This study elucidated the structure-activity relationships (SAR) of three distinct opioid ligand series at the μ-opioid receptor (μ-OR) and investigated the ligand-dependent role of arrestin in downstream signaling. Radioligand binding assays across 13 compounds revealed that high-affinity μ-OR binding is not restricted to a single chemical scaffold. For fentanyl analogs, SAR analysis identified four key structural determinants: the N-phenethyl group (R1) is essential for μ-OR binding, the piperidine 4-position (R2) is sterically constrained and tolerates only small substituents such as carbomethoxy, the acyl side chain (R3) tolerates diverse chemical modifications including alkyl, alkoxy, and heteroaryl groups without substantial loss of affinity, and para-substitution on the phenethyl ring (R4) with electron-withdrawing groups like fluorine is well-tolerated. Analysis of non-fentanyl scaffolds (2-Methyl AP-237, W-15, and brorphine) demonstrated that specific side-chain functionalization, rather than core scaffold architecture, primarily determines binding potency. Comparison of classical opioids further revealed that structural flexibility, exemplified by methadone, can confer superior binding affinity compared to the rigid morphine scaffold. Consistent with this structural diversity, the contribution of arrestins to ERK activation varied substantially across compounds, suggesting that μ-OR-biased signaling is not dictated exclusively by intrinsic receptor properties but emerges from the interplay between receptor conformation and ligandspecific structural features. Collectively, our results provide a molecular framework for understanding opioid pharmacology with important implications for rational drug design aimed at minimizing adverse effects while maintaining analgesic efficacy.

Objective: To systematically analyze the stability and decay kinetics of coagulation factors in thawed cryoprecipitate stored at different temperatures under the new storage guidelines, and to provide an evidence basis for optimizing storage strategies. Methods: A total of 30 bags of 2U cryoprecipitate prepared at our blood center from January to June 2025 were selected. After thawing in a 37℃ water bath and thorough mixing, each bag was equally divided into two portions and stored at room temperature (20-24℃) or under refrigerated temperature (2~6℃), respectively. Dynamic sampling was performed at 0, 4, 6, 24, 30, and 120 h after thawing to measure fibrinogen (FIB) content, coagulation factor Ⅷ(FⅧ) activity, and von Willebrand factor (vWF) activity. Two-way repeated measures ANOVA was used to evaluate the effects of storage temperature, time, and their interaction. A one-phase exponential decay model was applied to fit the decay kinetics of FⅧ activity and vWF activity. Results: After thawing, FⅧ activity and vWF activity in cryoprecipitate showed a decreasing trend with prolonged storage time, and a time×temperature interaction was observed for both factors (all P< 0.001). The decay rates of FⅧ activity and vWF activity were lower under room temperature storage than under refrigerated storage, with statistically significant differences between the two groups starting from 24 h. Kinetic fitting revealed that the half-life of FⅧ activity in the room temperature group (19.83 h) was 3.4 times longer than that in the refrigerated group (5.85 h); the half-life of vWF activity in the room temperature group (204.6 h) was 5.9 times longer than that in the refrigerated group (34.6 h). FIB content remained stable throughout the observation period under both storage temperatures, with no statistically significant differences. Conclusion: Storage of thawed cryoprecipitate at room temperature effectively delays the loss of FⅧ activity and vWF activity and reduces cryoprecipitate formation induced by low temperature, providing experimental evidence for optimizing transfusion strategies based on the decay kinetics of different coagulation factors and improving the utilization efficiency of cryoprecipitate resources.

Objective By exploring changes of six degrees of freedom(6DOF)kinematics of the knee joint during extra weight bearing of the body trunk,the influence of extra weight on knee joint movement patterns was studied.Methods A total of 24 healthy subjects were recruited to walk/run on a treadmill at four speeds under two states:self-weight and wearing a 16 kg vest,and gait analysis was conducted.A three-dimensional(3D)portable knee kinematics analysis system based on infrared stereophotography was used to capture 6DOF movement trajectory data of the tibia relative to the femur.Results Compared to the self-weight state,when additional trunk weight was added,the knee external rotation angle was reduced at 3.6 km/h speed(1.4°-2.1°)and 5.4 km/h speed(2.2°-2.7°);the knee internal rotation angle was reduced at 10.8 km/h speed(2.1°-4.2°);the knee flexion angles was increased significantly at the speed of 3.6 km/h(1.5°-1.8°),9 km/h(1.6°-3.3°)和 10.8 km/h(1.9°-3.1°);the knee adduction angle increased at 5.4 km/h speed(0.5°-0.6°),and decreased at 10.8 km/h speed(0.9°-1.3°).At 10.8 km/h speed,the distal knee displacement(0.2-0.4 mm)was increased,and the lateral knee displacement(0.1-0.2 mm),and anterior knee displacement(0.2-0.3 mm)were significantly reduced.Conclusions The 6DOF kinematics of human knee is significantly affected by the extra trunk weight.Performance is also different at lower and higher speeds.It is suggested that there may exist a hidden injury in military training,and this study provides a kinematic basis for the occurrence of sports injury.

