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Abstract Delta opioid receptor (δOR) plays a pivotal role in modulating human sensation and emotion. It is an attractive target for drug discovery since, unlike Mu opioid receptor, it is associated with low risk of drug dependence. Despite its potential applications, the pharmacological properties of δOR, including the mechanisms of activation by small-molecule agonists and the complex signaling pathways it engages, as well as their relation to the potential side effects, remain poorly understood. In this study, we use cryo-electron microscopy (cryo-EM) to determine the structure of the δOR-Gi complex when bound to a small-molecule agonist (ADL5859). Moreover, we design a series of probes to examine the key receptor-ligand interaction site and identify a region involved in signaling bias. Using ADL06 as a chemical tool, we elucidate the relationship between the β-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the β-arrestin recruitment of δOR might be linked to reduced gastrointestinal motility. These insights enhance our understanding of δOR’s structure, signaling pathways, and biological functions, paving the way for the structure-based drug discovery.

Abstract Background Simultaneous bilateral total hip arthroplasty (SI-THA) results in more blood loss and a greater need for postoperative allogeneic blood transfusion (ABT). Previous studies have reported that multimodal patient blood management (PBM) strategies were associated with a smaller effect of intraoperative cell salvage (ICS) in unilateral total hip arthroplasty. However, there are few studies on the role of ICS in SI-THA. This study aims to explore the effect of ICS with multimodal PBM strategies on SI-THA and to identify risk factors associated with ABT. Methods This retrospective matched cohort study included 72 patients in the ICS group and 72 patients in the control group who were matched according to age, sex, and year of hospitalization. Demographic data, hematological indicators, blood loss, and ABT were compared between the two groups. Logistic regression analysis was performed to identify independent risk factors for postoperative ABT. Postoperative outcomes were also recorded. Results In the cohort of 144 patients, 27 patients (37.5%) in the ICS group while 45 patients (62.5%) in the control group received postoperative ABT after SI-THA. Compared with the control group, the ICS group showed significant differences in terms of blood loss, postoperative hemoglobin and hematocrit. The transfused volume of allogeneic red blood cells per ABT patient was also lower in the ICS group. Multivariate logistic regression analysis indicated that sex, the utilization of ICS, and preoperative hematocrit level were identified as independent factors associated with postoperative ABT. The utilization of ICS significantly shortened off-bed time and length of hospital stay, but had no effect on early pain and functional outcomes. Conclusion The utilization of ICS can significantly affect postoperative ABT in SI-THA patients with multimodal PBM strategies. Sex, the utilization of ICS and preoperative hematocrit level were identified as independent factors associated with postoperative ABT. The utilization of ICS promoted weight-bearing functional exercises, but had no effect on early outcomes.

Aiming at the influence of hard and thick roof fracture and structural evolution on the impact of working face, taking the hard and thick roof condition of 63 upper 05 working face in Dongtan Coal Mine as the engineering background, the critical condition and structural evolution process of hard and thick roof fracture and instability are studied by theoretical analysis and numerical simulation, and the dangerous area of working face impact is divided. It is concluded that the thickness and strength of the roof are proportional to the vertical load at the end of the block breaking. The structure of immediate roof and main roof gradually evolved from “V” type to “U” type. The first and periodic steps of the double hard thick roof increase obviously compared with the conventional condition, and the evolution of the basic roof structure is more retarded than that of the direct roof. The vertical stress of the roof evolves in the form of stress arch, and many stress concentration phenomena are formed in the mined-out area during mining. Based on the above research results, the impact danger area of 63 upper 05 working face was divided and the accuracy was verified by microseismic monitoring technology.

Multifunctional therapeutics have emerged as a solution to the constraints imposed by drugs with singular or insufficient therapeutic effects. The primary challenge is to integrate diverse pharmacophores within a single-molecule framework. To address this, we introduced DeepSA, a novel edit-based generative framework that utilizes deep simulated annealing for the modification of articaine, a well-known local anesthetic. DeepSA integrates deep neural networks into metaheuristics, effectively constraining molecular space during compound generation. This framework employs a sophisticated objective function that accounts for scaffold preservation, anti-inflammatory properties, and covalent constraints. Through a sequence of local editing to navigate the molecular space, DeepSA successfully identified AT-17, a derivative exhibiting potent analgesic properties and significant anti-inflammatory activity in various animal models. Mechanistic insights into AT-17 revealed its dual mode of action: selective inhibition of NaV1.7 and 1.8 channels, contributing to its prolonged local anesthetic effects, and suppression of inflammatory mediators via modulation of the NLRP3 inflammasome pathway. These findings not only highlight the efficacy of AT-17 as a multifunctional drug candidate but also highlight the potential of DeepSA in facilitating AI-enhanced drug discovery, particularly within stringent chemical constraints.

