Somatostatin receptor 1 (SSTR1) is a crucial therapeutic target for various neuroendocrine and oncological disorders. Current SSTR1-targeted treatments, including the first-generation somatostatin analog lanreotide (Lan) and the second-generation analog pasireotide (Pas), show promise but encounter challenges related to selectivity and efficacy. This study presents high-resolution cryo-electron microscopy structures of SSTR1 complexed with Lan or Pas, revealing the distinct mechanisms of ligand-binding and activation. These structures illustrate unique conformational changes in the SSTR1 orthosteric pocket induced by each ligand, which are critical for receptor activation and ligand selectivity. Combined with the biochemical assays and molecular dynamics simulations, our results provide a comparative analysis of binding characteristics within the SSTR family, highlighting subtle differences in SSTR1 activation by Lan and Pas. These insights pave the way for designing next-generation therapies with enhanced efficacy and reduced side effects through improved receptor subtype selectivity.

Objective To investigate the mechanism of Yiqi Huoxue Huazhuo Jiedu Prescription in regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway to improve cerebral ischemia reperfusion injury in rats.Methods A total of 48 male SD rats were randomly divided into sham-operation group,model group,TCM group and edaravone group,with 12 rats in each group.Cerebral ischemia reperfusion injury rat model was prepared using middle cerebral artery occlusion method,and administration 24 hours after modeling.The edaravone group was given intraperitoneal injection of 1.4 mg/mL edaravone injection,TCM group was given 55 g/(kg·d)of Yiqi Huoxue Huazhuo Jiedu Prescription for gavage,while the sham-operation group and model group were given equal volumes of normal saline for gavage,twice a day for 3 consecutive days.The neurological deficit scores of the rats in each group were observed,TTC staining was used to detect the volume of cerebral infarction,HE staining was used to observe the morphology of brain tissue in the ischemia-reperfusion area,immunohistochemistry staining was used to detect the positive expressions of glucose regulated protein 78(GRP78),protein kinase R-like endoplasmic reticulum kinase(PERK)and transcription activator factor(ATF)4 in the ischemia-reperfusion area brain tissue,RT-PCR was used to detect the mRNA expressions of GRP78,PERK and ATF4 in the ischemia-reperfusion area brain tissue,Western blot was used to detect the protein expressions of GRP78,PERK and ATF4 in the ischemia-reperfusion area brain tissue.Results Compared with the sham-operation group,the neurological deficit score of the model group rats increased,the volume of cerebral infarction increased,the number of neurons in the ischemia-reperfusion area decreased,the arrangement was loose,and the nuclei were condensed,the mRNA and protein expressions of GRP78,PERK and ATF4 increased,with statistical significance(P<0.05).Compared with the model group,the neurological deficit score of TCM group and edaravone group decreased,the cerebral infarction volume decreased,the number and arrangement of neurons of the brain tissue in the ischemia reperfusion area increased,and nuclear condensation decreased in rats,the mRNA and protein expressions of GRP78,PERK and ATF4 were all reduced,with statistical significance(P<0.05).There was no statistical significance in various indicators between TCM group and the edaravone group(P>0.05).Conclusion Yiqi Huoxue Huazhuo Jiedu Prescription can improve cerebral ischemia reperfusion injury,and its mechanism may be related to down-regulating the expression of PERK/ATF4 signaling pathway and alleviating endoplasmic reticulum stress.

Objective To investigate the mechanism of Yiqi Huoxue Huazhuo Jiedu Prescription in regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway to improve cerebral ischemia reperfusion injury in rats.Methods A total of 48 male SD rats were randomly divided into sham-operation group,model group,TCM group and edaravone group,with 12 rats in each group.Cerebral ischemia reperfusion injury rat model was prepared using middle cerebral artery occlusion method,and administration 24 hours after modeling.The edaravone group was given intraperitoneal injection of 1.4 mg/mL edaravone injection,TCM group was given 55 g/(kg·d)of Yiqi Huoxue Huazhuo Jiedu Prescription for gavage,while the sham-operation group and model group were given equal volumes of normal saline for gavage,twice a day for 3 consecutive days.The neurological deficit scores of the rats in each group were observed,TTC staining was used to detect the volume of cerebral infarction,HE staining was used to observe the morphology of brain tissue in the ischemia-reperfusion area,immunohistochemistry staining was used to detect the positive expressions of glucose regulated protein 78(GRP78),protein kinase R-like endoplasmic reticulum kinase(PERK)and transcription activator factor(ATF)4 in the ischemia-reperfusion area brain tissue,RT-PCR was used to detect the mRNA expressions of GRP78,PERK and ATF4 in the ischemia-reperfusion area brain tissue,Western blot was used to detect the protein expressions of GRP78,PERK and ATF4 in the ischemia-reperfusion area brain tissue.Results Compared with the sham-operation group,the neurological deficit score of the model group rats increased,the volume of cerebral infarction increased,the number of neurons in the ischemia-reperfusion area decreased,the arrangement was loose,and the nuclei were condensed,the mRNA and protein expressions of GRP78,PERK and ATF4 increased,with statistical significance(P<0.05).Compared with the model group,the neurological deficit score of TCM group and edaravone group decreased,the cerebral infarction volume decreased,the number and arrangement of neurons of the brain tissue in the ischemia reperfusion area increased,and nuclear condensation decreased in rats,the mRNA and protein expressions of GRP78,PERK and ATF4 were all reduced,with statistical significance(P<0.05).There was no statistical significance in various indicators between TCM group and the edaravone group(P>0.05).Conclusion Yiqi Huoxue Huazhuo Jiedu Prescription can improve cerebral ischemia reperfusion injury,and its mechanism may be related to down-regulating the expression of PERK/ATF4 signaling pathway and alleviating endoplasmic reticulum stress.

Objective To design a pH-sensitive nintedanib liposomes(Nb-Lips)which targeted the acidic microenvironment of pulmonary fibrosis.The entrapment efficiency(EE%)was optimized by the formulation process.Methods Nintedanib liposomes were prepared by membrane hydration method,and the formulation of nintedanib liposomes were optimized by single factor experiments and response surface method(RSM).The particle size,polymer dispersity index(PDI),Zeta potential and encapsulation rate was investigated by dynamic light scattering technique and microcolumn centrifugation method.The release behavior of nintedanib liposomes in artificial lung fluid with pH 7.4 and artificial lung fluid with pH 5.3 was investigated by dialysis method.Nintedanib liposomes were atomized with a compressed air atomizer and its atomization stability and aerodynamic particle size were investigated.Results The particle size of nintedanib liposomes was(100.651±7.315)nm,the PDI was(0.328±0.026),the zeta potential was(21.633±2.004)mV,and the encapsulation rate was higher than 80%.Compared with nintedanib solution at pH 7.4,the total release of nintedanib liposomes in pH 5.3 artificial lung solution was 60.78%higher,and the release of nintedanib liposomes in pH 5.3 artificial lung solution was 48h delayed,which was much higher than that of nintedanib solution.The data reveals no significant differences in particle size,potential and PDI before and after atomization of nintedanib liposomes,and the encapsulation rate decreased 4.25%.The fine particle fraction of the atomized droplets was 37.49%.Conclusion The response surface method can effectively improve the encapsulation rate of nintedanib liposomes,and successfully prepare nintedanib liposomes that are sensitive to acidic environment,and can be inhaled and released slowly.

Intestinal flora and bile acid metabolism regulate and influence each other,and an imbalance in the"intestinal flora-bile acid"pathway is closely related to atherosclerosis.Based on TCM theory and clinical practice,it is found that"earth congestion and wood depression"is the key mechanism of atherosclerosis,but its biological connotation needs to be further elucidated.Combined with the results of modern research,it is believed that intestinal flora imbalance is an important foundation of"earth congestion",and bile acid metabolism abnormality is an important manifestation of"wood depression".In the process of atherosclerosis,the imbalance of the"intestinal flora-bile acid"pathway is closely related to the"earth congestion and wood depression"pathogenesis of TCM in atherosclerosis.Exploring the biological connotation of the pathogenesis of"earth congestion and wood depression"of atherosclerosis from the"intestinal flora-bile acids"pathway is of far-reaching significance for clarifying the scientific connotation of TCM theory and guiding the TCM prevention and treatment of atherosclerosis.

ObjectiveTo systematically analyze international disability data policies and standards, as well as the application of disability data in policymaking, service optimization and inclusive social development, and to clarify the importance of international disability data policies, standard systems and disability data application for the development of disability-related services. MethodsThrough the analysis of policy content and research on the data standard system, this study explored the disability data policy framework, standard system and technical path of data interoperability and integration of international organizations including the United Nations (United Nations Statistics Division and United Nations Children's Fund), World Health Orgnization, United Nations Educational Scientific and Cultural Organization, and International Labour Organization. ResultsInternational organizations established disability data policy frameworks based on their respective mandates, involving data and service development, data standards, data governance, and data application. The international community established a disability data standard system for disability data collection, coding, exchange, interoperability, statistical analysis, data fusion and application. Building a standardized disability data standard system based on the framework of international health classification standards such as International Classification of Functioning, Disability and Health, and International Classification of Diseases, Eleventh Revision would ensure the consistency of cross-national disability data policies, and the interoperability and comparability of disability data, promoting the development of data-driven disability-related services, accurately identifying the service needs of people with disabilities, and optimizing service provision, thereby improving the quality of life and social participation of people with disabilities. ConclusionThe construction and implementation of international disability data policies and data standards have promoted the standardization and interoperability of disability data. With the application of big data, artificial intelligence and blockchain technologies in disability data, international cooperation and cross-industry data fusion in the field of disability data have been promoted, further promoting the development of data-driven disability services, ensuring equal opportunities for people with disabilities to enjoy service resources, and improving the coverage and quality of disability services.

