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Objectives: Marine biodiversity and ecosystem services in the high seas are threatened by numerous stress factors caused by human activities, including global shipping, high-sea fishing, marine plastic pollution, and anthropogenic climate change. Socioeconomic factors are one of the criteria for the establishment of area-based management tools in the high seas for marine biodiversity conservation beyond national jurisdiction. The aim of the work is to propose a spatiotemporal approach to identify risks from marine human activities and recommendations for high seas governance. Methods: Data related to human activities from 2014 to 2022 were used to calculate the distribution and changes of human-related stressors, and the risk to marine biodiversity in the high seas caused by human activities. Results: The North Atlantic, Philippine Sea, Arabian Sea, Bay of Bengal, and East Central Atlantic show high and increasing intensities of human-related stressors, and are therefore particularly at need for the protection and conservation of marine biodiversity. Risks from human activities vary within the marine areas that are prioritized for biodiversity protection. The study recommends that the designation of high seas protected areas should take into account the types of risks to which the different marine areas are exposed, and that the high seas protected areas should be established gradually. At the same time, appropriate management measures should be formulated according to the intensity of human activities in the different marine areas. Conclusions: Quantifying and classifying the risk from human-related stressors could help identify solution for the protection and conservation and facilitate the marine spatial planning, establishment area based management tools, including marine protected areas in the high seas.

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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 ß-arrestin pathway of the δOR and its biological functions, such as analgesic tolerance and convulsion activities. Notably, we discover that the ß-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.

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BACKGROUND: In total knee arthroplasty (TKA), the practical use of patient-specific instrumentation (PSI) has been reported previously with both advantage and disadvantage. The application of artificial intelligent (AI) forces overwhelmingly development of medical industries, while the impact of AI on PSI efficiency remains unknown. Thus, this study aimed to assess the efficiency of Intelligent-PSI (i-PSI) in TKA, compared with the conventional instrumentation-TKA (CI). METHODS: 102 late-stage OA patients who met inclusive criteria were recruited in this prospective randomized controlled trial and separated into two groups (i-PSI vs. CI). In both groups, an AI preoperative planning engine was applied for surgery decision making. In CI group, conventional instrumentation was applied for bony resection, while resection of i-PSI group was completed with i-PSI. A convolutional neural network was applied to automatically process computer tomography images and thus produced i-PSI. With the help of three-dimension printing, the workflow of production was largely simplified. AI-driven preoperative planning guided resection and alignment decisions. Resection measurement, perioperative radiography and perioperative clinical outcomes were analyzed to verify efficiency of i-PSI. RESULTS: In resection outcomes, smaller deviation of lateral and medial distal femoral resection were found in i-PSI group than CI group (P = 0.032 and 0.035), while no difference was found in other resection planes. In radiography outcomes, postoperative coronal alignments of i-PSI group, including postoperative Hip-knee-ankle axis (HKA) (P = 0.025), postoperative HKA outliners (P = 0.042), Femoral coronal alignment (FCA) (P = 0.019) and Joint line convergence angle (JLCA) (P = 0.043) showed closer to neutral position than CI group. Moreover, Femoral sagittal alignment (FSA) of i-PSI group showed closer to neutral position than CI group(P = 0.005). No difference was found in other alignments. In clinical outcomes, i-PSI group seemed to cost more surgical time than CI group (P = 0.027), while others showed no differences between the two groups. CONCLUSION: Intelligent Patient-specific Instrumentation in TKA achieved simplified production flow than conventional PSI, while also showed more accurate resection, improved synthesis position and limb alignment than conventional instrumentation. Above all, this study proved that i-PSI being an applicable and promising tool in TKA.

