The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H₂S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H₂S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2A^EC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST-H₂S signaling pathway. A robust reduction in endothelial MPST-dependent H₂S production followed PP2A deficiency. Exogenous H₂S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2A^EC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H₂S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.

Objective To explore the causal relationship between use of analgesic drugs and incidence of Clostridium difficile enteritis(CDE).Methods Univariate and multivariate Mendelian randomization(MR)methods were employed to investigate the potential causal relationship between use of analgesic drugs and incidence of CDE,using inverse variance weighted as the primary analytical approach.Results Univariate MR analysis indicated that use of nonsteroidal anti-inflammatory drug(NSAID)(OR=2.680,95％CI:1.689-4.252,P＜0.001)and aniline derivatives(OR=2.521,95％CI:1.503-4.229,P＜0.001)increased the risk of CDE,whereas use of opioids(OR=0.955,95％CI:0.818-1.114,P=0.556)and salicylates(OR=1.081,95％CI:0.820-1.425,P=0.579)were not identified as risk factors for CDE.The MR-Steiger test did not suggest the presence of reverse causality between exposure and outcome.After adjustment in the multivariate MR analysis,the use of NSAID was no longer a risk factor for CDE(OR=1.709,95％CI:0.864-3.308,P=0.123),while use of aniline derivatives remained a risk factor(OR=2.147,95％CI:1.239-3.721,P=0.003).Sensitivity analyses showed no evidence of heterogeneity,horizontal pleiotropy,or outliers,and no single nucleotide polymorphisms independently influenced the results.Conclusion The use of opioids does not increase the risk of CDE infection.The causal relationship between NSAID use and CDE remains inconclusive.However,the use of aniline derivatives within the NSAID class is a risk factor for CDE,while use of salicylates is not a risk factor for CDE.

Objective:To evaluate the efficacy and safety of nebulized inhalation of recombinant human interferon (IFN) α1b injection in the treatment of respiratory syncytial virus (RSV) associated lower respiratory tract infections (pneumonia and bronchiolitis) in children.Methods:A randomized, double-blind, parallel, placebo-controlled add-on design was used.Children with pneumonia or bronchiolitis aged 2 months to 5 years who tested positive for RSV antigen within 72 hours of onset from 30 clinical trial sites including Beijing Children′s Hospital, Capital Medical University between February 2021 and December 2022 were included in this study and randomly divided into 2 groups at a ratio of 1∶1 based on a stratified-block method.Both groups received basic treatments such as cough control, asthma relieving, expectorant treatment, fever reduction, oxygen therapy, etc.The experimental group received additional nebulized inhalation of IFN α1b injection at a dose of 2.0 μg/(kg·time), twice a day.The control group received nebulized inhalation of placebo twice a day.Clinical efficacy was evaluated based on indicators such as the duration of clinical symptoms and signs, and the Kaplan-Meier method was used to calculate the median and 95% CI of the duration of clinical symptoms and signs.The Log-rank test was used to compared data between groups.Safety was assessed through the incidence of adverse reactions and laboratory tests, and the Chi-square test was used to analyze the difference between groups. Results:There were 123 children in the experimental group and 122 children in the control group.The median durations of all the 5 clinical symptoms and signs [including shortness of breath, wheezing, dyspnea (visible retractions), decreased transcutaneous oxygen saturation, and abnormal mental state] in the experimental group after treatment were slightly shortened than those in the control group [2.7 d(95% CI: 1.9-3.0 d)] vs.[2.9 d(95% CI: 2.6-3.6 d), P=0.027].The improvement in dyspnea (retractions) was especially pronounced in the experimental group, with a relief rate of 50.0% (0, 100%) on the first day of administration[compared with 0 (0, 50.0%) in the control group ( Z=2.002, P=0.025)].The median duration of dyspnea in the experimental group was nearly 1 day shorter than that in the control group [1.0 d(95% CI: 0.7-1.7 d) vs.1.8 d(95% CI: 1.0-2.5 d), P=0.046].There were no significant difference in hospital stay [6.0(5.0, 8.0) d vs.6.5(5.0, 8.0) d, Z=0.675, P=0.500], oxygen therapy duration [32.0(14.0, 96.3) h vs.39.0 (24.0, 83.2) h, Z=0.094, P=0.925], the recovery rate from clinical symptoms during treatment [(105/106, 99.1%) vs.(96/101, 95.0%)], and recurrence rate [(0/106, 0) vs.(2/101, 2.0%)] between the 2 groups (all P>0.05).However, the above-mentioned four indicators in the experimental group showed a trend of clinical benefits.The quantitative virus detection results showed that the RSV viral load in both groups decreased after treatment compared to before treatment.After 2 days of treatment, the decline rate of RSV viral load from the baseline was 0.90 lg copies/(mL·d) in the experimental group and 0.25 lg copies/(mL·d)in the control group, with a statistically significant difference ( P<0.05).Furthermore, there was no statistically significant difference in the incidence of adverse reactions between the 2 groups ( P>0.05).Importantly, no drug-related serious adverse reactions occurred in both groups. Conclusions:The nebulized inhalation therapy of IFN α1b demonstrates efficacy and safety in treating pediatric RSV associated lower respiratory tract infections.It particularly offers outstanding clinical therapeutic value for severe children.

