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The essential trace element, zinc, regulates virtually all aspects of cellular physiology, particularly cell proliferation and survival. Diverse families of metal transporters, metallothioneins, and metal‐responsive transcriptional regulators are linked to zinc homeostasis. However, the mechanism underlying the regulation of systemic zinc homeostasis remains largely unknown. Here, it is reported that the intestinal transporter SLC30A1 plays an essential role in maintaining systemic zinc homeostasis. Using several lines of tissue‐specific knockout mice, it is found that intestinal Slc30a1 plays a critical role in survival. Furthermore, lineage tracing reveals that Slc30a1 is localized to the basolateral membrane of intestinal epithelial cells (IECs). It is also found that Slc30a1 safeguards both intestinal barrier integrity and systemic zinc homeostasis. Finally, an integrative analysis of the cryo‐EM structure and site‐specific mutagenesis of human SLC30A1 are performed and a zinc transport mechanism of SLC30A1 unique within the SLC30A family, with His43 serving as a critical residue for zinc selectivity, is identified. Intestinal SLC30A1 plays an essential role for controlling systemic zinc homeostasis via its basolateral membrane‐localized transporter activity of zinc ions from intestinal epithelial cells (IECs) to the circulation. The lethal phenotype of intestinal Slc30a1 deficient mice can be fully rescued by systemic zinc supplementation. The Cryo‐EM structure and mutagenesis of human SLC30A1 reveal the protein's mechanism for transporting metal ions.

GABAB receptor is a Class C G protein‐coupled receptor (GPCR) for γ‐aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABAB receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo‐EM) structures of the drosophila GABAB receptor in both antagonist‐bound inactive state and GABA‐bound active state in complex with Gi protein are reported. The drosophila GABAB receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABAB receptor constitutive activity. Four key residues, which are not conserved in drosophila GABAB receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABAB receptor and new insights for future development of allosteric modulators for medication and insecticides. This study explores the structural and functional mechanisms of the drosophila GABAB receptor, a key role in neurotransmission. Using cryo‐EM, the research reveals how the receptor's activation differs from its human counterpart, highlighting unique evolutionary features. These findings offer valuable insights for developing GABAB‐targeted allosteric modulators with therapeutic potential for medication and insecticides.

G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABAB receptor, activated by the main inhibitory transmitter, GABA, is an obligatory heterodimer. It is the target of two therapeutic drugs, baclofen and GHB, and can form stable oligomers. The existence, roles, and possible allosteric interaction of GABAB oligomers remain elusive. Here, we show that GABAB oligomers exist in neurons. Their function can be specifically affected by human disease-associated mutations, demonstrating their essential role for normal brain function. The cryo-EM structure of a hetero-tetramer in the apo state reveals the heterodimers interacting in an asymmetrical way to prevent one unit from being activated. This represents a nice example of a negative allosteric interaction between GPCRs related to human diseases.G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABAB receptor, activated by the main inhibitory transmitter, GABA, is an obligatory heterodimer. It is the target of two therapeutic drugs, baclofen and GHB, and can form stable oligomers. The existence, roles, and possible allosteric interaction of GABAB oligomers remain elusive. Here, we show that GABAB oligomers exist in neurons. Their function can be specifically affected by human disease-associated mutations, demonstrating their essential role for normal brain function. The cryo-EM structure of a hetero-tetramer in the apo state reveals the heterodimers interacting in an asymmetrical way to prevent one unit from being activated. This represents a nice example of a negative allosteric interaction between GPCRs related to human diseases.

GABA B receptor is a Class C G protein‐coupled receptor (GPCR) for γ‐aminobutyric acid (GABA), the principal inhibitory neurotransmitter. It forms an obligatory heterodimer consisting of two subunits, GB1 and GB2. Whether the activation mechanism of the GABA B receptor is conserved during evolution remains unknown. Here, the cryogenic electron microscopy (cryo‐EM) structures of the drosophila GABA B receptor in both antagonist‐bound inactive state and GABA‐bound active state in complex with G i protein are reported. The drosophila GABA B receptor exhibits an asymmetric activation, mirroring its human homolog. However, a larger inactive interface prevents drosophila GABA B receptor constitutive activity. Four key residues, which are not conserved in drosophila GABA B receptor, are responsible for the activity of the positive allosteric modulator in its human homolog. Whereas the intracellular loop 2 of drosophila GB2 (dGB2) is less involved, the ordered C terminus of dGB2 and its corresponding region in its human homolog are required for G protein coupling. These evolutionary variations provide a complete understanding of the activation mechanism of the GABA B receptor and new insights for future development of allosteric modulators for medication and insecticides.

