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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.

Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.

Nowadays, electricity theft has been a major problem worldwide. Although many single-classification algorithms or an ensemble of single learners (i.e., homogeneous ensemble learning) have proven able to automatically identify suspicious customers in recent years, after the accuracy of these methods reaches a certain level, it still cannot be improved even if it continues to be optimized. To break through this bottleneck, a heterogeneous ensemble learning method with stacking integrated structure of different strong individual learners for detection of electricity theft is presented in this paper. Firstly, we use the grey relation analysis (GRA) method to select the heterogeneous strong classifier combination of LG + LSTM + KNN as the base model layer of stacking structure based on the principle of the highest comprehensive evaluation index value. Secondly, the support vector machine (SVM) model with relatively good results of the stacking overall structure experiment is selected as the model of the meta-model layer. In this way, a heterogeneous integrated learning model for electricity theft detection of the stacking structure is constructed. Finally, the experiments of this model are conducted on electricity consumption data from State Grid Corporation of China, and the results show that the detection performance of the proposed method is better than that of the existing state-of-the-art detection method (where the area under receiver operating characteristic curve (AUC) value is 0.98675).

Diabetic wounds are a common and challenging complication of diabetes, characterized by delayed healing and increased risk of infection. Current treatment methods are limited and often ineffective in promoting wound repair. Mesenchymal stem cell (MSC)-derived exosomes have shown promise in regenerative medicine, but enhancing their therapeutic potential remains a key area of research. In this study, MSCs were pretreated with empagliflozin (EMPA), and exosomes were isolated using ultracentrifugation. The morphology, size, and protein markers of EMPA-Exos were characterized. Their effects on human umbilical vein endothelial cells (HUVECs) were assessed using EdU assays, CCK-8 assays, scratch assays, Transwell assays, and Matrigel tube formation assays. The PTEN/AKT/VEGF signaling pathway was analyzed through Western blotting. In vivo, diabetic mouse wound models were used to evaluate the healing efficacy of EMPA-Exos. EMPA pretreatment enhanced the functional properties of MSC-derived exosomes, significantly improving HUVECs' proliferation, migration, invasion, and angiogenesis compared to non-pretreated exosomes (P < 0.05). Transcriptomic analysis and pathway activation studies revealed that EMPA-Exos promoted angiogenesis through the PTEN/AKT/VEGF signaling pathway. In vivo experiments demonstrated accelerated wound healing and increased vascularization in diabetic mice treated with EMPA-Exos (P < 0.05). EMPA-pretreated MSC-derived exosomes effectively enhance angiogenesis and accelerate diabetic wound healing by activating the PTEN/AKT/VEGF signaling pathway. This strategy offers a promising approach for improving diabetic wound repair and provides a potential new therapeutic avenue in regenerative medicine.

To determine the relevance of morphometric properties attributed to the meat yield and fatness index of the saltwater hard clam Meretrix meretrix . A new strain of M . meretrix with red shell color was produced after five generations of selection within a family of full-sibs. 7 morphometric traits, including shell length ( SL ), shell height ( SH ), shell width ( SW ), ligament length ( LL ), projection length ( PL ), projection width ( PW ), and live body weight ( LW ), and 2 meat characteristics, including meat yield ( MY ) and fatness index ( FI ) were measured from 50 individuals of three-year-old M . meretrix . The correlation coefficients, path coefficients, determination coefficients among attributes were analyzed. The results indicated that correlation achieved very significant levels ( P <0.01). In addition, the multiple regression equations were formulated by considering the meat yield and fatness index as the dependent variables, respectively, and 7 other morphometric traits as independent variables. The correlation indices ( R 2 ) of morphometric traits against the meat yield and fatness index of clams were 0.901 and 0,929, respectively, indicating that the live body weight and shell length were the common main factors influencing the meat characteristics. By testing the significance of partial regression coefficient and gradually removing the non-significant morphometric traits, a multiple regression equation was established to estimate the relationship between shell length ( SL , mm), live body weight ( LW , g), ligament length ( LL , mm) and meat yield ( MY , %), fat index ( FI , %): MY (%) = 0.432 SL +0.251 LW and FI (%) = 0.156 SL +0.067 LL +0.42 LW -3.533. The study draws a conclusion that live body weight and shell length have a predominant direct effect on the meat yield and fatness index, which provides theoretical information for the breeding of M . meretrix .

