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.

AIM:To investigate the effects of exercise preconditioning(EP)combined with electroacupunc-ture(EA)on learning and memory ability of rats with vascular dementia(VD),and to explore role of hippocampal ferrop-tosis in this process.METHODS:Seventy-two male SD rats were randomly divided into non-EP group and EP group,with 36 rats in each group.The rats were subjected to EP,and subsequently to establish the VD model.The rats from non-EP group were randomly divided into sham group,model group(VD group)and VD-EA group,each with 12 rats,while those in EP group were randomly divided into EP-sham group,EP-VD group and EP-VD-EA group,each with 12 rats.All rats in EP group underwent 4 weeks of swimming exercise training,5 d per week,30 min per day.At the end of the 4th week,the rats in VD,EP-VD,EP-VD-EA and VD-EA groups were used to induce the VD model,and the rats in sham and EP-sham groups received a sham surgery to simulate the VD model.On the 7th day after successful modeling,the rats in EP-VD-EA and VD-EA groups were treated with EA for 4 weeks,6 d per week,30 min per day.At the end of the inter-vention,the learning and memory ability of the rats was evaluated using Morris water maze.Neuron morphology in the CA1 area of rat hippocampus was observed through Nissl staining.Ferrous ion(Fe2+),malondialdehyde(MDA)and re-duced glutathione(GSH)contents in the rat hippocampal tissues were quantified using the colorimetric assay.The expres-sion levels of ferroptosis-related proteins,nuclear factor E2-related factor 2(Nrf2)and glutathione peroxidase 4(GPX4),in the hippocampal tissues were quantified by Western blot method.RESULTS:Compared with sham group,the rats in VD group exhibited longer mean evasion latency and decreased number of traversals across the plateau(P<0.01).The neurons in the CA1 region of the hippocampus were loose and disorganized,exhibiting an irregular cellular morphology.The hippocampal Fe2+and MDA content was elevated,and the GSH content was reduced(P<0.01).The protein levels of hippocampal Nrf2 and GPX4 were decreased(P<0.01).Compared with VD group,the rats in EP-VD,EP-VD-EA and VD-EA groups showed a shorter average escape latency and an increased number of traversals across the plateau(P<0.05).Neurons in the hippocampal CA1 area were more neatly arranged,showing regular cellular morphology.The hip-pocampal Fe2+and MDA contents of the rats in EP-VD group were significantly reduced(P<0.01),while the GSH content was elevated(P<0.05).Hippocampal Fe2+and MDA contents were significantly reduced and GSH contents were signifi-cantly increased in EP-EA and EA groups(P<0.01).The protein levels of hippocampal Nrf2 and GPX4 in EP-VD,EP-VD-EA and VD-EA groups were significantly increased(P<0.01).CONCLUSION:Exercise preconditioning combined with EA improves learning and memory ability in VD rats by reducing hippocampal intra-neuronal iron overload,maintain-ing organismal redox homeostasis,and inhibiting ferroptosis.