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General parenting research indicates parenting shifts, such as declines in parental warmth, parent-child conflict, and parental monitoring and increases in parental autonomy support, as youth progress through adolescence. Culturally and contextually informed scholarship, however, acknowledges that stability and change in parenting behaviors among ethnically and racially minoritized families and across different neighborhood environments may follow distinct patterns. Neighborhood structural disadvantages might disrupt parenting, and parents might adapt parenting in response to neighborhood opportunities and challenges. This study explored stability and change in parenting processes (e.g., conflict, warmth, control, solicitation, autonomy support) from early to middle adolescence among Latinx families across neighborhoods that varied on key characteristics: concentrated poverty, ethnic concentration, and ethnic-racial diversity. Data derived from the "Caminos" study, which utilized an accelerated longitudinal design of 547 Latinx adolescents (MW1age = 13.31 years; 55.4% girls; 89.6% U.S. born). Two-level growth models were used to analyze 10 time points of data following adolescents from Spring of sixth to Fall of 11th grade. Parent-adolescent conflict and warmth declined linearly; parental solicitation showed a curvilinear increase that flattened over time; parental behavioral control and autonomy support remained stable. Some parenting trajectories varied systematically by neighborhood structural characteristics. This study underscored the significance of culturally and contextually informed frameworks for understanding changes in Latinx parenting during offspring adolescence. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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BACKGROUND: Accurate breed identification is essential for the conservation and sustainable use of indigenous farm animal genetic resources. In this study, we evaluated the phylogenetic relationships and genomic breed compositions of 13 sheep breeds using SNP and InDel data from whole genome sequencing. The breeds included 11 Chinese indigenous and 2 foreign commercial breeds. We compared different strategies for breed identification with respect to different marker types, i.e. SNPs, InDels, and a combination of SNPs and InDels (named SIs), different breed-informative marker detection methods, and different machine learning classification methods. RESULTS: Using WGS-based SNPs and InDels, we revealed the phylogenetic relationships between 11 Chinese indigenous and two foreign sheep breeds and quantified their purities through estimated genomic breed compositions. We found that the optimal strategy for identifying these breeds was the combination of DFI_union for breed-informative marker detection, which integrated the methods of Delta, Pairwise Wright's FST, and Informativeness for Assignment (namely DFI) by merging the breed-informative markers derived from the three methods, and KSR for breed assignment, which integrated the methods of K-Nearest Neighbor, Support Vector Machine, and Random Forest (namely KSR) by intersecting their results. Using SI markers improved the identification accuracy compared to using SNPs or InDels alone. We achieved accuracies over 97.5% when using at least the 1000 most breed-informative (MBI) SI markers and even 100% when using 5000 SI markers. CONCLUSIONS: Our results provide not only an important foundation for conservation of these Chinese local sheep breeds, but also general approaches for breed identification of indigenous farm animal breeds.

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Based on the important feature of sulfur with excellent selectivity toward selenite in the presence of selenate, a simple and low-cost adsorbent of solid phase extraction known as sulfur loading activated carbon (SAC-6) was successfully prepared and applied for selenite (Se(IV)) analysis in water. Microstructure and morphological characteristics of SAC-6 had been identified by XRD, TEM, BET and FT-IR. In the static adsorption experiments, Se(IV) could be separated in a wide range of pH values (pH=3-11). The retention process of Se(IV) onto SAC-6 was characterized as spontaneous exothermic reaction. An obvious change of adsorption mechanism occurred in static and dynamic adsorption processes shown that the behaviors followed monolayer and hybrid adsorption. The theoretical maximum adsorption capacity of SAC-6 calculated by Langmuir-Freundlich was 13.48 mg/g. The microcolumn filled with SAC-6 was applied to extract Se(IV) in water solution. The detection limit of Se(IV) analytical procedure was confirmed as 0.27 µg/L within a linear range of 10-1000 µg/L. A good precision with relative standard deviation of 1.34 % (100 µg/L, n = 6) was achieved. The high adaptability and accuracy of SAC-6 microcolumn was validated by analyzing natural water samples and certified reference materials. Our work successfully excavated the application value of the sulfur selectivity, and also provided a new adsorbent for Se(IV) extraction and analysis.

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X-ray ghost imaging with a crystal beam splitter has advantages in highly efficient imaging due to the simultaneous acquisition of signals from both the object beam and reference beam. However, beam splitting with a large field of view, uniform distribution and high correlation has been a great challenge up to now. Therefore, a dedicated beam splitter has been developed by optimizing the optical layout of a synchrotron radiation beamline and the fabrication process of a Laue crystal. A large field of view, consistent size, uniform intensity distribution and high correlation were obtained simultaneously for the two split beams. Modulated by a piece of copper foam upstream of the splitter, a correlation of 92% between the speckle fields of the object and reference beam and a Glauber function of 1.25 were achieved. Taking advantage of synthetic aperture X-ray ghost imaging (SAXGI), a circuit board of size 880 × 330 pixels was successfully imaged with high fidelity. In addition, even though 16 measurements corresponding to a sampling rate of 1% in SAXGI were used for image reconstruction, the skeleton structure of the circuit board can still be determined. In conclusion, the specially developed beam splitter is applicable for the efficient implementation of X-ray ghost imaging.

