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Ketamine, an N -methyl- d -aspartate receptor (NMDAR) antagonist 1 , has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects 2 – 4 . Although the elimination half-life of ketamine is only 13 min in mice 5 , its antidepressant activities can last for at least 24 h 6 – 9 . This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine–NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine–NMDAR interactions opens up new opportunities for the therapeutic use of ketamine. The discrepancy between the short half-life of ketamine and its long-lasting effects is due to ketamine being trapped in NMDA receptors, and its release depends on neural activity in the lateral habenula.

Analysis at high temporal and spatial resolution shows that the number and dynamics of SNARE proteins available during exocytosis determines the size and stability of fusion pores. Membrane pores ruled by SNAREs A critical early event during exocytosis is the transient formation of fusion pores in the cell membrane. Edwin Chapman and colleagues provide insights into the regulation of the size and kinetics of these structures. They were intrigued that, in neurons, reducing the number of SNARE proteins, which mediate membrane fusion and thus pore formation, results in changes in both neurotransmitter release and fusion pores. To investigate how these alterations come about, they used in vitro reconstitution analyses with microsecond time resolution and single-event space resolution. The analyses reveal that the number of SNARE proteins affects not only the rate of cargo release from individual pores, but also the size and stability of the pores and, consequently, the size of the released cargo. This approach also reveals that mimicking the action of botulinum neurotoxin A reduces fusion pore stability. The fusion pore is the first crucial intermediate formed during exocytosis, yet little is known about the mechanisms that determine the size and kinetic properties of these transient structures 1 . Here, we reduced the number of available SNAREs (proteins that mediate vesicle fusion) in neurons and observed changes in transmitter release that are suggestive of alterations in fusion pores. To investigate these changes, we employed reconstituted fusion assays using nanodiscs to trap pores in their initial open state. Optical measurements revealed that increasing the number of SNARE complexes enhanced the rate of release from single pores and enabled the escape of larger cargoes. To determine whether this effect was due to changes in nascent pore size or to changes in stability, we developed an approach that uses nanodiscs and planar lipid bilayer electrophysiology to afford microsecond resolution at the single event level. Both pore size and stability were affected by SNARE copy number. Increasing the number of vesicle (v)-SNAREs per nanodisc from three to five caused a twofold increase in pore size and decreased the rate of pore closure by more than three orders of magnitude. Moreover, pairing of v-SNAREs and target (t)-SNAREs to form trans -SNARE complexes was highly dynamic: flickering nascent pores closed upon addition of a v-SNARE fragment, revealing that the fully assembled, stable SNARE complex does not form at this stage of exocytosis. Finally, a deletion at the base of the SNARE complex, which mimics the action of botulinum neurotoxin A, markedly reduced fusion pore stability. In summary, trans -SNARE complexes are dynamic, and the number of SNAREs recruited to drive fusion determines fundamental properties of individual pores.

Deer antler-derived medicinal materials, including antler velvet, antlers, and deer antler base, exhibit differential therapeutic efficacy across developmental stages, though their molecular mechanisms at the proteomic level remain uncharacterized. This study employed Data-Independent Acquisition (DIA) quantitative proteomics to systematically analyze protein profiles in sika deer antler velvet, antlers, and deer antler base. Comparative analysis revealed 3154 differentially expressed proteins (DEPs, 95% upregulated) between antler velvet and antlers, which were significantly enriched in Ribosome Biogenesis (e.g., Polyadenylate-binding protein), oxidative phosphorylation, and neurodegenerative disease pathways. In the comparison of deer antler base versus antlers, 1024 DEPs (92% upregulated) were identified, primarily involved in proteolysis (e.g., ACTC protein), glycolysis, and complement and coagulation cascades. Between deer antler base and antler velvet, 2749 DEPs (87% downregulated) were enriched in Thioredoxin domains, cytoskeleton regulation, and RNA-binding functions. Subcellular localization demonstrated antler velvet proteins predominantly distributed in the cytoplasm (37.6%) and nucleus (19.6%), while deer antler base proteins showed marked enrichment in extracellular regions (19.7%) and cytoskeletal components. As the first comprehensive proteomic characterization of these materials, this study identifies ribosomal proteins and complement pathway-related proteins as key biomarkers, thus establishing a scientific foundation for precise authentication, quality control, and efficacy–mechanism interpretation of deer antler-derived medicines. It further highlights antler velvet’s neuroprotective potential and deer antler base’s immunomodulatory applications.