BackgroundIn patients with tibial plateau bone cysts undergoing total knee arthroplasty (TKA), bone defects commonly occur following tibial plateau resection. Current strategies for addressing these defects include bone grafting, bone cement filling, and the cement-screw technique. However, there remains no consensus on the optimal approach to achieve the best surgical outcomes. This study aims to evaluate the most effective repair method for residual bone defects following tibial plateau bone cyst repair during TKA from a biomechanical perspective.MethodsThe treatment options for tibial plateau bone defects were classified into four categories: no treatment, cancellous bone filling, bone cement filling, and the cement-screw technique. Finite-element analysis (FEA) was employed to evaluate stress distribution and displacement across the models for each treatment group. In addition, static compression mechanical tests were used to assess the displacement of the models within each group.ResultsFEA results indicate that when employing the cement-screw technique to repair tibial plateau bone defects, the maximum stress on the prosthesis and the cement below the prosthesis is minimized, while the maximum stress on the cancellous bone is maximized. And the displacement of each component is minimized. Biomechanical tests results further demonstrate that the displacement of the model is minimized when utilizing the cement-screw technique for tibial plateau bone defects.ConclusionUsing cement-screw technique in treating residual tibial bone defects due to bone cysts in TKA offers optimal biomechanical advantages.

Breast cancer (BRCA) is the most common cancer among women. Adriamycin (ADR), also known as doxorubicin (Dox), is a commonly used chemotherapeutic agent for BRCA patients, however, the susceptibility of tumor cells to develop resistance to Dox has severely limited its clinical use. One new promising therapeutic target for breast cancer patients is exosomes. The objective of this study was to investigate the role of exosomes in regulating Dox resistance in BRCA.In this study, the exosomes from both types of cells were extracted by differential centrifugation. The effect of exosomes on drug resistance was assessed by laser confocal microscopy, MTT assay, and qRT-PCR. The miRNA was transfected into cells using Lipofectamine 2000, which was then evaluated for downstream genes and changes in drug resistance.Exosomes from MCF-7 cells (MCF-7/exo) and MCF-7/ADR cells (ADR/exo) were effectively extracted in this study. The ADR/exo was able to endocytose MCF-7 cells and make them considerably more resistant to Dox. Moreover, we observed a significant difference in miR-34a-5p expression in MCF-7/ADR and ADR/exo compared to MCF-7 and MCF-7/exo. Among the miR-34a-5p target genes, NOTCH1 displayed a clear change with a negative correlation. In addition, when miR-34a-5p expression was elevated in MCF-7/ADR cells, the expression of miR-34a-5p in ADR/exo was also enhanced alongside NOTCH1, implying that exosomes may carry miRNA into and out of cells and perform their function.In conclusion, exosomes can influence Dox resistance in breast cancer cells by regulating miR-34a-5p/NOTCH1. These findings provide novel insights for research into the causes of tumor resistance and the enhancement of chemotherapy efficacy in breast cancer.

According to the World Health Organization's world report on hearing, nearly 2.5 billion people worldwide will suffer from hearing loss by 2050, which may contribute to a severe impact on individual life quality and national economies. Sensorineural hearing loss (SNHL) occurs commonly as a result of noise exposure, aging, and ototoxic drugs, and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear, which is mainly triggered by reactive oxygen species accumulation, inflammation, and mitochondrial dysfunction. Though recent advances have been made in understanding the ability of cochlear repair and regeneration, there are still no effective therapeutic drugs for SNHL. Chinese herbal medicine which is widely distributed and easily accessible in China has demonstrated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine. Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL, and elucidate their molecular mechanisms of action, to pave the way for further research and development of novel effective drugs in this field.