Objective To investigate the effect of electroacupuncture(EA)on the expression of vasopressin type 2 receptor(V2R),aquaporin-2(AQP2)and epithelial sodium channel-α(ENaC-α)in guinea pigs with arginine vasopressin(AVP)-induced endolymphatic hydrops(EH).Methods Male albino guinea pigs were randomly divided into normal control,EH model and EA groups(n=12 guinea pigs in each group).The EH model was established by continuous injection intraperitoneally of AVP,4μg/(kg·d)for 7 days,and then 6μg/(kg·d)for 3 days,totally 10 days.EA(100Hz,1mA)was applied to Baihui(GV 20)and unilateral Tinggong(SI 19)for 20 min,once a day for continuous 10 days.Cochlear hydrops severity was measured using hematoxylin-eosin(HE)staining,and then the ratio of scala media(SM)area to SM + scala vestibuli(SV)area(R value)was calculated.The expression level of V2R,AQP2 and ENaC-α in the cochlea was detected by western blot.Results Following modeling,R value,the V2R,AQP2 and ENaC-α protein expression were significantly increased in comparison with the normal group(all P<0.01).After EA intervention,R value,the V2R,AQP2 and ENaC-α protein expression were notably down-regulated in comparison with the model group(all P<0.01).Conclusion EA can relieve the cochlear hydrops of EH guinea pigs,which may be related to its effect in down-regulating the expression of V2R,AQP2 and ENaC-α protein in the cochlea.

Objective To establish a new model of indocyanine green (ICG) clearance test combined with total bilirubin actual resident rate (TBARR) for predicting the short-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) treated with artificial liver support system (ALSS) therapy. Methods A retrospective analysis was performed for the clinical data of 136 patients with HBV-ACLF who underwent ALSS therapy in Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, from June 2017 to July 2021, and according to the prognosis at 3-month follow-up, they were divided into survival group with 92 patients and death group with 44 patients. Related indicators were measured at the time of the confirmed diagnosis of ACLF, including biochemical parameters, coagulation, indocyanine green retention rate at 15 minutes (ICGR 15 ), and effective hepatic blood flow (EHBF), and related indices were calculated, including Model for End-Stage Liver Disease (MELD) score, MELD difference (ΔMELD), Child-Turcotte-Pugh (CTP) score, total bilirubin clearance rate (TBCR), total bilirubin rebound rate (TBRR), and TBARR. The Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups; the chi-square test was used for comparison of categorical data between groups. A binary logistic regression analysis was used to establish a combined predictive model for the prognosis of HBV-ACLF after ALSS therapy. The area under the ROC curve (AUC) was used to compare the accuracy of various models in judging the short-term prognosis of patients with HBV-ACLF after ALSS therapy, and the Z test was used for comparison of AUC. Results There were significant differences between the death group and the survival group in MELD score, ΔMELD, CTP score, ICGR 15 , EHBF, TBRR, TBARR, neutrophil count, percentage of neutrophils, lymphocyte count, platelet count, alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin, albumin, prothrombin time, international normalized ratio, prothrombin time activity, prealbumin, fibrinogen, serum sodium, age, and the incidence rate of hepatic encephalopathy (all P < 0.05). The multivariate logistic regression analysis showed that age (odds ratio [ OR ]=1.096, 95% confidence interval [ CI ]: 1.056-1.137, P < 0.001), neutrophil count ( OR =1.214, 95% CI : 1.044-1.411, P =0.012), TBRR ( OR =0.989, 95% CI : 0.982-0.996, P =0.001), TBARR ( OR =1.073, 95% CI : 1.049-1.098, P < 0.001), ΔMELD ( OR =1.480, 95% CI : 1.288-1.701, P < 0.001), CTP score ( OR =2.081, 95% CI : 1.585-2.732, P < 0.001), and ICGR 15 ( OR =1.116, 95% CI : 1.067-1.168, P < 0.001) were independent influencing factors for short-term mortality in patients with HBV-ACLF after ALSS therapy. The binary logistic regression analysis was used to establish four combined predictive models for predicting the prognosis of HBV-ACLF after ALSS therapy, i.e., TBRR-ICGR 15 , TBARR-ICGR 15 , TBARR-ICGR 15 -ΔMELD, and TBARR-ICGR 15 -ΔMELD-age, with an AUC of 0.830, 0.867, 0.900, and 0.917, respectively, and the combined predictive models had a larger AUC than each index alone (age, neutrophil count, TBRR, TBARR, ΔMELD, MELD score, CTP score, and ICGR 15 ), among which the TBARR-ICGR 15 -ΔMELD-age model had the largest AUC. The combined models TBARR-ICGR 15 -ΔMELD and TBARR-ICGR 15 -ΔMELD-age had sensitivities and specificities of > 80%. Conclusion The combined predictive model established by ICGR 15 and TBARR has a good value for in predicting the short-term prognosis of patients with HBV-ACLF after ALSS therapy, and the combined predictive model has a better accuracy than the single model in judging prognosis.

