Spatial scale effects on the value of ecosystem services in China's terrestrial area.

Identifying the response characteristics of ecosystem service value (ESV) to changes in spatial scales, known as spatial scale effects, is crucial in guiding the development of corresponding management strategies. This paper examines ESV in China's terrestrial area during the year 2020, revealing the spatial aggregation characteristics of ESV and the trade-off and synergistic relationships of ecosystem services at different spatial scales, ranging from 1 km × 1 km-10 km × 10 km, with a gradient of 1 km. The results indicate: 1) The distribution pattern of ESV in China's terrestrial area is "high in the southeast and low in the northwest." 2) The spatial characteristics of ESV in China's terrestrial area undergo a distinct transition at the 3 km × 3 km scale. In detail, the spatial clustering features show a trend of first rising and then falling with the increase in spatial scale, while the synergistic relationships between different ecosystem services strengthen and the trade-off relationships weaken with the increase of the spatial scale. These findings can inform the formulation of differentiated ecological protection compensation policies and enable cross-area trading of ecological values in China.

Demonstration and Suggestion on the Communication Efficiency of New Media of Environmental Education Based on Ideological and Political Education.

With the rapid development of the economy, we are facing more and more problems, and the construction of ecological civilization has become the focus of our national concern. With the rapid development of network technology, the immediacy of the new media and the huge audience have brought new development trends to the dissemination of environmental information. The number of new environmental media is increasing, but there are still some problems, such as formality, rigid content and lack of innovation, which make it difficult to achieve better communication effects. However, the research on new environmental media is still in its infancy, and there is not yet a set of targeted and specialized new media evaluation systems. Based on the social function of new environmental news media and the social responsibility of media as the entry point, the article establishes a set of index systems to measure the efficiency of environmental news dissemination and proposes corresponding improvement measures accordingly. The results of the study show that the best use of environmental education publicity is at 81.3%. In terms of cognitive efficiency and attitudinal efficacy, the scores of environmental education weibo public numbers were not high, at 60.7% and 71.5%, respectively. From the perspective of ideological and political education, the environmental protection class of WeChat plays a good role in attracting the attention of college students, and can provide ideological and political education to them and improve their ideological awareness. In terms of cognition, new media is responsible for conveying environmental knowledge and concepts to college students, so the development of new media centers on environmental information, and the content directly affects the cognitive level of college students, fully reflecting the importance of cognitive efficacy in new media of environmental education. On attitude efficacy, only one indicator is set for identity shaping, which has the highest score, but the lowest is 4.0, showing that the public number is still not obvious enough in terms of identifying with college student groups, influencing college students' emotions and attitudes. Based on this, this paper points out the problems of the current communication efficiency of environmental education new media through the analysis of the evaluation results and puts forward suggestions to improve its communication efficiency in this regard.

Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer.

Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-negative breast cancer (TNBC). We previously reported SBI-0206965, a small molecule inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2). One inhibitor, SBP-7455 (compound 26), displayed improved binding affinity for ULK1/2 compared with SBI-0206965, potently inhibited ULK1/2 enzymatic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice. SBP-7455 inhibited starvation-induced autophagic flux in TNBC cells that were dependent on autophagy for survival and displayed synergistic cytotoxicity with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib against TNBC cells. These data suggest that combining ULK1/2 and PARP inhibition may have clinical utility for the treatment of TNBC.

Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2).

Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 (Unc-51-like autophagy activating kinase 1) has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2 (Unc-51-like autophagy activating kinase 2). Here, we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor-binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provide structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.

Acetylation of p53 Protein at Lysine 120 Up-regulates Apaf-1 Protein and Sensitizes the Mitochondrial Apoptotic Pathway.

The p53 tumor suppressor controls cell growth, metabolism, and death by regulating the transcription of various target genes. The target-specific transcriptional activity of p53 is highly regulated. Here we demonstrate that acetylation of p53 at Lys-120 up-regulates its transcriptional activity toward Apaf-1, a core component in the mitochondrial apoptotic pathway, and thus sensitizes caspase activation and apoptosis. We found that histone deacetylase (HDAC) inhibitors, including butyrate, augment Lys-120 acetylation of p53 and thus Apaf-1 expression by inhibiting HDAC1. In p53-null cells, transfection of wild-type but not K120R mutant p53 can restore the p53-dependent sensitivity to butyrate. Strikingly, transfection of acetylation-mimicking K120Q mutant p53 is sufficient to up-regulates Apaf-1 in a manner independent of butyrate treatment. Therefore, HDAC inhibitors can induce p53 acetylation at lysine 120, which in turn enhances mitochondrion-mediated apoptosis through transcriptional up-regulation of Apaf-1.