The storage time of rice determines its quality and nutritional value, and the longer the storage time, the greater the impact. In this study, different excitation wavelengths (405 nm, 365 nm, 310 nm) were used to detect the fluorescence spectrum of “Dongdao 12” brown rice. Support vector machine (SVM), K-nearest neighbor (KNN), and wide neural network (WNN) were used for modeling and analysis. Under the excitation of 310 nm, the accuracy of WNN classification is up to 99.2%. In order to reduce the scattering effect and other interference in the data, multiplicative scatter correction (MSC), standard normal variable (SNV), and Savitzky–Goray smoothing (SG) preprocessing methods were used. The results showed that SG + KNN classification achieved an accuracy of 99.3% under 310 nm excitation. In order to further improve the classification accuracy, the original spectrum and the preprocessed spectrum under different excitation light sources were fused. The classification accuracy of all methods was improved, and the original data fusion was combined with the WNN model to reach 100%. It shows that fluorescence spectroscopy has excellent potential in identifying rice storage years.

The origin of agricultural products significantly influences their quality and safety. Fluorescence spectroscopy was used to analyse Japonica rice 830, grown in different areas of Jilin Province, by examining rice seed, brown rice, and rice flour from 12 origins. Fluorescence spectra were pre-processed through normalisation and smoothing to remove noise. These processed spectra were input into decision trees, support vector machines (SVMs), K-nearest neighbour (KNN), and neural network models for classification. The analysis revealed that the combined four models achieved an average classification accuracy of 98.05% with a computation time of 180 s, while the reduced-scale models improved accuracy to 98.36% and reduced computation time to 11.25 s. Additionally, prediction models using standard rice starch content values across different states achieved R² values over 0.8. This method provides a rapid, precise approach for assessing rice quality and origin, demonstrating significant potential for application in rice analysis.

Background and objectiveStent-assisted coil (SAC) embolization is a commonly used endovascular treatment for unruptured intracranial aneurysms (UIAs) but can be associated with symptomatic delayed intracerebral hemorrhage (DICH). Our study aimed to investigate the hemodynamic risk factors contributing to DICH following SAC embolization and to establish a classification for DICH predicated on hemodynamic profiles.MethodsThis retrospective study included patients with UIAs located in the internal carotid artery (ICA) treated with SAC embolization at our institution from January 2021 to January 2022. We focused on eight patients who developed postoperative DICH and matched them with sixteen control patients without DICH. Using computational fluid dynamics, we evaluated the hemodynamic changes in distal arteries [terminal ICA, the anterior cerebral artery (ACA), and middle cerebral artery (MCA)] pre-and post-embolization. We distinguished DICH-related arteries from unrelated ones (ACA or MCA) and compared their hemodynamic alterations. An imbalance index, quantifying the differential in flow velocity changes between ACA and MCA post-embolization, was employed to gauge the flow distribution in distal arteries was used to assess distal arterial flow distribution.ResultsWe identified two types of DICH based on postoperative flow alterations. In type 1, there was a significant lower in the mean velocity increase rate of the DICH-related artery compared to the unrelated artery (−47.25 ± 3.88% vs. 42.85 ± 3.03%; p

In order to study the mechanical response and crack evolution law of different lithologic rock bodies under different stress environments in deep stress mines, based on the deviator stress theory, the actual triaxial disturbance unloading rock test system was used to simulate the stress occurrence environment of the original rock. The mechanical characteristics of different σ2 coal rock masses were studied, and the crack evolution law of coal and sandstone under different stress environments was analyzed. The results show that the increase of σ2 inhibits the deformation in the σ2 direction of coal and sandstone, promotes the expansion and deformation in the σ3 direction, and enhances its peak strength and elastic modulus. The development characteristics of internal cracks in rock mass are directly related to the stress environment, and the increase of σ2 promotes the increase of the proportion of coal RA value, weakens the proportion of sandstone RA value, aggravates the development of coal internal shear cracks, and inhibits the development of internal shear cracks in sandstone. The larger σ2, the greater the initial AE ringing count of coal and sandstone, and the greater the AE cumulative energy when the rock mass is finally damaged. At the same time, due to the self-organizing behavior in the process of crystal failure in sandstone, the cumulative energy curve of sandstone fluctuates in a step-like manner. The ringing count and cumulative energy increase suddenly, which can predict the imminent instability and failure of the rock, and the research results can provide an experimental basis for the sudden instability of deep high-stress roadways.