Objective To explore the causal relationship between use of analgesic drugs and incidence of Clostridium difficile enteritis(CDE).Methods Univariate and multivariate Mendelian randomization(MR)methods were employed to investigate the potential causal relationship between use of analgesic drugs and incidence of CDE,using inverse variance weighted as the primary analytical approach.Results Univariate MR analysis indicated that use of nonsteroidal anti-inflammatory drug(NSAID)(OR=2.680,95％CI:1.689-4.252,P＜0.001)and aniline derivatives(OR=2.521,95％CI:1.503-4.229,P＜0.001)increased the risk of CDE,whereas use of opioids(OR=0.955,95％CI:0.818-1.114,P=0.556)and salicylates(OR=1.081,95％CI:0.820-1.425,P=0.579)were not identified as risk factors for CDE.The MR-Steiger test did not suggest the presence of reverse causality between exposure and outcome.After adjustment in the multivariate MR analysis,the use of NSAID was no longer a risk factor for CDE(OR=1.709,95％CI:0.864-3.308,P=0.123),while use of aniline derivatives remained a risk factor(OR=2.147,95％CI:1.239-3.721,P=0.003).Sensitivity analyses showed no evidence of heterogeneity,horizontal pleiotropy,or outliers,and no single nucleotide polymorphisms independently influenced the results.Conclusion The use of opioids does not increase the risk of CDE infection.The causal relationship between NSAID use and CDE remains inconclusive.However,the use of aniline derivatives within the NSAID class is a risk factor for CDE,while use of salicylates is not a risk factor for CDE.

Objective:To evaluate the efficacy and safety of nebulized inhalation of recombinant human interferon (IFN) α1b injection in the treatment of respiratory syncytial virus (RSV) associated lower respiratory tract infections (pneumonia and bronchiolitis) in children.Methods:A randomized, double-blind, parallel, placebo-controlled add-on design was used.Children with pneumonia or bronchiolitis aged 2 months to 5 years who tested positive for RSV antigen within 72 hours of onset from 30 clinical trial sites including Beijing Children′s Hospital, Capital Medical University between February 2021 and December 2022 were included in this study and randomly divided into 2 groups at a ratio of 1∶1 based on a stratified-block method.Both groups received basic treatments such as cough control, asthma relieving, expectorant treatment, fever reduction, oxygen therapy, etc.The experimental group received additional nebulized inhalation of IFN α1b injection at a dose of 2.0 μg/(kg·time), twice a day.The control group received nebulized inhalation of placebo twice a day.Clinical efficacy was evaluated based on indicators such as the duration of clinical symptoms and signs, and the Kaplan-Meier method was used to calculate the median and 95% CI of the duration of clinical symptoms and signs.The Log-rank test was used to compared data between groups.Safety was assessed through the incidence of adverse reactions and laboratory tests, and the Chi-square test was used to analyze the difference between groups. Results:There were 123 children in the experimental group and 122 children in the control group.The median durations of all the 5 clinical symptoms and signs [including shortness of breath, wheezing, dyspnea (visible retractions), decreased transcutaneous oxygen saturation, and abnormal mental state] in the experimental group after treatment were slightly shortened than those in the control group [2.7 d(95% CI: 1.9-3.0 d)] vs.[2.9 d(95% CI: 2.6-3.6 d), P=0.027].The improvement in dyspnea (retractions) was especially pronounced in the experimental group, with a relief rate of 50.0% (0, 100%) on the first day of administration[compared with 0 (0, 50.0%) in the control group ( Z=2.002, P=0.025)].The median duration of dyspnea in the experimental group was nearly 1 day shorter than that in the control group [1.0 d(95% CI: 0.7-1.7 d) vs.1.8 d(95% CI: 1.0-2.5 d), P=0.046].There were no significant difference in hospital stay [6.0(5.0, 8.0) d vs.6.5(5.0, 8.0) d, