9 research outputs found

    Table1_Efficiency of green and low-carbon coordinated development for mega urban agglomerations: an empirical study.XLSX

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    As a critical engine for national economic growth, mega urban agglomerations have significant scale effects and economic and environmental spillover effects. This paper aims to study the green and low-carbon coordinated development of mega urban agglomerations to evaluate the country’s level of ecological civilization and its green and low-carbon development. The traditional research on green and low-carbon urban development tends to homogenize the redistribution theme, leading to significant errors in spatial allocation. This results in a lower accuracy of spatial distribution calculations for green development. Additionally, the research is constrained by data precision and methodology, making it challenging to measure the spatial differences in green and low-carbon development within urban clusters at the block level. This limitation hinders the ability to conduct detailed studies on the efficiency variations of green and low-carbon development in urban clusters. To achieve this aim, the study adopts the DPSR framework of the economic, resource, social, and ecological environment complex system and focuses on the Guangdong-Hong Kong-Macao Greater Bay Area in China. The study uses the entropy method, Gini coefficient method, and non-expected output super-efficiency SBM model to analyze the spatial effects and development efficiency of green and low-carbon development in this region from 2006 to 2020. The study results indicate that: (1) the overall level of green and low-carbon development in the Greater Bay Area is on the rise, with Shenzhen, Guangzhou, Foshan, and Zhuhai showing more stable development than other cities. Foreign direct investment and fixed asset investment in science and technology have significantly promoted green and low-carbon development. (2) The spatial differences in the region’s level of green and low-carbon development have narrowed trends, mainly due to differences between regions. However, well-developed cities such as Guangzhou and Shenzhen have taken the initiative to lead the development of other cities, fully leveraging their advantages in science and technology, geographical location, and other resources to promote the improvement of the external orientation of other cities. (3) The overall development efficiency of green and low-carbon in the Greater Bay Area is on the rise, with Guangzhou region showing overall stability, and Shenzhen region and Zhuhai region experiencing multiple ups and downs in their development. The three sub-regions show significant differences, but the balance and coordination of development have significantly improved. Finally, this study provides theoretical support for the future green and low-carbon development of urban clusters. It is advantageous for integrating the mainstream policy analysis framework of environmental economics with the complex adaptive systems of urban clusters. The research expands the boundaries of existing theoretical studies and offers new methodological approaches for interdisciplinary research. The study achieves a balance between the opportunity effects of green and low-carbon development and environmental policy constraints in super large urban clusters, effectively enhancing resource utilization efficiency in these clusters.</p

    Table2_Efficiency of green and low-carbon coordinated development for mega urban agglomerations: an empirical study.XLSX

    No full text
    As a critical engine for national economic growth, mega urban agglomerations have significant scale effects and economic and environmental spillover effects. This paper aims to study the green and low-carbon coordinated development of mega urban agglomerations to evaluate the country’s level of ecological civilization and its green and low-carbon development. The traditional research on green and low-carbon urban development tends to homogenize the redistribution theme, leading to significant errors in spatial allocation. This results in a lower accuracy of spatial distribution calculations for green development. Additionally, the research is constrained by data precision and methodology, making it challenging to measure the spatial differences in green and low-carbon development within urban clusters at the block level. This limitation hinders the ability to conduct detailed studies on the efficiency variations of green and low-carbon development in urban clusters. To achieve this aim, the study adopts the DPSR framework of the economic, resource, social, and ecological environment complex system and focuses on the Guangdong-Hong Kong-Macao Greater Bay Area in China. The study uses the entropy method, Gini coefficient method, and non-expected output super-efficiency SBM model to analyze the spatial effects and development efficiency of green and low-carbon development in this region from 2006 to 2020. The study results indicate that: (1) the overall level of green and low-carbon development in the Greater Bay Area is on the rise, with Shenzhen, Guangzhou, Foshan, and Zhuhai showing more stable development than other cities. Foreign direct investment and fixed asset investment in science and technology have significantly promoted green and low-carbon development. (2) The spatial differences in the region’s level of green and low-carbon development have narrowed trends, mainly due to differences between regions. However, well-developed cities such as Guangzhou and Shenzhen have taken the initiative to lead the development of other cities, fully leveraging their advantages in science and technology, geographical location, and other resources to promote the improvement of the external orientation of other cities. (3) The overall development efficiency of green and low-carbon in the Greater Bay Area is on the rise, with Guangzhou region showing overall stability, and Shenzhen region and Zhuhai region experiencing multiple ups and downs in their development. The three sub-regions show significant differences, but the balance and coordination of development have significantly improved. Finally, this study provides theoretical support for the future green and low-carbon development of urban clusters. It is advantageous for integrating the mainstream policy analysis framework of environmental economics with the complex adaptive systems of urban clusters. The research expands the boundaries of existing theoretical studies and offers new methodological approaches for interdisciplinary research. The study achieves a balance between the opportunity effects of green and low-carbon development and environmental policy constraints in super large urban clusters, effectively enhancing resource utilization efficiency in these clusters.</p