ObjectiveTo provide reference for further strengthening the management of laboratory animals in Sichuan Province by reviewing and analyzing the results of parasitic and microbial quality inspections of laboratory animals from 2017 to 2023. Methods Sichuan Province has 31 licensed laboratory animal production units, with the main species including mice, rats, guinea pigs, rabbits, dogs, monkeys, and pigs. Sampling inspections and reports were conducted for units with laboratory animal production qualifications in accordance with current national and local standards for laboratory animal classification. The quality inspection results for various laboratory animals in Sichuan Province from 2017 to 2023 were analyzed. Results With the exception of 2018, annual quality inspections of laboratory animals were conducted every year between 2017 and 2023. Mice: In 2017, positive results for helminths, flagellates, Salmonella, murine hepatitis virus antibodies, and murine pneumonia virus antibodies were detected, with a pass rate of only 42.9%. In 2019, Staphylococcus aureus and Klebsiella pneumoniae were detected, with a pass rate of 86.7%. In 2021, Sendai virus antibodies were detected, yielding a pass rate of 85.7%.The pass rate in 2020, 2022, and 2023 was 100%. Rats: In 2017, positive results were found for helminths, mycoplasma antibodies, Staphylococcus aureus, Sendai virus antibodies, murine pneumonia virus antibodies, rat parvovirus RV strain antibodies, rat parvovirus (H-1) strain antibodies, and rat coronavirus antibodies, with a pass rate of 40.0%. In 2019, mycoplasma antibodies, Staphylococcus aureus and Klebsiella pneumoniae were detected, with a pass rate of 35.0%. No positive indicators were detected in 2020. In 2021, Sendai virus antibodies and rat parvovirus RV strain antibodies were detected, with a pass rate of 50.0%. In 2022, positive results for rat parvovirus RV strain antibodies were found, yielding a pass rate of 87.5%. In 2023, Pasteurella pneumotropica and Klebsiella pneumoniae were detected, with a pass rate of 85.7%. Dogs: In 2017 and 2019, the antibody titers for rabies virus and canine distemper virus were below the required standard, with pass rates of 33.3% and 20.0%, respectively. In 2020 and 2022, the pass rate was 100%. Guinea pigs (general grade): In 2019, positive results for Toxoplasma antibodies were detected, with a pass rate of 80.0%. In all other years, the pass rate was 100%. Monkeys: In 2019, positive results for Toxoplasma gondii and rhesus herpesvirus type I antibodies were found, with a pass rate of 87.5%.In 2020 and 2022, rhesus herpesvirus type I antibodies were positively detected, yielding pass rates of 93.3% and 97.5%, respectively. The pass rates in 2021 and 2023 were 100%. Clean guinea pigs, rabbits and pigs all passed the inspection each year. ConclusionIssues related to the parasitic and microbial quality of laboratory animals persist in Sichuan Province. Supervision and sampling inspections have proven to be effective in identifying these issues promptly, serving as a critical measure to ensure the quality of laboratory animals. The results of these inspections offer valuable data to support the healthy development of the laboratory animal industry in Sichuan Province.

Objective To investigate the efficacy and safety of cryoablation combined with Camrelizumab monoclonal antibody in the treatment of hepatocellular carcinoma(HCC).Methods A total of 103 HCC patients who were admitted to our hospital from June 2020 to June 2023 were enrolled and randomly divided into combined treatment group with 53 patients and control group with 50 patients.The patients in the control group received percutaneous argon-helium cryoablation,and those in the combined treatment group received percutaneous argon-helium cryoablation combined with Camrelizumab monoclonal antibody.The two groups were compared in terms of short-term response,changes in T lymphocyte subsets after treatment,changes in liver function and alpha-fetoprotein(AFP)after treatment,and progression-free survival and overall survival during follow-up.The t-test was used for comparison of normally distributed continuous data between groups,and the chi-square test was used for comparison of categorical data between groups.The Kaplan-Meier method was used to plot survival curves,and the log-rank test was used for comparison of survival time between the two groups.Results The combined treatment group had significantly higher overall response rate and disease control rate than the control group(χ2=4.156 and 4.348,P=0.042 and 0.037).After treatment,the combined treatment group had significant increases in the percentages of CD3+and CD4+T lymphocytes and CD4+/CD8+ratio(P＜0.05)and a significant reduction in the percentage of CD8+T lymphocytes(P＜0.05),while the control group had no significant changes in T lymphocyte subsets after treatment(P＞0.05),and compared with the control group after treatment,the combined treatment group had significantly higher percentages of CD3+and CD4+T lymphocytes and CD4+/CD8+ratio(all P＜0.05)and a significantly lower percentage of CD8+T lymphocytes(P＜0.05).After treatment,both groups had significant reductions in the levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),and AFP(all P＜0.05)and a significant increase in the level of albumin(Alb)(P＞0.05),and compared with the control group after treatment,the combined treatment group had significantly lower levels of ALT,AST,and AFP(all P＜0.05)and a significantly higher level of Alb(P＜0.05).There were no significant differences in the incidence rates of grade Ⅲ—Ⅳ(moderate to severe)adverse reactions between the two groups(P＞0.05).Compared with the control group,the combined treatment group had significantly better median progression-free survival(21.32 months vs 15.31 months,χ2=4.689,P=0.030)and median overall survival(28.36 months vs 20.75 months,χ2=5.030,P=0.025).Conclusion Argon-helium cryoablation combined with Camrelizumab monoclonal antibody can effectively improve short-term response,enhance immune function,and prolong survival time,with a favorable safety profile.