Titanite is a widespread accessory mineral in igneous, metamorphic, and hydrothermal rocks, but few comply with gem-grade requirements. Previous studies on Moroccan titanite focused on elementary composition and U-Pb dating. In this study, two gem-grade titanites (MA-1 and MA-2) from the Moroccan Central High Atlas were investigated through gemological and chemical studies, including infrared spectrum, Raman spectrum, SEM-EDS, and LA-ICP-MS. Two titanite samples are yellow, transparent–translucent with a greasy luster, 3.5 and 2.5 mm long. MA-1 and MA-2 have similar gemological properties, the refractive index (RI) is beyond the range of the refractometer (>1.78), the specific gravity (SG) values fall in the range of 3.52~3.54 and both are inert to short-wave and long-wave UV radiation. The spectral characteristics have high consistency with the RRUFF database. The major elements’ composition shows a negative correlation between Al, Fe, V, and Ti, suggesting the titanites underwent substitutions such as (Al, Fe3+) + (F, OH) ↔ Ti + O. The titanite samples, characterized by a low abundance of REE (802~4088 ppm) and enriched in LREE, exhibit positive Eu (δEu: 1.53~7.79) and Ce (δCe: 1.08~1.33) anomalies, indicating their formation in a hydrothermal environment with low oxygen fugacity. The 238U/206Pb and 207Pb/206Pb ratios of the titanites yield lower intercept ages of 152.6 ± 2.2 and 151.4 ± 5.3 Ma (1s), consistent with their weighted average 206Pb/238U ages of 152.3 ± 2.0 and 150.7 ± 3.2 Ma (1s) respectively. The results of U-Pb dating are matched with the second main magmatic activities in the High Atlas intracontinental belt of Morocco during the Mesozoic to Cenozoic period. Moreover, the two titanite samples have almost no radiational damage. All the results show that the titanite from High Atlas, Morocco, has the potential to be a reference material for LA-ICP-MS U–Pb dating, but further experiments are needed to be sure.

Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, β9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and β-arrestin signaling pathways. The activation of diverse pathways could result in on-target side effects and cannabis addiction, which may hinder therapeutic potential. A significant challenge in pharmacology is the design of a ligand that can modulate specific signaling of CB1. By leveraging insights from the structure-function selectivity relationship (SFSR), we have identified Gi signaling-biased agonist-allosteric modulators (ago-BAMs). Further, two cryoelectron microscopy (cryo-EM) structures reveal the binding mode of ago-BAM at the extrahelical allosteric site of CB1. Combining mutagenesis and pharmacological studies, we elucidated the detailed mechanism of ago-BAM-mediated biased signaling. Notably, ago-BAM CB-05 demonstrated analgesic efficacy with fewer side effects, minimal drug toxicity and no cannabis addiction in mouse pain models. In summary, our finding not only suggests that ago-BAMs of CB1 provide a potential nonopioid strategy for pain management but also sheds light on BAM identification for GPCRs. [ABSTRACT FROM AUTHOR]

The promotion of energy efficiency (EE) helps address energy constraints and promote environmental sustainability. This study comprehensively explores the spatiotemporal variations, influencing factors, and configuration promotion paths of EE in 284 Chinese cities during 2003-2019 using the global super-efficiency minimum distance to strong efficient frontier (G-S-MinDS), exploratory spatial data analysis (ESDA), multiscale geographically weighted regression (MGWR), and fuzzy set qualitative comparative analysis (fsQCA) methods. The findings are: (1) China' s cities have an annual average EE of 0.658 with a growth rate of 0.53%, showing considerable promotion potential. (2) Industrial structure optimization, population agglomeration, economic development, and increased green coverage contribute positively, while government intervention and openness hinder China' s urban EE. (3) Four configurational promotion paths for enhancing China' s urban EE are identified, where among those paths population density is a core condition, while government intervention is not. This study provides valuable insights into substantially improving urban EE, emphasizing the need for targeted policies to address energy and environmental crises in China. [ABSTRACT FROM AUTHOR]

