Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

BACKGROUND:Hormonal osteonecrosis of the femoral head is strongly associated with aging,but the regulatory targets and mechanisms are still unclear.Through bioinformatics combined with machine learning analysis and experimental verification,the key genes of hormonal osteonecrosis of the femoral head mediated by cell senescence will be identified,which will provide new ideas for the prevention and treatment of hormonal osteonecrosis of the femoral head.OBJECTIVE:To screen and validate the senescence core genes of hormonal osteonecrosis of the femoral head using bioinformatics analysis to explore its mechanism of action.METHODS:The GSE123568 dataset was obtained from the GPL15207 platform of the GEO database,which contained the gene expression profiles of peripheral serum samples of 30 hormonal osteonecrosis of the femoral head patients and 10 healthy controls.Data on 279 cellular senescence-related genes were obtained from the CellAge database.Differential analysis and weighted correlation network analysis(WGCNA)were performed on hormonal osteonecrosis of the femoral head gene profiles,and both were intersected with senescence-related genes and then concatenated to obtain hormonal osteonecrosis of the femoral head senescence potential genes,and GO and KEGG analyses were performed.The machine learning method screened out the pivotal genes,constructed nomogram model,and performed consensus clustering and immune infiltration analysis.Finally,clinical femoral samples were collected for validation by qPCR and western blot assay.RESULTS AND CONCLUSION:(1)41 potential genes were obtained,which were mainly enriched in biological processes such as aging and oxidative stress response,as well as FoxO and tumor necrosis factor signaling pathways.(2)The pivotal genes catalase,connective tissue growth factor,forkhead box protein O3,insulin receptor substrate 2,and mitogen-activated protein kinase kinase 11 were obtained after machine learning identification,and the predictive ability of nomogram model was good.(3)The patients were classified into three groups,namely a,b and c,by the consensus clustering analysis.Catalase,forkhead box protein O3,insulin receptor substrate 2,and mitogen-activated protein kinase kinase 11 were differentially expressed among the three molecular subtypes(P＜0.05).Results of immune infiltration showed that the abundance of immune cells,such as activated CD4+T cells,activated CD8+T cells,and eosinophils,differed among the three molecular subclasses(P＜0.05).(4)The results of qPCR and western blot assay showed that the expression of catalase,connective tissue growth factor,forkhead box protein O3,and mitogen-activated protein kinase kinase 11 was lower in hormonal osteonecrosis of the femoral head group compared to the control group(P＜0.05),and the expression of insulin receptor substrate 2 was elevated(P＜0.05).(5)It is concluded that through in-depth analysis combined with bioinformatics and machine learning,and further experimental verification,five hormonal osteonecrosis of the femoral head age-related hub genes were finally identified.These genes are catalase,connective tissue growth factor,forkhead box o3,insulin receptor substrate 2,and serine/threonine kinase 11.These genes may provide potential molecular targets for the prevention and treatment of hormonal osteonecrosis of the femoral head in the future by regulating the cellular aging process.

Objective To develop a toolkit suitable for assisting community health institutions in the early identification and inter-vention of mild cognitive impairment(MCI)among older adults.Methods A literature review was conducted to construct a draft of the identification and intervention toolkit.Tools with an expert approval rate above 70%were included after expert consultation.The final version of the toolkit was developed by integrating these tools with officially recommended tools in China.Results The expert consultation yielded an authority coefficient of 0.84.The finalized toolkit included the assessment tools of Mini-Mental State Examination,Montreal Cognitive Assessment,General Practitioner Assessment of Cognition,Cognitive Abilities Screening Instrument and Clock Drawing Test,and 18 intervention measures in-cluding pharmacological treatment,cognitive training and psychological interventions,etc.Conclusion The MCI Identification-Intervention Toolkit may serve as a reference for guiding the identification and inter-vention of MCI among older adults for community health institutions.

Objective To develop a toolkit suitable for assisting community health institutions in the early identification and inter-vention of mild cognitive impairment(MCI)among older adults.Methods A literature review was conducted to construct a draft of the identification and intervention toolkit.Tools with an expert approval rate above 70%were included after expert consultation.The final version of the toolkit was developed by integrating these tools with officially recommended tools in China.Results The expert consultation yielded an authority coefficient of 0.84.The finalized toolkit included the assessment tools of Mini-Mental State Examination,Montreal Cognitive Assessment,General Practitioner Assessment of Cognition,Cognitive Abilities Screening Instrument and Clock Drawing Test,and 18 intervention measures in-cluding pharmacological treatment,cognitive training and psychological interventions,etc.Conclusion The MCI Identification-Intervention Toolkit may serve as a reference for guiding the identification and inter-vention of MCI among older adults for community health institutions.

BACKGROUND:Hormonal osteonecrosis of the femoral head is strongly associated with aging,but the regulatory targets and mechanisms are still unclear.Through bioinformatics combined with machine learning analysis and experimental verification,the key genes of hormonal osteonecrosis of the femoral head mediated by cell senescence will be identified,which will provide new ideas for the prevention and treatment of hormonal osteonecrosis of the femoral head.OBJECTIVE:To screen and validate the senescence core genes of hormonal osteonecrosis of the femoral head using bioinformatics analysis to explore its mechanism of action.METHODS:The GSE123568 dataset was obtained from the GPL15207 platform of the GEO database,which contained the gene expression profiles of peripheral serum samples of 30 hormonal osteonecrosis of the femoral head patients and 10 healthy controls.Data on 279 cellular senescence-related genes were obtained from the CellAge database.Differential analysis and weighted correlation network analysis(WGCNA)were performed on hormonal osteonecrosis of the femoral head gene profiles,and both were intersected with senescence-related genes and then concatenated to obtain hormonal osteonecrosis of the femoral head senescence potential genes,and GO and KEGG analyses were performed.The machine learning method screened out the pivotal genes,constructed nomogram model,and performed consensus clustering and immune infiltration analysis.Finally,clinical femoral samples were collected for validation by qPCR and western blot assay.RESULTS AND CONCLUSION:(1)41 potential genes were obtained,which were mainly enriched in biological processes such as aging and oxidative stress response,as well as FoxO and tumor necrosis factor signaling pathways.(2)The pivotal genes catalase,connective tissue growth factor,forkhead box protein O3,insulin receptor substrate 2,and mitogen-activated protein kinase kinase 11 were obtained after machine learning identification,and the predictive ability of nomogram model was good.(3)The patients were classified into three groups,namely a,b and c,by the consensus clustering analysis.Catalase,forkhead box protein O3,insulin receptor substrate 2,and mitogen-activated protein kinase kinase 11 were differentially expressed among the three molecular subtypes(P＜0.05).Results of immune infiltration showed that the abundance of immune cells,such as activated CD4+T cells,activated CD8+T cells,and eosinophils,differed among the three molecular subclasses(P＜0.05).(4)The results of qPCR and western blot assay showed that the expression of catalase,connective tissue growth factor,forkhead box protein O3,and mitogen-activated protein kinase kinase 11 was lower in hormonal osteonecrosis of the femoral head group compared to the control group(P＜0.05),and the expression of insulin receptor substrate 2 was elevated(P＜0.05).(5)It is concluded that through in-depth analysis combined with bioinformatics and machine learning,and further experimental verification,five hormonal osteonecrosis of the femoral head age-related hub genes were finally identified.These genes are catalase,connective tissue growth factor,forkhead box o3,insulin receptor substrate 2,and serine/threonine kinase 11.These genes may provide potential molecular targets for the prevention and treatment of hormonal osteonecrosis of the femoral head in the future by regulating the cellular aging process.

Objective To explore the effect of intermittent fasting combined with diversified management mode on weight loss of overweight and obese people. Methods A total of 120 overweight and obese patients were selected as research objects, and randomly divided into control group (n=60) and experimental group (n=60). The control group was given intermittent fasting, and the experimental group was given diversified management mode on the basis of the control group. Waist circumference, body mass, body mass index (BMI), waist-to-hip ratio and blood lipid level were compared between the two groups; the scores of hunger, satiety, satisfaction and the incidence of adverse reactions were compared between the two groups. Results After intervention, waist circumference, body mass, BMI, waist-to-hip ratio, total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the experimental group were significantly lower, and high-density lipoprotein cholesterol (HDL-C) was significantly higher than that in the control group (P < 0.05). After intervention, the hunger score of the experimental group was significantly lower, and the satiety score and satisfaction score were significantly higher than those of the control group (P < 0.05). The total incidence of adverse reactions in the experimental group was 6.67%, which was significantly lower than 20.00% in the control group (P < 0.05). Conclusion The application of intermittent fasting combined with diversified management mode in overweight and obese people is better, which can improve the relevant clinical indicators and blood lipid levels, and has high safety.

Objective:To investigate the postoperative prosthesis position and early clinical efficacy of 3D printing patient-specific instrumentation (PSI)-assisted unicompartmental knee arthroplasty (UKA).Methods:The clinical data of 15 patients (17 knees, PSI group) with medial compartment knee osteoarthritis who underwent PSI-assisted UKA in the Second Affiliated Hospital, the Air Force Medical University from May to August 2023 were retrospectively analyzed, matched with fifteen patients (17 knees, non-PSI group) with medial compartment knee osteoarthritis undergoing conventional UKA. The differences in the prosthesis placement positions in the postoperative X-ray films between the two groups were compared, including the coronal varus-valgus angles of the tibial and femoral prostheses, the sagittal posterior inclination angle of the tibial prosthesis, the flexion-extension angle of the femoral prosthesis, and the height of the reconstructed joint line. The indicators related to the lower limb alignment (including the femoral valgus angle, the lateral femoral angle, the hip-knee-ankle angle, and the femur-tibia angle) and the range of motion of the knee joint before and after the operation were compared. The Oxford knee score (OKS), American Knee Society (AKS) knee score and function score, and the visual analogue scale (VAS) were used to evaluate the clinical effects of the two groups.Results:In the PSI group, the coronal varus-valgus angle of the tibial prosthesis was 1.6°±0.3° after the operation, and the sagittal posterior inclination angle was 5.7°±0.8°. The coronal varus-valgus angle of the femoral prosthesis was -0.5°±1.5°, and the sagittal flexion-extension angle was 4.0°±1.9°. In the non-PSI group, the corresponding angles were 2.3°±0.6°, 4.5°±1.0°, 1.4°±1.5°, and 7.3°±2.2° respectively with significant differences between the two groups ( P<0.05). The OKS of the PSI group before and after the operation were 26.5±1.8 and 38.6±4.1 points respectively. The AKS knee score were 56.9±8.6 and 89.2±7.2 points. The AKS function score were 70.1±4.2 and 77.5±9.4 points. The VAS were 4.5±3.7 and 2.3±0.3 points, and the range of motion of the knee joint were 115.2°±4.8° and 125.9°±4.6° with significant differences ( P<0.05). The OKS of the non-PSI group before and after the operation were 25.3±6.2 and 38.2±3.5 points respectively. The AKS knee score were 50.6±9.3 and 84.5±6.6 points. The AKS function score were 73.4±3.9 and 77.2±4.8 points. The VAS were 5.8±2.4 and 2.5±1.6 points, and the range of motion of the knee joint were 113.6°±6.7° and 122.3°±5.0° with significant differences ( P<0.05). There were inter-group differences in the AKS knee score and the range of motion of the knee joint after the operation between the two groups with significant differences ( P<0.05). Conclusion:PSI guides-assisted UKA can effectively correct the lower limb alignment of patients and improve knee joint function with good short-term efficacy. Compared with conventional UKA, PSI guides-assisted UKA is less time-consuming with higher precision in prosthesis installation position and fewer post-operative complications.

Objective:To evaluate the role of NF-E2-related factor 2 (Nrf2)/heme oxygenase (HO-1) signaling pathway in reduction of endotoxin-induced acute lung injury (ALI) by esketamine and the relationship with NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in mice.Methods:SPF male wild-type (WT) and Nrf2 knockout (KO) C57BL/6J mice, aged 6-8 weeks, weighing 20-25 g, were divided into 3 groups ( n=6 each) using a random number table method: control group (WT+ C group, KO+ C group), ALI group (WT+ ALI group, KO+ ALI group) and ALI+ esketamine group (WT+ ALI+ E group, KO+ ALI+ E group). ALI model was developed by injection of lipopolysaccharide (LPS) 15 mg/kg via the tail vein. Esketamine 10 mg/kg was intraperitoneally injected at 30 min after LPS injection, and 6 h later the medication was repeated for one time in WT+ ALI+ E and KO+ ALI+ E groups, while the equal volume of normal saline was given in the other groups. The mice were anesthetized at 12 h after LPS injection, and blood samples were obtained by cardiac puncture for determination of serum interleukin-1beta (IL-1β) and IL-18 concentrations, and bilateral lung tissues were also obtained for examination of the pathological changes of lung tissues(with the light microscope) which were scored and for determination of the content of reduced glutathione (GSH) and expression of Nrf2, HO-1 and NLRP3 inflammasome-mediated pyroptosis-related proteins (NLRP3, apoptosis-associated speck-like protein containing a CARD[ASC], pro-caspase-1, cleaved-caspase-1, gasdermin D[GSDMD]) (by Western blot). Results:Compared with the corresponding C group (WT+ C group or KO+ C group), the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in WT+ ALI group and KO+ ALI group ( P<0.05), and the expression of Nrf2 and HO-1 was significantly up-regulated in WT+ ALI group( P<0.05). Compared with the corresponding ALI group (WT+ ALI group or KO+ ALI group), the lung injury score and concentrations of IL-1β and IL-18 were significantly decreased, the content of GSH in lung tissues was increased, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was down-regulated in WT+ ALI+ E group and KO+ ALI+ E group ( P<0.05), and Nrf2 and HO-1 expression was significantly up-regulated in WT+ ALI+ E group( P<0.05). Compared with WT+ ALI+ E group, the lung injury score and concentrations of IL-1β and IL-18 were significantly increased, the content of GSH in lung tissues was decreased, the expression of Nrf2 and HO-1 was down-regulated, and the expression of NLRP3, ASC, pro-caspase-1, cleved-caspase-1 and GSDMD was up-regulated in KO+ ALI+ E group ( P<0.05). Conclusions:The mechanism by which esketamine reduces endotoxin-induced ALI may be related to activation of Nrf2/HO-1 signaling pathway, thus inhibiting NLRP3 inflammasome-mediated pyroptosis in mice.