Physiological response to thermal stimuli in mammals is mediated by a structurally diverse class of ion channels, many of which exhibit polymodal behavior. To probe the diversity of biophysical mechanisms of temperature-sensitivity, we characterized the temperature-dependent activation of MthK, a two transmembrane calcium-activated potassium channel from thermophilic archaebacteria. Our functional complementation studies show that these channels are more efficient at rescuing K + transport at 37°C than at 24°C. Electrophysiological activity of the purified MthK is extremely sensitive (Q 10 >100) to heating particularly at low-calcium concentrations whereas channels lacking the calcium-sensing RCK domain are practically insensitive. By analyzing single-channel activities at limiting calcium concentrations, we find that temperature alters the coupling between the cytoplasmic RCK domains and the pore domain. These findings reveal a hitherto unexplored mechanism of temperature-dependent regulation of ion channel gating and shed light on ancient origins of temperature-sensitivity.

Blockchain technology allows fresh agricultural enterprises to share records stored on the chain, and the technology can benefit information management systems, such as decentralization and transparency. This study uses game theory to examine a blockchain introduction strategy for fresh agricultural enterprises in a competitive environment, considering consumer traceability preferences. We establish a pricing decision model in traditional and blockchain traceability modes and identify optimal solutions. Additionally, we analyze the impact of the blockchain introduction strategy, consumer preferences, and blockchain influence factor on optimal pricing decisions. The results indicate that the introduction of blockchain could improve the profits of enterprises under certain conditions. Moreover, consumer traceability preferences and the blockchain influence factor could significantly affect the blockchain introduction strategy. We also discover that when the blockchain influence factor meets a certain range, introducing blockchain technique in the traceability system could shift demand from traditional enterprises to blockchain enterprises. The total market demand for blockchain enterprises under the blockchain traceability mode will increase, whereas that of traditional enterprises under the blockchain traceability mode will decrease. Both consumer traceability preferences and the blockchain influence factor could significantly affect optimal pricing. Finally, some management suggestions are provided for the traceability of fresh agricultural enterprises based on the research conclusions.

(1) Background: Lotus (Nelumbo nucifera Gaertn.) is an aquatic plant with a long history and ornamental, edible, medicinal, and commercial value. All parts of the lotus are important “homologous and different effects” medicinal herbs as distinct parts of the same plant with different medicinal effects. (2) Methods: Six representative medicinal parts of lotus were selected, i.e., the lotus flower (Nelumbinis Flos, Flo), lotus petiole (Nelumbinis Petiolus, Pet), lotus seedpod (Nelumbinis Receptaculum, Rec), lotus stamen (Nelumbinis Stamen, Sta), lotus seed (Nelumbinis Semen, Sem), and lotus plumule (Nelumbinis Plumula, Plu), and analyzed via UPLC-MS/MS for metabolite profiling and RNA sequencing for gene expression. Weighted gene co-expression network analysis identified several transcription factor families related to flavonoid synthesis. (3) Results: Distinct metabolite accumulation and gene expression patterns were observed, particularly in the flavonoid synthesis pathway. Key findings included important metabolic profiles in stamens, high flavonoid content in light-exposed tissues, and functional differentiation in seeds and plumules. The discovered transcription factor families are essential for flavonoid biosynthesis and contribute to molecular breeding and resource utilization. (4) Conclusion: This study provides an important theoretical basis for molecular breeding of lotus, quality control of medicinal materials, and the rational use of resources obtained from different medicinal parts of lotus.

In the global trend of urban shrinkage, urban vitality, as one of the important representations of high-quality urban development, has become a breakthrough. More and more scholars advocate to awaken urban vitality, so as to realize the high-quality development of shrinking cities. This paper takes the municipal districts of 34 cities in the three northeastern provinces of China as study areas, based on the broad concept of urban shrinkage, selects the indicators of population, economy and society, and uses the “two-step diagnostic method” which is consistent with Chinese conditions to identify the urban shrinkage from 2010 to 2018. In this research, the indexes of economic, social, cultural, environmental and spatial dimensions are selected, and the urban vitality and the vitality of each dimension from 2010 to 2018 are calculated and analyzed by using the entropy weight method (EWM). Then, this paper analyzes the correlation between urban shrinkage and urban vitality by Pearson correlation coefficient. The results show that: (1) urban shrinkage in the three northeastern provinces of China has become a regional remarkable phenomenon, which is also an inevitable process in some regions of China and even the world; (2) overall, the urban vitality of cities in the three northeastern provinces of China is steady and rising a little, and there is an obvious spatial agglomeration pattern like “central city polarization”; (3) there is a significant correlation between urban shrinkage and urban vitality, that is, the lower the degree of urban shrinkage, the higher the urban vitality, showing the opposite trend in the process of urban development; (4) the influence of urban shrinkage on each dimension of urban vitality is different, and the correlation results are different, too. In the planning process of shrinking cities in the future, paying attention to the relationship between urban vitality and urban shrinkage, conducting benign guidance on this basis, and adjusting urban vitality elements of different dimensions to stimulate urban development power can enhance urban competitiveness and achieve better development.