The sources of fluids and metals in porphyry systems of continental-collision settings are poorly constrained. Mercury isotopes display unique mass-independent fractionation (expressed as Δ199Hg) and may provide important constraints on metal and volatile sources given that Hg is a highly volatile metal. Here, we report Hg isotope data on ore-forming porphyries, barren magmatic rocks, and mantle-derived mafic magmas from southern Tibet. The fertile porphyries and coeval mafic magmas display mainly positive Δ199Hg values (up to +0.25 per mil), while Δ199Hg values in barren magmatic rocks and mafic magmas are largely negative (-0.54 to 0.00 per mil). The positive Δ199Hg values observed here are consistent with seawater and marine sediments, suggesting that the ultimate source of fluids involved in the genesis of post-subduction porphyry copper deposits was the mantle lithosphere metasomatized by previous oceanic plate subduction. Our Hg isotope data provide an alternative view to current metallogenetic models on collisional porphyry systems that focus on melting of the lower continental crust. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV), a leading cause of lower respiratory tract infection (LRTI) among children, has resurged in the form of endemic or even pandemic in many countries and areas after the easing of COVID-19 containment measures. This study aimed to investigate the differences in epidemiological and clinical characteristics of children hospitalized for RSV infection during pre- and post-COVID-19 eras in Yunnan, China., Methods: A total of 2553 pediatric RSV inpatients from eight hospitals in Yunnan were retrospectively enrolled in this study, including 1451 patients admitted in 2018-2019 (pre-COVID-19 group) and 1102 patients admitted in 2023 (post-COVID-19 group). According to the presence or absence of severe LRTI (SLRTI), patients in the pre- and post-COVID-19 groups were further divided into the respective severe or non-severe subgroups, thus analyzing the risk factors for RSV-associated SLRTI in the two eras. Demographic, epidemiological, clinical, and laboratory data of the patients were collected for the final analysis., Results: A shift in the seasonal pattern of RSV activity was observed between the pre-and post-COVID-19 groups. The peak period of RSV hospitalizations in the pre-COVID-19 group was during January-April and October-December in both 2018 and 2019, whereas that in the post-COVID-19 group was from April to September in 2023. Older age, more frequent clinical manifestations (fever, acute otitis media, seizures), and elevated laboratory indicators [neutrophil-to-lymphocyte ratio (NLR), c-reactive protein (CRP), interleukin 6 (IL-6), co-infection rate] were identified in the post-COVID-19 group than those in the pre-COVID-19 group (all P < 0.05). Furthermore, compared to the pre-COVID-19 group, the post-COVID-19 group displayed higher rates of SLRTI and mechanical ventilation, with a longer length of hospital stay (all P < 0.05). Age, low birthweight, preterm birth, personal history of atopy, underlying condition, NLR, IL-6 were the shared independent risk factors for RSV-related SLRTI in both pre- and post-COVID-19 groups, whereas seizures and co-infection were independently associated with SLRTI only in the post-COVID-19 group., Conclusions: An off-season RSV endemic was observed in Yunnan during the post-COVID-19 era, with changed clinical features and increased severity. Age, low birthweight, preterm birth, personal history of atopy, underlying condition, NLR, IL-6, seizures, and co-infection were the risk factors for RSV-related SLRTI in the post-COVID-19 era., (© 2024. The Author(s).)

Introduction: Off-season upsurge of respiratory syncytial virus (RSV) infection with changed characteristics and heightened clinical severity during the post-COVID-19 era are raising serious concerns. This study aimed to develop and validate a nomogram for predicting the risk of severe acute lower respiratory tract infection (SALRTI) in children hospitalized for RSV infection during the post-COVID-19 era using machine learning techniques., Methods: A multicenter retrospective study was performed in nine tertiary hospitals in Yunnan, China, enrolling children hospitalized for RSV infection at seven of the nine participating hospitals during January-December 2023 into the development dataset. Thirty-nine variables covering demographic, clinical, and laboratory characteristics were collected. Primary screening and dimension reduction of data were performed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, followed by identification of independent risk factors for RSV-associated SALRTI using Logistic regression, thus finally establishing a predictive nomogram model. Performance of the nomogram was internally evaluated by receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) based on the development dataset. External validation of our model was conducted using same methods based on two independent RSV cohorts comprising pediatric RSV inpatients from another two participating hospitals between January-March 2024., Results: The development dataset included 1102 patients, 239 (21.7%) of whom developed SALRTI; while the external validation dataset included 249 patients (142 in Lincang subset and 107 in Dali subset), 58 (23.3%) of whom were diagnosed as SALRTI. Nine variables, including age, preterm birth, underlying condition, seizures, neutrophil-lymphocyte ratio (NLR), interleukin-6 (IL-6), lactate dehydrogenase (LDH), D-dimer, and co-infection, were eventually confirmed as the independent risk factors of RSV-associated SALRTI. A predictive nomogram was established via integrating these nine predictors. In both internal and external validations, ROC curves indicated that the nomogram had satisfactory discrimination ability, calibration curves demonstrated good agreement between the nomogram-predicted and observed probabilities of outcome, and DCA showed that the nomogram possessed favorable clinical application potential., Conclusion: A novel nomogram combining several common clinical and inflammatory indicators was successfully developed to predict RSV-associated SALRTI. Good performance and clinical effectiveness of this model were confirmed by internal and external validations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Zhang, Liu, Li, Li, Wang, Li, Xiang, Lu, Yuan and Fu.)