Objective:To explore the long-term effect of endoscopic radiofrequency ablation for the treatment of unresectable ampullary carcinoma.Methods:Clinical data of patients with ampullary carcinoma who received endoscopic radiofrequency ablation in the Third Affiliated Hospital of Naval Medical University from January 2012 to May 2019 were retrospectively collected, including basic information, frequency of radiofrequency ablation, the type of biliary stent, postoperative complications, and follow-up. Kaplan-Meier method was used to analyze the survival of patients after endoscopic radiofrequency ablation. Relationship between frequency of radiofrequency ablation, type of biliary stent and overall survival time was analyzed.Results:A total of 50 patients were enrolled, including 31 males and 19 females, aged 73.0±9.7 years. Twenty-five patients (50.0%) underwent 1 radiofrequency ablation treatment, while 25 patients (50.0%) underwent radiofrequency ablation treatments more than twice. Postoperative complications occurred in 6 patients (12.0%), all of which were mild symptoms. The average follow-up was 22.3 months, with a total of 39 (78.0%) deaths, 5 (10.0%) lost to follow-up, and 6 (12.0%) surviving. The median overall survival time was 16.9 (95% CI: 9.1-24.8) months, with cumulative survival rates of 62.0%, 38.5%, 27.0%, and 12.6% at 1, 2, 3, and 5 years, respectively. The median overall survival time of those treated with radiofrequency ablation ≥2 times showed a trend of prolongation compared to patients treated once, but the difference was not statistically significant [26.7 (95% CI: 9.7-43.7) months VS 12.6 (95% CI: 4.9-20.3) months, χ2=3.049, P=0.081]. Plastic stents were used in 32 patients (64.0%) and metal stents in 18 patients (36.0%). There was no significant difference in median overall survival time between patients using metal and plastic stents [17.1 (95% CI: 6.1-28.0) months VS 15.9 (95% CI: 6.9-24.9) months， χ2=0.029， P=0.865]. Conclusion:Endoscopic radiofrequency ablation is a safe treatment for unresectable ampullary carcinoma, and multiple consecutive treatments may increase the survival benefit.

Objective:To evaluate the efficacy of endoscopic stenting drainage for patients with malignant hilar biliary obstruction caused by unresectable hepatocellular carcinoma.Methods:Data of 106 patients with malignant hilar obstruction caused by unresectable hepatocellular carcinoma who received endoscopic stenting drainage in the Third Affiliated Hospital of Naval Medical University from January 2012 to January 2019 were retrospectively analyzed. According to the different stent types, they were divided into the metal stent group (30 cases) and the plastic stent group (76 cases). The observation indexes included clinical success rate, complication incidence, stent patency and overall survival time. The independent predictors for stent patency and overall survival of patients were analyzed by multivariate Cox regression model.Results:The overall clinical success rate was 67.9% (72/106) and the incidence of postoperative cholangitis was 29.2% (31/106). The clinical success rates were 93.3% (28/30) and 57.9% (44/76) ( χ2=12.40, P<0.001), and the incidences of postoperative cholangitis were 13.3% (4/30) and 35.5% (27/76) ( χ2=5.12, P=0.024) in the metal stent group and the plastic stent group, respectively. The median stent patency was 5.2 (95% CI:3.7-6.0) months, and the overall survival time was 3.0 (95% CI:2.5-3.7) months. Multivariate Cox regression analysis showed that hepatic drainage volume <30% was an independent predictor for stent patency ( HR=2.12, 95% CI:1.01-4.46, P=0.048). Bismuth type Ⅳ ( HR=2.06, 95% CI:1.12-3.77, P=0.020), Child-Pugh class C ( HR=4.09, 95% CI: 2.00-8.39, P<0.001) and plastic stent ( HR=1.87, 95% CI:1.21-2.90, P=0.005) were independent predictors for overall survival time. Conclusion:Hepatocellular carcinoma involving the hilar bile duct has a poor prognosis. Compared with plastic stents, metal stents show advantages in clinical success rate and incidence of postoperative cholangitis. Hepatic drainage volume <30% is an independent predictor for stent patency, and Bismuth type Ⅳ, Child-Pugh class C and plastic stent are independent predictors for overall survival time.