Fibrosis is a typical aging-related pathological process involving almost all organs, including the heart, kidney, liver, lung, and skin. Fibrogenesis is a highly orchestrated process defined by sequences of cellular response and molecular signals mechanisms underlying the disease. In pathophysiologic conditions associated with organ fibrosis, a variety of injurious stimuli such as metabolic disorders, epigenetic changes, and aging may induce the progression of fibrosis. Sirtuins protein is a kind of deacetylase which can regulate cell metabolism and participate in a variety of cell physiological functions. In this review, we outline our current understanding of common principles of fibrogenic mechanisms and the functional role of SIRT3/6 in aging-related fibrosis. In addition, sequences of novel protective strategies have been identified directly or indirectly according to these mechanisms. Here, we highlight the role and biological function of SIRT3/6 focus on aging fibrosis, as well as their inhibitors and activators as novel preventative or therapeutic interventions for aging-related tissue fibrosis. Graphical abstract

The Belt and Road Initiative, as an important measure for China in terms of opening up and participating in international economic and trade cooperation, has become a new driving force for the sustainable development of China’s forest products trade. This paper takes the Belt and Road Initiative as a policy event and evaluates its policy effects on the development of China’s forest products trade from the causal level through the difference-in-differences model (DID), explores the policy effect in detail from the perspectives of product heterogeneity and regional heterogeneity, and clarifies the specific impact mechanism. The main results are as follows: (1) there is a significant policy promotion effect of the Belt and Road Initiative on the growth of the bilateral trade scale of forest products between China and the countries along the route. (2) In terms of product structure, the policy promotion effect of the Belt and Road Initiative is mainly manifested in processed wood products. (3) In terms of regional distribution, the policy promotion effects of the Belt and Road Initiative are mainly concentrated in Europe, Africa, and Asia. (4) The “logistics performance, political partnership with China, and Internet penetration” of trading countries play a significant positive mediating role in the policy effects of the Belt and Road Initiative. Therefore, in view of the significant role of the Belt and Road Initiative in promoting the development of bilateral forest products trade, China should promote more countries to participate in the joint construction of the Belt and Road and tap new momentum for the development of the forest products trade by focusing on key countries, priority areas, and key products.

Troposphere augmentation is of great importance for global navigation satellite system (GNSS) real-time precise point positioning (PPP) service. This contribution focuses on the feasibility of modeling the regional troposphere by polynomial fitting and the benefits of precise tropospheric corrections for triple-frequency and multi-GNSS PPP and PPP with integer ambiguity resolution (PPP-IAR) during a period of typhoon weather. A modified optimal fitting coefficient (MOFC) method is proposed with the height-related parameters removed by a priori fitted exponential function. Two spatial scales of networks are chosen to verify the effect of the GNSS station distribution on troposphere modeling. The results show that the MOFC model can provide centimeter-level accuracy with average root mean square (RMS) of 2.1 and 2.2 cm for dense and sparse networks, respectively, while that of GPT2w and real-time VMF3-FC products are 6.6 and 3.3 cm during typhoon periods. PPP/PPP-IAR tests with zenith troposphere delay (ZTD) augmentation based on the MOFC model are conducted when a typhoon eye passes over. Accuracy improvements of 18.2 and 16.6% for vertical components are observed in BDS-only and BDS/Galileo/GPS PPP-IAR solutions with ZTD augmentation, while those for PPP float solutions are marginal. Additionally, 2-h positioning arcs for PPP float solutions and 1224 10-min arcs for PPP-IAR solutions confirm that ZTD augmentation plays an important role in convergence, especially for PPP-IAR solutions. The percentage of instantaneous convergence in BDS-only PPP-IAR solutions improves from 42.1, 44.0 and 18.9% to 51.3, 52.3 and 48.9% for the east, north and up components, respectively, indicating that decorrelation between ZTD and vertical coordinates can be achieved with MOFC ZTD corrections in the initial stage of positioning. The percentages further improved from 89.7, 89.5 and 74.6% to 94.1, 94.2 and 93.7% for BDS/Galileo/GPS PPP-IAR solutions.