Objective To explore the effect of applying comprehensive interventions on promoting pathogen detec-tion before antimicrobial therapy in hospitalized patients.Methods Hospitalized patients who received therapeutic use of antimicrobial agents in a tertiary first-class hospital from January 2020 to December 2021 were selected as the research subjects.Comprehensive intervention measures were implemented from January 2021.The pathogen detec-tion rates,detection classification,and detection rates of key monitored departments before antimicrobial therapy were compared between the pre-intervention group(January-December 2020)and the post-intervention group(Janu-ary-December 2021).Results A total of 10 239 hospitalized patients who received therapeutic use of antimicrobial agents were included in analysis,4 526 cases were in the pre-intervention group and 5 713 cases in the post-interven-tion group.The pathogen detection rates before antimicrobial therapy,before restricted grade antimicrobial therapy,and before special grade antimicrobial therapy after intervention were 94.56％,94.72％,and 96.03％,respective-ly,which were higher than 83.74％,84.47％,and 84.95％before intervention,with statistical significance(all P＜0.05).The detection rate of targeted pathogens after intervention was 64.87％,higher than that before interven-tion(28.04％),with statistically significant difference(P＜0.05).The pathogen detection rates before therapeutic use of antimicrobial agents in departments of critical care medicine,pulmonary and critical care medicine,pediatrics,neurosurgery,and general surgery after intervention were 93.20％,91.17％,92.20％,94.12％,and 91.15％,re-spectively,higher than the rates before intervention,namely 85.00％,82.19％,83.20％,83.33％,and 83.03％,respectively,with statistical significance(all P＜0.05).Conclusion The application of comprehensive intervention measures can improve the pathogen detection rate before antimicrobial therapy of hospitalized patients.Close atten-tion should be paid to the pathogen detection indicators related to healthcare-associated infection diagnosis and for the detection of sterile body fluid.

Objective To understand the distribution and changing resistance profiles of clinical isolates of Enterococcus in hospitals across China from 2015 to 2021.Methods Antimicrobial susceptibility testing was conducted for the clinical isolates of Enterococcus according to the unified protocol of CHINET program by automated systems,Kirby-Bauer method,or E-test strip.The results were interpreted according to the Clinical & Laboratory Standards Institute(CLSI)breakpoints in 2021.WHONET 5.6 software was used for statistical analysis.Results A total of 124 565 strains of Enterococcus were isolated during the 7-year period,mainly including Enterococcus faecalis(50.7％)and Enterococcus faecalis(41.5％).The strains were mainly isolated from urinary tract specimens(46.9％±2.6％),and primarily from the patients in the department of internal medicine,surgery and ICU.E.faecium and E.faecalis strains showed low level resistance rate to vancomycin,teicoplanin and linezolid(≤3.6％).The prevalence of vancomycin-resistant E.faecalis and E.faecium was 0.1％and 1.3％,respectively.The prevalence of linezolid-resistant E.faecalis increased from 0.7％in 2015 to 3.4％in 2021,while the prevalence of linezolid-resistant E.faecium was 0.3％.Conclusions The clinical isolates of Enterococcus were still highly susceptible to vancomycin,teicoplanin,and linezolid,evidenced by a low resistance rate.However,the prevalence of linezolid-resistant E.faecalis was increasing during the 7-year period.It is necessary to strengthen antimicrobial resistance surveillance to effectively identify the emergence of antibiotic-resistant bacteria and curb the spread of resistant pathogens.

Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus of the Orthopneumovirus  genus of the Pneumoviridae family in the order Mononegavirales. RSV can cause acute upper and lower respiratory tract infections, sometimes with extrapulmonary complications. The disease burden of RSV infection is enormous, mainly affecting infants and older adults aged 75 years or above. Currently, treatment options for RSV are largely supportive. Prevention strategies remain a critical focus, with efforts centered on vaccine development and the use of prophylactic monoclonal antibodies. To date, three RSV vaccines have been approved for active immunization among individuals aged 60 years and above. For children who are not eligible for these vaccines, passive immunization is recommended. A newly approved prophylactic monoclonal antibody, Nirsevimab, which offers enhanced neutralizing activity and an extended half-life, provides exceptional protection for high-risk infants and young children. This review provides a comprehensive and detailed exploration of RSV's virology, immunology, pathogenesis, epidemiology, clinical manifestations, treatment options, and prevention strategies.
Humans ; Respiratory Syncytial Virus Infections/prevention & control* ; Respiratory Syncytial Viruses/pathogenicity* ; Respiratory Syncytial Virus, Human/pathogenicity* ; Antiviral Agents/therapeutic use*

BACKGROUND: Stress cardiomyopathy (SCM) currently has a high incidence in older adults, and the theories regarding its causes include "catecholamine myocardial toxicity" and "sympathetic hyperactivation". However, the role of the central nervous system in the pathogenesis of SCM remains unknown. We investigated the role of microglia activation in the paraventricular hypothalamic nucleus (PVN) in the development of SCM. METHODS: An SCM model was created using male Sprague-Dawley (SD) rats, immobilized for 6 h every day for a week. Electrocardiogram, cardiac electrophysiology, and echocardiography examinations were performed to verify the changes in cardiac structure and function in rats with SCM. RNA sequencing was used to explore the changes in the hypothalamus during SCM. In addition, brain and heart tissues were collected to detect microglial activation and sympathetic activity. RESULTS: The main findings were as follows: (1) immobilization stress successfully induced SCM in SD rats; (2) microglia were significantly activated in the hypothalamus, as evidenced by cytosol thickening, increases in the number of microglial branches, and microglia enriched in the PVN; (3) in SCM, the microglia in the PVN exhibited increased central and peripheral cardiac sympathetic activity and increased the expression of neuroinflammatory factors; and (4) it is possible that inhibiting microglial activation could suppress the sympathetic activity of the central nervous system and heart and increase cardiac electrical stability in SCM rats. CONCLUSIONS SCM was induced in SD rats by immobilization stress, acting through the activation of the hypothalamic microglia. The activated microglia were specifically enriched in the PVN, increasing the activity of the central and peripheral sympathetic nervous systems by regulating the expression of neuro-inflammatory factors, mediating dysfunction of the left ventricle, and increasing the susceptibility to ventricular arrhythmias.

Objective:To investigate the diagnostic accuracy of serological indicators and evaluate the diagnostic value of a new established combined serological model on identifying the minimal hepatic encephalopathy (MHE) in patients with compensated cirrhosis.Methods:This prospective multicenter study enrolled 263 compensated cirrhotic patients from 23 hospitals in 15 provinces, autonomous regions and municipalities of China between October 2021 and August 2022. Clinical data and laboratory test results were collected, and the model for end-stage liver disease (MELD) score was calculated. Ammonia level was corrected to the upper limit of normal (AMM-ULN) by the baseline blood ammonia measurements/upper limit of the normal reference value. MHE was diagnosed by combined abnormal number connection test-A and abnormal digit symbol test as suggested by Guidelines on the management of hepatic encephalopathy in cirrhosis. The patients were randomly divided (7∶3) into training set ( n=185) and validation set ( n=78) based on caret package of R language. Logistic regression was used to establish a combined model of MHE diagnosis. The diagnostic performance was evaluated by the area under the curve (AUC) of receiver operating characteristic curve, Hosmer-Lemeshow test and calibration curve. The internal verification was carried out by the Bootstrap method ( n=200). AUC comparisons were achieved using the Delong test. Results:In the training set, prevalence of MHE was 37.8% (70/185). There were statistically significant differences in AMM-ULN, albumin, platelet, alkaline phosphatase, international normalized ratio, MELD score and education between non-MHE group and MHE group (all P<0.05). Multivariate Logistic regression analysis showed that AMM-ULN [odds ratio ( OR)=1.78, 95% confidence interval ( CI) 1.05-3.14, P=0.038] and MELD score ( OR=1.11, 95% CI 1.04-1.20, P=0.002) were independent risk factors for MHE, and the AUC for predicting MHE were 0.663, 0.625, respectively. Compared with the use of blood AMM-ULN and MELD score alone, the AUC of the combined model of AMM-ULN, MELD score and education exhibited better predictive performance in determining the presence of MHE was 0.755, the specificity and sensitivity was 85.2% and 55.7%, respectively. Hosmer-Lemeshow test and calibration curve showed that the model had good calibration ( P=0.733). The AUC for internal validation of the combined model for diagnosing MHE was 0.752. In the validation set, the AUC of the combined model for diagnosing MHE was 0.794, and Hosmer-Lemeshow test showed good calibration ( P=0.841). Conclusion:Use of the combined model including AMM-ULN, MELD score and education could improve the predictive efficiency of MHE among patients with compensated cirrhosis.