Objective By exploring changes of six degrees of freedom(6DOF)kinematics of the knee joint during extra weight bearing of the body trunk,the influence of extra weight on knee joint movement patterns was studied.Methods A total of 24 healthy subjects were recruited to walk/run on a treadmill at four speeds under two states:self-weight and wearing a 16 kg vest,and gait analysis was conducted.A three-dimensional(3D)portable knee kinematics analysis system based on infrared stereophotography was used to capture 6DOF movement trajectory data of the tibia relative to the femur.Results Compared to the self-weight state,when additional trunk weight was added,the knee external rotation angle was reduced at 3.6 km/h speed(1.4°-2.1°)and 5.4 km/h speed(2.2°-2.7°);the knee internal rotation angle was reduced at 10.8 km/h speed(2.1°-4.2°);the knee flexion angles was increased significantly at the speed of 3.6 km/h(1.5°-1.8°),9 km/h(1.6°-3.3°)和 10.8 km/h(1.9°-3.1°);the knee adduction angle increased at 5.4 km/h speed(0.5°-0.6°),and decreased at 10.8 km/h speed(0.9°-1.3°).At 10.8 km/h speed,the distal knee displacement(0.2-0.4 mm)was increased,and the lateral knee displacement(0.1-0.2 mm),and anterior knee displacement(0.2-0.3 mm)were significantly reduced.Conclusions The 6DOF kinematics of human knee is significantly affected by the extra trunk weight.Performance is also different at lower and higher speeds.It is suggested that there may exist a hidden injury in military training,and this study provides a kinematic basis for the occurrence of sports injury.

Objective To identify the multidimensional care needs for primary caregivers of the patients with spinal cord injury based on a journey map so as to provide a reference for caregivers to develop supportive interventions through the whole-journey.Method A longitudinal descriptive qualitative study was conducted,and purposive sampling was employed to select 14 primary caregivers for the patients with spinal cord injury from a Grade ⅢA hospital in Hefei between March and May 2024 for 3 rounds of semi-structured interviews.Content analysis was conducted to organise the data and to extract the themes.Based on the extracted themes,a journey map of the care needs for primary caregivers was plotted.Results The journey map was plotted based on 3 phases of the patients with spinal cord injury:diagnosis,discharge transition and rehabilitation as the horizontal axis of time,and the tasks,emotions,and barriers during the care-providing period as the vertical axis of tasks.Nine themes were identified and plotted by journey map,including three domains on tasks for three phases(high demand for hospitalisation assistance,urgent need for home care skills and dual role challenge),three domains on emotional conditions for three phases(psychological adjustment,heavy negative emotion experience and positive experience)and three domains on care-giving barriers for three phases(need for disease-related knowledge,lack of medicine-related laws and changes in family economy and structure).Conclusion The journey map of the care needs for primary caregivers among the patients with spinal cord injury is complex and multi-dimensional.Medical staff should accurately devise intervention plans according to the task axis at different stages of disease.This will enable the allocation of high-quality supporting resources throughout the whole care-providing journey,thereby improving the quality of care as well as the outcomes of care.

The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.

The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.