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OBJECTIVE: To explore the safety and effectiveness of the robot-assisted system for transforaminal percutaneous endoscopic in the treatment of lumbar disc herniation with lumbar instability. METHODS: From October 2021 to March 2023, 26 patients with single-segment lumbar disc herniation and lumbar spinal instability were treated with robot-assisted system for transforaminal percutaneous endoscopic. The operation time, intraoperative blood loss, incision length, postoperative drainage volume, postoperative ambulation activity time, postoperative hospitalization time were record. The intervertebral space height and the lumbar lordosis angle before and after surgery were observed and compared. Pain level was evaluated using the visual analogue scale(VAS). The clinical efficacy was evaluated by Oswestry disability index(ODI). The interbody fusion was evaluated by Brantigan Steffee criteria. RESULTS: All patients successfully completed the operation, the operation time ranged form 105 to 109 min with an average of (150.8±24.1) min. Intraoperative blood loss ranged form 35 to 88 ml with an average of (55.5±16.4) ml. Incision length ranged form 1.4 to 3.5 cm with an average of (2.3±0.8) cm. Postoperative drainage volume ranged form 15 to 40 ml with an average of (28.5±7.8) ml. Postoperative ambulation time ranged form 15 to 30 h with an average of (22.8±4.5) h. Postoperative hospitalization time was 3 to 7 d with an average of (4.2±1.3) d. Total of 26 patients were followed up, the duration ranged from 12 to 16 months with an average of (14.0±1.3) months. The VAS and ODI at 1 week [(2.96±0.72) points, (41.63±4.79)%] and 12 months[(1.27±0.60) points, (13.11±2.45)%] were significantly different from those before surgery[(6.69±0.93) points, (59.12±5.92)%], P<0.01. The height of the intervertebral space (11.95±1.47) mm and lumbar lordosis (57.46±7.59)° at 12 months were significantly different from those before surgery [(6.67±1.20) mm, (44.08±7.79)°], P<0.01. At 12 months after surgery, all patients had no pedicle screw rupture or dislocation of the fusion cage, and the intervertebral fusion was successful. According to Brantigan-Steffee classification, 17 cases were grade D and 9 cases were grade E. CONCLUSION: Robot-assisted system for transforaminal percutaneous endoscopic for the treatment of single-segment lumbar disc herniation with lumbar instability improved the accuracy and safety of the operation, and the clinical effect of early follow-up is accurate.

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The stability of protein folded states is crucial for its function, yet the relationship with the protein sequence remains poorly understood. Prior studies have focused on the amino acid composition and thermodynamic couplings within a single folded conformation, overlooking the potential contribution of protein dynamics. Here, we address this gap by systematically analyzing the impact of alanine mutations in the C-terminal ß-strand (ß5) of ubiquitin, a model protein exhibiting millisecond timescale interconversion between two conformational states differing in the ß5 position. Our findings unveil a negative correlation between millisecond dynamics and thermal stability, with alanine substitutions at seemingly flexible C-terminal residues significantly enhancing thermostability. Integrating spectroscopic and computational approaches, we demonstrate that the thermally unfolded state retains a substantial secondary structure but lacks ß5 engagement, recapitulating the transition state for millisecond dynamics. Thus, alanine mutations that modulate the stabilities of the folded states with respect to the partially unfolded state impact both the dynamics and stability. Our findings underscore the importance of conformational dynamics with implications for protein engineering and design.

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Four new fungi from Xizang in southwest China, Caloceraramaria, Ceraceomycesrhizomorphus, Leptosporomyceslinzhiensis, and Ramariaxizangensis are described and illustrated based on the morphological and molecular evidence. Caloceraramaria is characterized by the ramal and bright orange basidiomata, a monomitic hyphal system with simple septa generative hyphae, usually 4-septate basidiospores; Ceraceomycesrhizomorphus is characterized by the cream to yellowish basidiomata with rhizomorphs, cylindrical basidiospores; Leptosporomyceslinzhiensis is characterized by white with pink basidiomata, cylindrical to oblong ellipsoid basidiospores; Ramariaxizangensis is characterized by flesh pink basidiomata, branched dichotomously in 4-5 ranks, a monomitic hyphal system with clamped generative hyphae, ellipsoid to cylindrical and densely warted basidiospores.

