIMER. We validated ACYP1 expression, prognostic value, and association with immune cells in tumor tissues by immunohistochemistry and flow cytometry. Results: ACYP1 was overexpressed across cancers. High expression of ACYP1 correlated with a poor prognosis in most tumor types, especially in LIHC. ACYP1 was significantly implicated in immune and metabolic related pathways. High ACYP1 expression showed significant correlations with the abundances of Th2 cells, Tregs, macrophages, dendritic cells, and myeloid-derived suppressor cells in LIHC. LIHC patients with high ACYP1 expression showed significantly shorter overall survival and relapse-free survival rates concomitant with increased infiltration of CD4+ T cells. Mouse subcutaneous tumors with ACYP1 overexpression exhibited significantly accelerated tumor progression with increased aggregation of CD4+ T cells. Conclusion: Overall, ACYP1 may serve as a vital prognostic biomarker and play an immunoregulatory role in LIHC.

APN-mediated phosphorylation of BCKDK promotes hepatocellular carcinoma metastasis and proliferation via the ERK signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most prevalent human malignancies worldwide and has high morbidity and mortality. Elucidating the molecular mechanisms underlying HCC recurrence and metastasis is critical to identify new therapeutic targets. This study aimed to determine the roles of aminopeptidase N (APN, also known as CD13) in HCC proliferation and metastasis and its underlying mechanisms. We detected APN expression in clinical samples and HCC cell lines using immunohistochemistry, flow cytometry, real-time PCR, and enzyme activity assays. The effects of APN on HCC metastasis and proliferation were verified in both in vitro and in vivo models. RNA-seq, phosphoproteomic, western blot, point mutation, co-immunoprecipitation, and proximity ligation assays were performed to reveal the potential mechanisms. We found that APN was frequently upregulated in HCC tumor tissues and high-metastatic cell lines. Knockout of APN inhibited HCC cell metastasis and proliferation in vitro and in vivo. Functional studies suggested that a loss of APN impedes the ERK signaling pathway in HCC cells. Mechanistically, we found that APN might mediate the phosphorylation at serine 31 of BCKDK (BCKDKS31), promote BCKDK interacting with ERK1/2 and phosphorylating it, thereby activating the ERK signaling pathway in HCC cells. Collectively, our findings indicate that APN mediates the phosphorylation of BCKDKS31 and activates its downstream pathway to promote HCC proliferation and metastasis. Therefore, the APN/BCKDK/ERK axis may serve as a new therapeutic target for HCC therapy, and these findings may be helpful to identify new biomarkers in HCC progression.

The Influencing Factors of Haze Tolerance in China.

Haze pollution has become the most serious environmental risk in China and generated a large amount of public concerns. Influencing almost all the citizens in the polluted area, it is necessary and important to take public perception as an essential element in haze abatement. From the perspective of social psychology, this paper explores haze tolerance in Beijing, Shanghai, and Guangzhou, also the key influential factors on haze tolerance from four dimensions: political trust, perceived risk, cost perception, and haze knowledge. Based on the sample of 517 respondents, the results show that compared with Shanghai and Guangzhou, Beijing residents had the lowest tolerance level of haze pollution but have the highest levels of trust in the government's capacity to control haze and self-evaluation of their own haze knowledge. People in Shanghai had the lowest cost perception and the strongest willingness to acquire haze knowledge. Meanwhile, the empirical analysis revealed that political trust and cost perception could enhance the public's haze tolerance while perceived risk and haze knowledge had negative impacts on tolerance. Also, our research could provide some suggestions to government officials when making policies for abating haze pollution from the perspective of social risk control. Policy makers are supposed to launch various policy instruments to control haze effectively and engage the citizens in the decision-making process to improve their political trust, and publicize the knowledge of haze pollution to help the public to acquire objective and scientific knowledge and diminish unnecessary worries.