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The urban-rural fringe is located between the central urban built-up area and the rural hinterland, which is a transition zone for land use, economic development, and population structure. It is the most dynamic area between urban and rural areas and has become the focus of academic research in terms of geography, sociology, and urban planning. Boundary definition is the most fundamental and primary task for urban research and is particularly important for the spatial definition of the urban-rural fringe. However, a literature review reveals that an unclear spatial definition hinders in-depth scientific research on the urban-rural fringe. The absence of a spatial scope also results in a lack of targeted spatial governance policies attuned to the unique characteristics of urban, non-urban, rural, and both urban and rural areas. Existing policy instruments that exclusively focus on urban or rural areas face significant challenges in fringe regions. Recently, the establishment of a national land spatial planning system has created favorable conditions for studying the spatial definition of urban-rural junction areas. The simultaneous implementation of Territorial and Spatial Planning surveys as part of the construction of this planning system also provides technical support for accurately defining these junction areas. High precision "three adjustments" data allows for an accurate representation of the current state of urban and rural land use, enabling the precise identification of the physical geographical extent of cities. In the context of this study, a reasonable and widely accepted method for spatially defining the urban-rural fringe is essential. To address these issues, this study proposes a spatial definition method based on the urban entity regions identified in three land spatial planning surveys. The approach relies on mature territorial planning technology and addresses three key questions: indicators, thresholds, and units for defining the urban-rural fringe. 1) These indicators were derived from the precise identification of physical urban areas by the Ministry of Natural Resources of the People's Republic of China. The research units were administrative villages and neighborhood committees from previous government policies. It can effectively connect with the territorial spatial planning technology system; 2) Adopt the 25% to 75% ideal value and cluster analysis method recognized based on a comprehensive review of relevant literature and practices in spatially defining the urban-rural fringe domestically and internationally. At the end of the paper, Guangzhou is taken as a typical case study to test the effectiveness of the proposed method in defining the spatial boundaries of the urban-rural fringe. It was determined that a threshold of 10%-75% is reasonable for the spatial definition of the urban-rural fringe in Guangzhou. 3) Through the literature review and practice of government on the spatial definition of urban-rural fringe, as well as the urban-rural fringe identification and examination in Guangzhou. This study proposes a definitive approach based on the physical urban areas of territorial and spatial planning. Finally, accurate measurement indicators, clear research units and highly operable definition methods has an effective integration into the process of Territorial and Spatial Planning, which could provide a solid foundation for further spatial research and the implementation of effective governance strategies.

The function of proteins depends on their correct structure and proper dynamics. Understanding the dynamics of target proteins facilitates drug design and development. However, dynamic information is often hidden in the spatial structure of proteins. It is important but difficult to identify the specific residues that play a decisive role in protein dynamics. Here, we report that a critical glycine residue (Gly463) dominates the motion of threonyl-tRNA synthetase (ThrRS) and the sensitivity of the enzyme to antibiotics. Obafluorin (OB), a natural antibiotic, is a novel covalent inhibitor of ThrRS. The binding of OB induces a large conformational change in ThrRS. Through five crystal structures, biochemical and biophysical analyses, and computational simulations, we found that Gly463 plays an important role in the dynamics of ThrRS. Mutating this flexible residue into more rigid residues did not damage the enzyme's three-dimensional structure but significantly improved the thermal stability of the enzyme and suppressed its ability to change conformation. These mutations cause resistance of ThrRS to antibiotics that are conformationally selective, such as OB and borrelidin. This work not only elucidates the molecular mechanism of the self-resistance of OB-producing Pseudomonas fluorescens but also emphasizes the importance of backbone kinetics for aminoacyl-tRNA synthetase-targeting drug development. Crystal structures and molecular dynamics simulations reveal that a critical glycine residue dominates the motion of threonyl-tRNA synthetase and the sensitivity of the enzyme to conformation selective inhibitors. [ABSTRACT FROM AUTHOR]

Ti3C2Tx, as a member of the two-dimensional (2D) MXene family, is subject to severe self-restacking due to van der Waals forces between the surfaces of the nanosheets, which limits its application in supercapacitors. In addition, Ti3C2Tx always stores electrical energy non-Faradaic, resulting in a low specific capacitance about 100 F g–1 in basic electrolytes. In this work, we report conductive bismuth-catecholate metal–organic frameworks (Bi-(HHTP)) with one-dimensional (1D) channels grown on the surfaces of 2D Ti3C2Tx nanosheets (Ti3C2Tx/Bi-(HHTP)) for supercapacitors. In the hybrid structure, conductive Bi-(HHTP) serves not only as the spacers to relieve the self-stacking of Ti3C2Tx nanosheets but also as the active component to provide battery-type capacitance. Meanwhile, Ti3C2Tx nanosheets provide skeletons for the conductive Bi-(HHTP), further enhancing the overall specific capacitance of Ti3C2Tx/Bi-(HHTP). By taking advantage of appropriate porosity, redox activity, and good properties of charge transport of Bi-(HHTP), the specific capacitance of Ti3C2Tx nanosheets is significantly increased. The Ti3C2Tx/Bi-(HHTP) electrode obtained exhibits an impressive specific capacitance of 326 F g–1 at 0.5 A g–1 and a good rate capacity of 52%. Additionally, an asymmetric device is assembled with a Ni-(OH)2 cathode and a Ti3C2Tx/Bi-(HHTP) anode, demonstrating remarkable performance with a maximum specific energy of 22.3 Wh kg–1 and a maximum specific power of 11.2 kW kg–1. This work presents a promising strategy for developing high-performance supercapacitor electrodes based on Ti3C2Tx, offering potential avenues for enhancing performance in energy storage applications. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of l-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS. Using a combination of biochemical and structural approaches, the authors demonstrate that derivatization of kinase inhibitors can yield new repurposed anti-malarial drugs that specifically target Plasmodium falciparum Lysine-tRNA synthetase. [ABSTRACT FROM AUTHOR]

Autophagy, an important cellular stress response mechanism, is often exploited by a variety of cancer cells to sustain rapid growth under stresses such as nutrient deprivation and hypoxia. Autophagy also plays a key role in tumor resistance to chemotherapy, radiotherapy or targeted therapy. Inhibition of autophagy is therefore a promising tumor treatment strategy. However, there is still a lack of effective autophagy inhibitors suitable for clinical use. Most drug development has focused on enzymes like the VPS34 and ULK1 kinases, or the cysteine protease ATG4B, which plays different roles in autophagy. We discovered a drug molecule Eltrombopag that inhibits the expression of autophagic lysosomal genes at the stage of transcriptional level, where the synthesis of these proteins has not really begun, by directly inhibiting the TFEB (transcription factor EB). This drug can improve the therapeutic effect of Temozolomide on glioblastoma treatment, further confirming the value of inhibiting autophagy in the treatment of cancer. Abbreviation: VPS34: vacuolar protein sorting 34; ULK1: unc-51 like autophagy activating kinase 1; TFEB: transcription factor EB; MITF: microphthalmia-associated transcription factor; TFE3: transcription factor E3; EO: Eltrombopag; ITC: isothermal titration calorimetry; bHLH-LZ: basic helix-loop-helix leucine zipper; LAMP1: lysosomal-associated membrane protein 1; CTSF: cathepsin F; HEXA: hexosaminidase subunit alpha. [ABSTRACT FROM AUTHOR]

Mitomycins make up a class of natural molecules produced by Streptomyces with strong antibacterial and antitumor activities. MitM is a key postmitosane modification enzyme involved in mitomycin biosynthesis in Streptomyces caespitosus . This protein was previously suggested to catalyze the aziridinium methylation of mitomycin A and the mitomycin intermediate 9a-demethyl-mitomycin A as an N -methyltransferase. The structural basis for MitM to recognize cofactor S -adenosyl-l-methionine (SAM) and substrate mitomycin A is unknown. Here, we determined the crystal structures of apo -MitM and MitM-mitomycin A- S -adenosylhomocysteine (SAH) ternary complexes with resolutions of 2.23 and 2.80 Å, respectively. We found that MitM adopts a class I SAM-dependent methyltransferase fold and forms a homodimer in solution. Conformational changes in a series of residues involved in the formation of active pockets assist MitM in binding SAH and mitomycin A. In particular, the 28 ALGAASLGE 36 loop changes most significantly. When mitomycin A binds, the bending direction of this loop is reversed, changing the entrance of the active site from open to closed. This study provides structural insights into MitM's involvement in the postmitosane stage of mitomycin biosynthesis and provides a template for the engineering of methyltransferases.

Multi-label few-shot learning (ML-FSL) refers to the task of tagging previously unseen images with a set of relevant labels, giving a small number of training examples. Modeling the correlations between instances and labels, formulated in the existing methods, allows us to extract more available knowledge from limited examples. However, they simply explore the instance and label correlations with a uniform importance assumption without considering the discrepancy of importance in different instances or labels, making the utilization of instance and label correlations a bottleneck for ML-FSL. To tackle the issue, we propose a unified framework named bilateral correlation reconstruction (BCR) to enable the network to effectively mine underlying instance and label correlations with varying importance information from both instance-to-label and label-to-instance perspectives. Specifically, from the instance-to-label perspective, we refine prototypes per category by reweighting each image with its specific instance-importance degree extracted from the similarity between the instance and the corresponding category. From the label-to-instance perspective, we smooth labels for each image by recovering latent label-importance with considering the integrated topology of all samples in a task. Experimental results on multiple benchmarks validate that BCR could outperform existing ML-FSL methods by large margins.