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BACKGROUND: The pedicle screw technique is widely employed for vertebral body fixation in the treatment of spinal disorders. However, traditional screw placement methods require the dissection of paraspinal muscles and the insertion of pedicle screws at specific transverse section angles (TSA). Larger TSA angles require more force to pull the muscle tissue, which can increase the risk of surgical trauma and ischemic injury to the lumbar muscles. AIM: To study the feasibility of zero-degree TSA vertical pedicle screw technique in the lumbosacral segment. METHODS: Finite element models of vertebral bodies and pedicle screw-rod systems were established for the L4-S1 spinal segments. A standard axial load of 500 N and a rotational torque of 10 N/m were applied. Simulated screw pull-out experiment was conducted to observe pedicle screw resistance to pull-out, maximum stress, load-displacement ratio, maximum stress in vertebral bodies, load-displacement ratio in vertebral bodies, and the stress distribution in pedicle screws and vertebral bodies. Differences between the 0-degree and 17-degree TSA were compared. RESULTS: At 0-degree TSA, the screw pull-out force decreased by 11.35% compared to that at 17-degree TSA (P < 0.05). At 0-degree and 17-degree TSA, the stress range in the screw-rod system was 335.1-657.5 MPa and 242.8-648.5 MPa, separately, which were below the fracture threshold for the screw-rod system (924 MPa). At 0-degree and 17-degree TSA, the stress range in the vertebral bodies was 68.45-78.91 MPa and 39.08-72.73 MPa, separately, which were below the typical bone yield stress range for vertebral bodies (110-125 MPa). At 0-degree TSA, the load-displacement ratio for the vertebral bodies and pedicle screws was slightly lower compared to that at 17-degree TSA, indicating slightly lower stability (P < 0.05). CONCLUSION: The safety and stability of 0-degree TSA are slightly lower, but the risks of screw-rod system fracture, vertebral body fracture, and rupture are within acceptable limits.

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OBJECTIVES: To investigate the risk factors for bronchopulmonary dysplasia (BPD) in twin preterm infants with a gestational age of <34 weeks, and to provide a basis for early identification of BPD in twin preterm infants in clinical practice. METHODS: A retrospective analysis was performed for the twin preterm infants with a gestational age of <34 weeks who were admitted to 22 hospitals nationwide from January 2018 to December 2020. According to their conditions, they were divided into group A (both twins had BPD), group B (only one twin had BPD), and group C (neither twin had BPD). The risk factors for BPD in twin preterm infants were analyzed. Further analysis was conducted on group B to investigate the postnatal risk factors for BPD within twins. RESULTS: A total of 904 pairs of twins with a gestational age of <34 weeks were included in this study. The multivariate logistic regression analysis showed that compared with group C, birth weight discordance of >25% between the twins was an independent risk factor for BPD in one of the twins (OR=3.370, 95%CI: 1.500-7.568, P<0.05), and high gestational age at birth was a protective factor against BPD (P<0.05). The conditional logistic regression analysis of group B showed that small-for-gestational-age (SGA) birth was an independent risk factor for BPD in individual twins (OR=5.017, 95%CI: 1.040-24.190, P<0.05). CONCLUSIONS: The development of BPD in twin preterm infants is associated with gestational age, birth weight discordance between the twins, and SGA birth.

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Chalcogen bond (ChB) catalysis, as a new type in the field of non-covalent bond catalysis, has become a hot research topic in the field of organocatalysis in recent years. In the present work, we investigated the catalytic performance of a series of hypervalent ChB catalysis based on the intramolecular Aza-Michael reaction of aminochalcone. The reaction includes the carbon-nitrogen bond coupling step (key step) and the proton transfer step. The catalytic performance of mono-dentate pentafluorophenyl chalcogen bond donor ChB1 was comparable to that of bis-dentate chalcogen bond donor ChB4, and stronger than that of mono-dentate chalcogen bond donors ChB2 and ChB3. The formation of the chalcogen bond between the catalyst and the carbonyl oxygen atom of the reactant, causing the charge rearrangement of the reactant and C(1) charge of the -C-Ph group to become more positive, thereby the ChB catalysis promoted the nucleophile reaction. The electron density of the chalcogen bond of the pre-complex, the most positive electrostatic potentials of the catalyst, and the NPA charge of the key atom are proportional to the Gibbs energy barrier of the C-N bond coupling process, which provides an idea to predict the catalytic activity of the ChB catalysis.