The N-methyl-D-aspartate receptor (NMDA-R) subunit GluN2B is abundantly expressed in brain regions critical for synaptic plasticity and cognitive processes. This study investigated the structure-activity relationships (SAR) of NMDA-R ligands using GluN2B as a molecular target. Thirty potential NMDA-R antagonists were categorized into two structural classes: 1-(1-phenylcyclohexyl) amines (series A) and α-amino-2-phenylcyclohexanone derivatives (series B). In series A compounds, the phenyl ring and R1 substituents were positioned at the carbon center of the cyclohexyl ring, with R2 substituents at the para- or meta-positions of the phenyl ring. SAR analysis revealed optimal binding affinity when R1 was carbonyl (C=O) and R2 was 4-methoxy (4-OMe). Series B compounds featured a cyclohexanone scaffold with NH-R1 at the α-position and a phenyl ring bearing R2 substituents at ortho-, meta-, or para-positions. Maximum binding affinity was achieved with R1 as hydrogen (H) and R2 as hydroxyl (OH). Compounds were assessed for GluN2B-mediated ERK activation to evaluate potential metabotropic signaling properties. Approximately 50% of the compounds demonstrated ERK activation through a non-ionotropic signaling cascade involving Src, phosphatidylinositol 3-kinase, and protein kinase C. This study elucidated key structural determinants for NMDA-R binding and characterized a novel metabotropic signaling pathway. Notably, our findings suggest that compounds acting as antagonists at the ionotropic site may simultaneously function as agonists through non-ionotropic mechanisms.

Objective To identify the multidimensional care needs for primary caregivers of the patients with spinal cord injury based on a journey map so as to provide a reference for caregivers to develop supportive interventions through the whole-journey.Method A longitudinal descriptive qualitative study was conducted,and purposive sampling was employed to select 14 primary caregivers for the patients with spinal cord injury from a Grade ⅢA hospital in Hefei between March and May 2024 for 3 rounds of semi-structured interviews.Content analysis was conducted to organise the data and to extract the themes.Based on the extracted themes,a journey map of the care needs for primary caregivers was plotted.Results The journey map was plotted based on 3 phases of the patients with spinal cord injury:diagnosis,discharge transition and rehabilitation as the horizontal axis of time,and the tasks,emotions,and barriers during the care-providing period as the vertical axis of tasks.Nine themes were identified and plotted by journey map,including three domains on tasks for three phases(high demand for hospitalisation assistance,urgent need for home care skills and dual role challenge),three domains on emotional conditions for three phases(psychological adjustment,heavy negative emotion experience and positive experience)and three domains on care-giving barriers for three phases(need for disease-related knowledge,lack of medicine-related laws and changes in family economy and structure).Conclusion The journey map of the care needs for primary caregivers among the patients with spinal cord injury is complex and multi-dimensional.Medical staff should accurately devise intervention plans according to the task axis at different stages of disease.This will enable the allocation of high-quality supporting resources throughout the whole care-providing journey,thereby improving the quality of care as well as the outcomes of care.

[Purpose]To analyze the diagnostic yield of quantitative fecal immunochemical test(FIT)at different cut-offs in colorectal cancer(CRC)screening.[Methods]The sequential screening method was adapted in Jiashan CRC screening program for local residents aged 40～74 years old,which included a quantitative FIT and high-risk factor questionnaire for primary screening and subsequent colonoscopy for the diagnostic screening.Subjects who participated in quantitative FIT were included in this study between September,2021 and August,2023.The positive predictive values(PPVs)for colorectal neoplasms were calculated at the cut-offs of 100,120,140,160,180 and 200 ng/mL of FIT.The Cochran-Armitage trend test was performed to compare the trend of PPVs at different cut-offs.The effects of different starting age and FIT cut-offs on requirement of colonoscopy and advanced neoplasia detection were assessed.[Results]A total of 58 256 individuals completed the quantitative FIT,and 3 106 had fecal hemoglobin concentrations＞100 ng/mL,among whom 2 186 underwent colonoscopic examination with a compliance rate of 70.38％.The colonoscopy detected 588 cases of non-advanced adenomas and 355 cases of advanced neoplasms(AN),in-cluding 30 cases of CRC and 325 cases of advanced adenomas.Progressively increasing the cut-off showed a decrease in PPVs of non-advanced adenomas and an increase of AN.The ratio of the rate of reduced requirement of colonoscopy to the missed rate of the progressive lesions was the smallest when the screening start age was 45 years old and the positive FIT threshold was set at 100 ng/mL.[Conclusion]There were significant differences in the diagnostic yield at different cut-offs of FIT.Increasing the cut-offs of FIT will elevate PPVs for the advanced neoplasms.