    Additional file 1: of Geochemistry of fine-grained sediments in the Yangtze River and the implications for provenance and chemical weathering in East Asia

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    Fig. S1. Compositional maturity plots of sediments in the Yangtze River. Most samples plot in the Wacke and Shale areas, indicating immaturity of the sediments. (PDF 368 kb

    Novel Benzo[<i>a</i>]quinolizidine Analogs Induce Cancer Cell Death through Paraptosis and Apoptosis

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    Paraptosis is nonapoptotic cell death characterized by massive endoplasmic reticulum (ER)- or mitochondria-derived vacuoles. Induction of paraptosis offers significant advantages for the treatment of chemotherapy-resistant tumors compared with anticancer drugs that rely on apoptosis. Because some natural alkaloids induce paraptotic cell death, a novel series of benzo­[<i>a</i>]­quinolizidine derivatives were synthesized, and their antiproliferative activity and ability to induce cytoplasmic vacuolation were analyzed. Structural optimization led to the identification of the potent compound <b>22b</b>, which inhibited cancer cell proliferation in vitro and in vivo and profoundly facilitated paraptosis-like cell death and induced caspase-dependent apoptosis. Further investigation revealed that <b>22b</b>-mediated vacuolation originated from persistent ER stress and upregulation of LC3B. Paraptosis induced by benzo­[<i>a</i>]­quinolizidine derivatives thus represents an alternative strategy for cancer chemotherapy

    Discovery of Potent Orally Active Protease-Activated Receptor 1 (PAR1) Antagonists Based on Andrographolide

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    Protease-activated receptor-1 (PAR1), a G-protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound <b>39</b> as the best PAR1 inhibitor. The further in vitro and ex vivo antiplatelet aggregation assays of compound <b>39</b> indicated that compound <b>39</b> was a potent antiplatelet agent. In addition, this compound is metabolically stable and displays a favorable pharmacokinetic profile with an elimination half-life of 3.1 h, which could be treated as a promising candidate for further clinical development

    Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[<i>a</i>]quinolizidine Library to Induce Paraptosis for Cancer Therapy

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    Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[a]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245. Comprehensive target validation revealed that BQZ-485 disrupts the intrinsic GDI2-Rab1A interaction, thereby abolishing vesicular transport from the endoplasmic reticulum (ER) to the Golgi apparatus and initiating subsequent paraptosis events including ER dilation and fusion, ER stress, the unfolded protein response, and cytoplasmic vacuolization. Based on the structure of BQZ-485, we created a small benzo[a]quinolizidine library by click chemistry and discovered more potent GDI2 inhibitors using a NanoLuc-based screening platform. Leveraging the engagement of BQZ-485 with GDI2, we developed a selective GDI2 degrader. The optimized inhibitor (+)-37 and degrader 21 described in this study exhibited excellent in vivo antitumor activity in two GDI2-overexpressing pancreatic xenograft models, including an AsPc-1 solid tumor model and a transplanted human PDAC tumor model. Altogether, our findings provide a promising strategy for targeting GDI2 for paraptosis in the treatment of pancreatic cancers, and these lead compounds could be further optimized to be effective chemotherapeutics

    Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[<i>a</i>]quinolizidine Library to Induce Paraptosis for Cancer Therapy

    No full text
    Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[a]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245. Comprehensive target validation revealed that BQZ-485 disrupts the intrinsic GDI2-Rab1A interaction, thereby abolishing vesicular transport from the endoplasmic reticulum (ER) to the Golgi apparatus and initiating subsequent paraptosis events including ER dilation and fusion, ER stress, the unfolded protein response, and cytoplasmic vacuolization. Based on the structure of BQZ-485, we created a small benzo[a]quinolizidine library by click chemistry and discovered more potent GDI2 inhibitors using a NanoLuc-based screening platform. Leveraging the engagement of BQZ-485 with GDI2, we developed a selective GDI2 degrader. The optimized inhibitor (+)-37 and degrader 21 described in this study exhibited excellent in vivo antitumor activity in two GDI2-overexpressing pancreatic xenograft models, including an AsPc-1 solid tumor model and a transplanted human PDAC tumor model. Altogether, our findings provide a promising strategy for targeting GDI2 for paraptosis in the treatment of pancreatic cancers, and these lead compounds could be further optimized to be effective chemotherapeutics
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