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In dairy cows, the occurrence of subclinical ketosis (SCK) is particularly high during early lactation. Previously, we documented alterations in the abundance of adiponectin (ADPN) in anestrus cows with SCK in comparison to cows in estrus. In the present study, 60 cows were divided into two groups: control (C, n = 30) and SCK (n = 30). Based on cow's estrus situation in two group at 55-60 days postpartum, 15 anestrus SCK cows and estrus cows were designated the SCK-A group and C-E group, respectively. The SCK-A group had downregulated serum and follicular fluid ADPN levels compared with the C-E group. The serum ADPN level was positively correlated with the insulin level and follicle growth rate, and there was a positive correlation between ADPN and glucose in the follicular fluid. Primary culture of dairy cow granulosa cells (GCs) was established to observe the effect of low glucose (Glu) and/or ADPN on GCs cyclins and proteins important for steroid synthesis. The results showed that the addition of 1 µg/mL ADPN alleviated the negative effects of low Glu treatment on the proliferation of GCs and the expression of steroid secretion related protein proteins. Treatment with LY294002 (PI3K inhibitor) four experimental GCs groups: control (0 µg/mL ADPN), 1 µg/mL ADPN, LY294002 inhibitor, and 1 µg/mL ADPN+LY294002. The results showed that ADPN promotes the secretion of steroid hormones by GCs through the PI3K-AKT. In summary, ADPN plays a crucial role in ameliorating postpartum anestrus in dairy cows with SCK.

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BACKGROUND: First rib tumors are extremely rare. Its compression of neurovascularity can easily lead to severe complications such as thoracic outlet syndrome, so early surgical resection is crucial. However, there is no standardized approach to surgery. CASE PRESENTATION: A previously healthy 18-year-old Chinese male undergoes a chest computed tomography (CT) scan that incidentally reveals a raised calcified mass on the right first rib, which is most likely an osteochondroma when combined with magnetic resonance imaging (MRI). We achieved excellent results with resection and thoracic reconstruction by adopting an inverse L-shaped incision in the anterior chest and a longitudinal split of the sternum. CONCLUSIONS: Our practice provides great reference for the surgical management of first rib tumors.

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Background: Spondylitis caused by Brucella infection is a rare but challenging condition, and its successful management depends on timely diagnosis and appropriate treatment. This study reports two typical cases of thoracic and lumbar brucellosis spondylitis, highlighting the pivotal roles of real-time polymerase chain reaction (real-time PCR) detection and surgical intervention. Case presentation: Case 1 involved a 49-year-old male shepherd who presented with a 6-month history of fever (40°C), severe chest and back pain, and 2-week limited lower limb movement with night-time exacerbation. Physical examination revealed tenderness and percussion pain over the T9 and T10 spinous processes, with grade 2 muscle strength in the lower limbs. CT showed bone destruction of the T9 and T10 vertebrae with narrowing of the intervertebral space, whereas MRI demonstrated abnormal signals in the T9-T10 vertebrae, a spinal canal abscess, and spinal cord compression. The Rose Bengal plate agglutination test was positive. Case 2 was a 59-year-old man who complained of severe thoracolumbar back pain with fever (39.0°C) and limited walking for 2 months. He had a 2.5 kg weight loss and a history of close contact with sheep. The Rose Bengal test was positive, and the MRI showed inflammatory changes in the L1 and L2 vertebrae. Diagnosis and treatment: real-time PCR confirmed Brucella infection in both cases. Preoperative antimicrobial therapy with doxycycline, rifampicin, and ceftazidime-sulbactam was administered for at least 2 weeks. Surgical management involved intervertebral foraminotomy-assisted debridement, decompression, internal fixation, and bone grafting under general anesthesia. Postoperative histopathological examination with HE and Gram staining further substantiated the diagnosis. Outcomes: both patients experienced significant pain relief and restored normal lower limb movement at the last follow-up (4-12 weeks) after the intervention. Conclusion: Real-time PCR detection offers valuable diagnostic insights for suspected cases of brucellosis spondylitis. Surgical treatment helps in infection control, decompression of the spinal cord, and restoration of stability, constituting a necessary and effective therapeutic approach. Prompt diagnosis and comprehensive management are crucial for favorable outcomes in such cases.