G protein coupled receptors (GPCRs) oligomerization may allow signal integration from different GPCR units. The GABA receptor, activated by the main inhibitory transmitter, GABA, is an obligatory heterodimer. It is the target of two therapeutic drugs, baclofen and GHB, and can form stable oligomers. The existence, roles, and possible allosteric interaction of GABA oligomers remain elusive. Here, we show that GABA oligomers exist in neurons. Their function can be specifically affected by human disease-associated mutations, demonstrating their essential role for normal brain function. The cryo-EM structure of a hetero-tetramer in the apo state reveals the heterodimers interacting in an asymmetrical way to prevent one unit from being activated. This represents a nice example of a negative allosteric interaction between GPCRs related to human diseases.

G-protein-coupled receptors (GPCRs) are significant signal transducers that exist as monomers and in multiple oligomeric forms. However, molecular mechanism driving their dynamic interconversion to regulate intricate signaling in class A GPCRs remains elusive, compounding our understanding of their related pathophysiological functions. Here, we present a set of 12 assemblies of the apelin receptor (APLNR), including dimeric apo state, monomeric and dimeric intermediate states and fully active state stimulated by small molecule or nanobody, providing a detailed dynamic view of the monomer-dimer transition. High-resolution cryo-EM structures reveal that different ligands induce varying degrees of pre-dissociation in intermediate-state dimers, with G-protein coupling facilitating the transition from dimeric to monomeric receptor. Functional studies further highlight the critical role of cholesterol clusters in stabilizing the APLNR dimers. These insights enhance our understanding of the dynamic regulation of class A GPCRs across different aggregated forms and advance the rational drug design strategies aimed at selectively modulating of APLNR signaling.Competing Interest StatementThe authors have declared no competing interest.

This paper analyzes the impact of the policy of replacing environmental protection “fees” with “taxes” on enterprise green innovation based on the Chinese A-share listed companies sample from 2015 to 2019. This paper tries to analyze the factors that may affect the level of green innovation of enterprises and the ability of enterprise green innovation (GI) under the background of the implementation of this policy. This paper adopts the difference-in-differences method (DID), takes 1 January 2018 as the time variable demarcation boundary and uses the heavily polluting industry as the dummy variable boundary, conducts group research on the experimental variables, and observes and analyzes the impact of heavily polluting industries and non-heavy pollution before and after the implementation of the policy. It is found that the policy significantly improves green innovation and the R&D efficiency of green innovation of enterprises in heavy pollution industries. Further research reveals that after the implementation of the policy, large enterprises and private enterprises, compared with SMEs and state-owned enterprises, lay more stress on improving green innovation technology. In the end, it examines the relationship between senior executives’ academic research experience and enterprises’ green innovation and finds that senior executives’ academic research experience can not only promote green innovation, but also improve the R&D efficiency of green innovation. The research results of this paper provide a theoretical basis for decision makers and enterprise management in formulating rules and managing enterprises.

Chinese Tuina, a fundamental manual therapy technique in traditional Chinese medicine (TCM), treats diseases by applying precisely regulated mechanical forces to the human body. Although its clinical benefits have been extensively documented across a range of conditions—from musculoskeletal pain to neurological disorders—the molecular mechanisms underlying its systemic effects remain partially understood. Meanwhile, exosomes, ubiquitous nanoscale extracellular vesicles, have emerged as key mediators of intercellular communication. These vesicles transfer proteins, lipids and nucleic acids to coordinate bodily homeostasis and responses to stimuli. This review integrates these two fields, proposing that the mechanical forces generated by Chinese Tuina (pressure: 50–300 kPa; shear force: 10–50 dyn/cm2; tension: 5%–20% strain; typical session duration: 15–45 min) constitute an efficient, non‐invasive physiological stimulus capable of systemically regulating the production and release of functional exosomes. We systematically dissect the complete pathway initiating from the perception of mechanical forces at the site of manipulation, followed by exosome release from target cells, distribution via the circulatory system, and finally, the multi‐dimensional impacts on distant organs. By defining Chinese Tuina as a “mechanical stimulator of the exosome network,” this review aims to establish a novel biological paradigm for manual therapy, providing profound insights into understanding its mechanisms of action and advancing the development of precision rehabilitation medicine. (1) Tuina's mechanical forces activate cellular mechanosensors; (2) Induce multi‐tissue exosome release to mediate intercellular communication; (3) Exosomes systemically regulate muscle, nerve, immune and vascular functions; (4) Target gene knockout confirms exosomes’ specific mediating role.

Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell–cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.

The rapid development of computer science over the past few decades has led to unprecedented progress in the field of artificial intelligence (AI). Its wide application in ophthalmology, especially image processing and data analysis, is particularly extensive and its performance excellent. In recent years, AI has been increasingly applied in optometry with remarkable results. This review is a summary of the application progress of different AI models and algorithms used in optometry (for problems such as myopia, strabismus, amblyopia, keratoconus, and intraocular lens) and includes a discussion of the limitations and challenges associated with its application in this field.