No abstract

No abstract

No abstract

Licochalcone A (LCA) is a major bioactive compound in Licorice, a widely used herbal medicine. In this study, the inhibitory effects of LCA against human UDP-glucuronosyltransferases (UGTs) and LCA associated herb-drug interactions were systematically investigated. Our results demonstrated that LCA displayed broad-spectrum inhibition against human UGTs. LCA exhibited strong inhibitory effects against UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 2B7 (both IC50 and Ki values lower than 5 μM), while showing moderate inhibitory effects against UGT1A8, 1A10, 2B4, 2B15, and 2B17. The inhibitory effects of LCA against two major UGTs, including UGT1A1 and 1A9, were further investigated in human liver microsomes (HLMs), where the potential risks of LCA via inhibition of UGT1A1 and 1A9 were predicted by combining the in vitro inhibitory data and physiological data. The results from this study also showed that several LCA-containing products were able to increase the area under the curve (AUC) of the substrates that were predominantly metabolized by UGT1A1 or 1A9. These findings together demonstrate that LCA has a potent and broad-spectrum inhibitory effect against most human UGTs and thus suggest that much caution should be exercised when high-dose LCA is co-administered with UGT substrates.

No abstract

ABSTRACT. As a conceptual framework for understanding contemporary sustainability challenges, telecoupling emphasizes the importance of socioeconomic and environmental interactions over long distances. These long-distance interactions can occur through multiple human activities. We focus on international trade, a major channel of telecoupling flows, and in particular on the international trade of metals. We use the data of physical products and embedded greenhouse gas (GHG) emissions trade in the World Input-Output Database (WIOD) to quantitatively examine how countries contribute to both economic and environmental flows through the trade of metals, but also how that contribution varies depending on their position in the global value chain (GVC) of contemporary international trade. This analysis is built on previously developed techniques for decomposing gross exports of products, which we apply to examine embedded GHG emissions. We make comparisons between countries' contributions to flows of economic value versus embedded GHG emissions, but also examine contributions beyond total volumes of trade and bilateral trade. Specifically, we quantify the economic and environmental spillover effects that occur in contemporary international trade because of the GVC in which flows of intermediate goods form components in other subsequently traded goods. We interpret differences between countries' contributions to the flows of economic value versus embedded GHG emissions as being related to the intensity and efficiency of resource use during production. In turn, differences in contributions to direct trade flows versus spillover flows are related to their positions in the GVC. Subsequently, we discuss other elements of the telecoupling framework in trade, i.e., agents, causes, and effects. Quantitatively incorporating these telecoupling framework elements alongside spillover flows will enable investigation of dynamics and relationships that traditional trade theories, data, and models do not currently account for well. Key Words: global value chain; international trade; metal industry; telecoupling framework; world input-output database INTRODUCTIONThe conceptual framework of telecoupling (Liu et al. 2013(Liu et al. , 2015 highlights the importance of socioeconomic and environmental interactions over large distances for understanding contemporary sustainability challenges. The framework integrates five elements: coupled human and natural systems (CHANS), flows, agents, causes, and effects. Local interactions within CHANS are mediated by agents making decisions, with socioeconomic and environmental causes and effects. Furthermore, in the telecoupling framework, CHANS are the origin and destination of long-distance interactions, connected by material and information flows, and can be distinguished from those that are sending systems, those that are receiving systems, and those that are recipients of spillover flows from the interaction of other systems. As highlighted previously (e.g., Liu et al. 2013), longdistance telecou...

Widespread adoption of artificial intelligence (AI) technologies is substantially affecting the human condition in ways that are not yet well understood. Negative unintended consequences abound including the perpetuation and exacerbation of societal inequalities and divisions via algorithmic decision making. We present six grand challenges for the scientific community to create AI technologies that are humancentered, that is, ethical, fair, and enhance the human condition. These grand challenges are the result of an international collaboration across academia, industry and government and represent the consensus views of a group of 26 experts in the field of human-centered artificial intelligence (HCAI). In essence, these challenges advocate for a human-centered approach to AI that (1) is centered in human wellbeing, (2) is designed responsibly, (3) respects privacy, (4) follows human-centered design principles, ( 5) is subject to appropriate governance and oversight, and (6) interacts with individuals while respecting human's cognitive capacities. We hope that these challenges and their associated research directions serve as a call for action to conduct research and development in AI that serves as a force multiplier towards more fair, equitable and sustainable societies.

Ezrin, primarily acts as a linker between the plasma membrane and the cytoskeleton, is involved in many cellular functions, including regulation of actin cytoskeleton, control of cell shape, adhesion, motility, and modulation of signaling pathways. Although ezrin is now recognized as a key component in tumor metastasis, its roles and the underlying mechanisms remain unclear. In the present study, we chose highly metastatic human lung carcinoma 95D cells, which highly express the ezrin proteins, as a model to examine the functional roles of ezrin in tumor suppression. An ezrin-silenced 95D cell line was established using lentivirus-mediated short hairpin RNA method. CCK-8 assay and soft agar assay analysis showed that downregulation of ezrin significantly suppressed the tumorigenicity and proliferation of 95D cells in vitro. cell migration and invasion studies showed that ezrin-specific deficiency in the cells caused the substantial reduction of the cell migration and invasion. In parallel, it also induced rearrangements of the actin cytoskeleton. Flow cytometry assay showed that changes in the ezrin protein level significantly affected the cell cycle distribution and eventual apoptosis. Furthermore, further studies showed that ezrin regulated the expression level of E-cadherin and CD44, which are key molecules involved in cell growth, migration, and invasion. Meanwhile, the suppression of ezrin expression also sensitized cells to antitumor drugs. Altogether, our results demonstrated that ezrin played an important role in the tumorigenicity and metastasis of lung cancer cells, which will benefit the development of therapeutic strategy for lung cancer.