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Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China. Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.

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Quercus myrsinifolia is one of the dominant species in the evergreen broad-leaf forest on the southern slope of Shennongjia. The study of spatial distribution pattern and spatial correlation of Q. myrsinifolia population will help to understand population development and potential ecological processes, as well as the structure and biodiversity maintenance mechanism of evergreen broad-leaf forests at the northern edge of the subtropics. Based on forest dynamic monitoring data from one 1 hm2 permanent plot on the southern slope of Shennongjia, we employed pair correlation functions g(r) and marked correlation functions to analyze the diameter structure of the Q. myrsinifolia population, spatial distribution patterns at different diameter classes, and intraspecific and interspecific spatial associations. The results showed that diameter structure of Q. myrsinifolia population exhibited an inverted 'J'-shaped distribution, suggesting a healthy regeneration status and belonging to a growing population type. The spatial distribution showed a decreasing trend in aggregation with increasing diameter. Positive correlations among individuals strengthened with closer diameter classes, while weakening with larger diameter differences. Interspecific spatial associations showed an increasing correlation of Q. myrsinifolia with understory dominant species with increasing spatial scales, but no correlation was observed with canopy-dominant species. Our results suggested that the spatial pattern of Q. myrsinifolia populations on the southern slope of Shennongjia was mainly influenced by habitat filtering, seed dispersal limitation, and intraspecific and interspecific competition. Furthermore, the adaptive strategies of Q. myrsinifolia varied when they coexisted with different species.

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Cannabis sativa is known for its therapeutic benefit in various diseases including pain relief by targeting cannabinoid receptors. The primary component of cannabis, Δ9-tetrahydrocannabinol (THC), and other agonists engage the orthosteric site of CB1, activating both Gi and ß-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.

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BACKGROUND: Inflammatory macrophage infiltration plays a critical role in acute kidney disease induced by ischemia-reperfusion (IRI-AKI). Calycosin is a natural flavone with multiple bioactivities. This study aimed to investigate the therapeutic role of calycosin in IRI-AKI and its underlying mechanism. METHODS: The renoprotective and anti-inflammatory effects of calycosin were analyzed in C57BL/6 mice with IRI-AKI and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. RNA-seq was used for mechanism investigation. The molecular target of calycosin was screened by in silico methods and validated by surface plasmon resonance (SPR). Macrophage chemotaxis was analyzed using Transwell and agarose gel spot assays. RESULTS: Calycosin treatment significantly reduced serum creatinine and urea nitrogen and attenuated tubular destruction in IRI-AKI mice. Additionally, calycosin markedly suppressed NF-κB signaling activation and the expression of inflammatory mediators IL-1ß and TNF-α in IRI-AKI kidneys and LPS-stimulated RAW 264.7 cells. Interestingly, RNA-seq revealed calycosin remarkably downregulated chemotaxis-related pathways in RAW 264.7 cells. Among the differentially expressed genes, Ccl2/MCP-1, a critical chemokine mediating macrophage inflammatory chemotaxis, was downregulated in both LPS-stimulated RAW 264.7 cells and IRI-AKI kidneys. Consistently, calycosin treatment attenuated macrophage infiltration in the IRI-AKI kidneys. Importantly, in silico target prediction, molecular docking, and SPR assay demonstrated that calycosin directly binds to macrophage migration inhibitory factor (MIF). Functionally, calycosin abrogated MIF-stimulated NF-κB signaling activation and Ccl2 expression and MIF-mediated chemotaxis in RAW 264.7 cells. CONCLUSIONS: In summary, calycosin attenuates IRI-AKI by inhibiting MIF-mediated macrophage inflammatory chemotaxis, suggesting it could be a promising therapeutic agent for the treatment of IRI-AKI.

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