ObjectiveTo observe the effect of Cuscutae Semen total flavonoids combined with Tripterygium wilfordii polyglycoside tablets （TWPT） on ovarian germline stem cells of female physiological mice through neurogenic locus notch homolog （Notch） signaling pathway. MethodSixty female Kunming mice （5 weeks old） were randomly divided into normal group， Tripterygium wilfordii polyglycoside tablets low-， high-dose groups （13.65 mg·kg^-1·d^-1 and 27.3 mg·kg^-1·d^-1， 1 and 2 times clinical equivalent dose）， Cuscutae Semen total flavonoids low- and high-dose groups （150 mg·kg^-1·d^-1 and 300 mg·kg^-1·d^-1）， and combination group （13.65 mg·kg^-1·d^-1 TWPT and 150 mg·kg^-1·d^-1 Cuscutae Semen total flavonoids）， with 10 in each group. After 3 weeks of continuous administration， the uterus/brain and ovarian/brain indexes were calculated， and the pathological changes of ovarian tissue were observed under light microscope. The content of estradiol in serum was determined by enzyme linked immunosorbent assay （ELISA）. Immunofluorescence assay was performed to observe the expressions of germline stem cell markers in ovarian epithelium， including mouse vasa homologue （Mvh）， octamer-binding transcription factor 4 （Oct4）， tyrosine-protein kinase receptor （c-kit）， Nanog， Notch signaling pathway molecules， neurogenic locus notch homolog protein 1 （Notch1）， hes family BHLH transcription factor 1（Hes1）， and jagged canonical Notch ligand 1 （JAG1）. ResultCompared with the normal group， low and high doses of TWPT had no significant effect on the uterus/brain and ovary/brain indexes and the uterus and ovary morphologies of mice， while only the number of atretic follicles was increased （P<0.01）. The expressions of ovarian germline stem cell markers and Notch signaling pathway molecules had a decreasing trend in TWPT low-dose group， while the expressions of Mvh， c-kit， and Nanog were down-regulated （P<0.05， P<0.01） and the expressions of Notch1 and Hes1 were also reduced （P<0.01） in TWPT high-dose group. However， the above indexes were increased in Cuscutae Semen total flavonoids low-dose group （P<0.05， P<0.01）. Compared with the low does of TWPT group， the combination group had a decrease in the increased number of atretic follicles （P<0.01）， an improvement in the down-regulated expressions of Mvh and Nanog （P<0.01）， and an increase in the expressions of Notch1 and Hes1 （P<0.05， P<0.01）. ConclusionOvarian germline stem cells are the source target of the reproductive toxicity of TWPT. Cuscutae Semen total flavonoids participate in the regulation of the germline stem cell pathways to alleviate the reproductive toxicity caused by TWPT， and its mechanism of action may be related to the Notch signaling pathway.