Pyoderma, commonly known as impetigo, is a bacterial skin infection causing pus formation, prevalent globally, especially in resource-poor areas. It affects both children and adults, including those with conditions like diabetes. Despite its significant impact and economic burden, research on its global epidemiology is limited. This study aims to address this gap by analyzing pyoderma trends from 1990 to 2019 using GBD data. The study aims to analyze global trends in pyoderma epidemiology from 1990 to 2019 using GBD data. Specifically, it investigates Age-Standardized Incidence Rate (ASIR), Mortality Rate (ASMR), and Disability-Adjusted Life Years Rate (ASDR) across 204 countries. Additionally, it provides insights into demographic and socioeconomic factors influencing pyoderma prevalence. Furthermore, it forecasts pyoderma’s development trends for the next decade to inform public health strategies. Data were sourced from the GBD 2019 database, comprising various sources such as censuses, surveys, and registries. Estimates for pyoderma incidence, mortality, and DALYs, along with their 95% uncertainty intervals (UI), were retrieved. The Sociodemographic Index (SDI) was used to assess socioeconomic status, and statistical calculations were performed using the WHO Health Equity Assessment Toolkit and R software (v4.3.2). From 1990 to 2019, the Age-Standardized Incidence Rate (ASIR) and Age-Standardized Mortality Rate (ASMR) of impetigo increased, while the Age-Standardized Disability-Adjusted Life Years Rate (ASDR) declined. Significant global geographical heterogeneity persists, closely associated with the Sociodemographic Index (SDI). Children under 5 and the elderly are particularly at risk, with lower SDI nations bearing higher burdens. Population growth and aging contribute to this rise, with disparities in impetigo trends persisting among countries and regions with varying SDI levels, expected to continue until 2030. Pyoderma exhibits significant heterogeneity across age, gender, and geography, with pronounced disparities evident in underdeveloped regions or countries. Therefore, prioritizing policy formulation and implementing tailored prevention and treatment strategies for high-risk populations are imperative to alleviate the disease burden effectively. Such targeted approaches are crucial in addressing the global impact of pyoderma.

Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects. Hydroxycarboxylic acid receptor 2 (HCAR2) has been implicated in cardiovascular and neuroinflammatory diseases. Here, the authors present cryo-EM structures of HCAR2-Gi1 complexes bound to different ligands and provide insights into the mechanisms of both orthosteric and allosteric modulation of HCAR2.

Colorectal cancer (CRC) is the third most common malignancy, with increasing prevalence and mortality. How the ethoxy-erianin phosphate (EBTP) mediates CRC development remains unclear. Therefore, the current study evaluated the effects of EBTP on the proliferation, migration, and angiogenesis of CRC cells using CCK-8, Wound-healing, Transwell, and Tube formation assays. RNA sequencing and molecular docking techniques helped predict that EBTP could inhibit angiogenesis by regulating PIK3R2 expression while clarifying the mechanism behind EBTP-mediated CRC angiogenesis. Subsequently, several in vitro experiments indicated that PIK3R2 overexpression significantly improved the proliferation, migration, and angiogenesis of CRC cells while knocking down PIK3R2 expression inhibited their proliferation, migration, and angiogenesis. Simultaneously, PIK3R2 expression in CRC cells gradually decreased with increased EBTP concentration and action duration. Moreover, PIK3R2 overexpression in CRC cells could reverse the inhibitory EBTP effect in angiogenesis. Mouse experiments also depicted that EBTP inhibited CRC angiogenesis by down-regulating PIK3R2 expression. In addition, EBTP could inhibit PI3K/AKT pathway activity and indirectly control PIK3R2 expression through the lncRNA TMPO-AS1/miR-126-3p axis. Our findings highlighted that EBTP could inhibit CRC angiogenesis using the TMPO-AS1/miR-126-3p/PIK3R2/PI3k/AKT axis, providing a novel strategy for anti-angiogenic therapy in CRC.

Sol–gel processed zinc oxide (ZnO) is one of the most widely used electron transport layers (ETLs) in inverted organic solar cells (OSCs). The high annealing temperature (≈200 °C) required for sintering to ensure a high electron mobility however results in severe damage to flexible substrates. Thus, flexible organic solar cells based on sol–gel processed ZnO exhibit significantly lower efficiency than rigid devices. In this paper, an indium‐doping approach is developed to improve the optoelectronic properties of ZnO layers and reduce the required annealing temperature. Inverted OSCs based on In‐doped ZnO (IZO) exhibit a higher efficiency than those based on ZnO for a range of different active layer systems. For the PM6:L8‐BO system, the efficiency increases from 17.0% for the pristine ZnO‐based device to 17.8% for the IZO‐based device. The IZO‐based device with an active layer of PM6:L8‐BO:BTP‐eC9 exhibits an even higher efficiency of up to 18.1%. In addition, a 1.2‐micrometer‐thick inverted ultrathin flexible organic solar cell is fabricated based on the IZO ETL that achieves an efficiency of 17.0% with a power‐per‐weight ratio of 40.4 W g−1, which is one of the highest efficiency for ultrathin (less than 10 micrometers) flexible organic solar cells. An indium‐doped zinc oxide (IZO) electron transport layer (ETL) is developed for high‐efficiency inverted organic solar cells, and indium doping can improve electron extraction and suppress charge recombination. A 1.2‐micrometer‐thick ultrathin flexible OSC achieves an efficiency of 17.0% with a power‐per‐weight ratio of 40.4 W g−1, which is one of the highest values among ultrathin flexible organic solar cells.