Objective:To evaluate the influence of telomerase reverse transcriptase (TERT) promoter mutation on radioiodine uptake status of radioactive iodine refractory papillary thyroid cancer (RAIR-PTC) and radioiodine therapy response by analyzing the mutation frequency of TERT promoter in RAIR-PTC.Methods:A total of 37 patients with RAIR-PTC (15 males, 22 females, age (49.8±16.1) years) and 40 PTC patients with effective radioiodine therapy (13 males, 27 females, age (39.8±10.9) years) between January 2005 and June 2020 in JiangYuan Hospital Affiliated to Jiangsu Institute of Nuclear Medicine were retrospectively analyzed. TERT promoter mutation and B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation of patients were observed. The differences across genotype patterns on radioiodine uptake status and therapy response were compared. The Fisher′s exact test and independent-sample t test were used for data analysis. Results:The incidence rate of TERT promoter mutation in the RAIR-PTC group was 40.54% (15/37, all C228T), which was significantly higher than that in the effective radioiodine therapy group (0, 0/40; P<0.001). No statistically significant difference was found for the mutation rate of BRAF V600E between the RAIR group (64.86%, 24/37) and the effective radioiodine therapy group (72.50%, 29/40; P=0.858). Patients with TERT promoter mutation were older ( t=3.76, P=0.001) and the non-intake rate of radioiodine in distant metastases of those patients was higher ( P=0.037). Furthermore, 2/3 of patients who received targeted therapies and 3/4 deaths had TERT promoter mutation. Among 35 patients with negative thyroglobulin antibody (TgAb), 11/14 of patients with TERT mutation had a rising stimulated thyroglobulin (sTg), while the percentage of the non-TERT mutation group was 57.1% (12/21; P=0.357). Conclusion:The TERT promoter mutation rate is significantly increased in RAIR-PTC patients and can serve as a prognostic predictor in RAIR.

Objective To understand the situation of cancer screening of community residents and its association with the knowledge of cancer core knowledge, and to provide reference for the formulation of secondary cancer prevention measures. Methods A cross-sectional survey was conducted among 2 037 residents aged 18-79 who lived in Bao 'an District, Shenzhen. Multivariate Logistic regression analysis was used to investigate the relationship between core knowledge and cancer screening behavior after adjusting for age, gender, education, marriage, occupation and smoking. Results The cancer screening rate of community residents was 28.10%, and the screening rate of middle-aged and elderly people aged 40-79 was 33.50 %.The proportion of ^“not very well understanding^”, ^“partial understanding^” and ^“basic understanding^” of the core knowledge of cancer were 43.91%, 42.33% and 13.76%, respectively, which was higher than that of the non-participants. Multivariate analysis showed that the women, the higher the level of education of college/university or above and the higher the level of knowledge of cancer prevention core knowledge, the higher the probability of participating in cancer screening was OR (95%CI ) : 2.40 (1.86-3.12), 1.65 (1.29-2.10), 1.38 (1.18 - 1.62), respectively. Conclusion The proportion of cancer screening in community residents needs to be improved, and the degree of core knowledge of cancer is closely related to cancer screening behavior. It is suggested to increase the publicity and education of the core knowledge of cancer, and at the same time, carry out the health education of secondary cancer prevention for the key population such as men and people with low education level, so as to improve the proportion of ^“early detection, early diagnosis and early treatment^” of cancer.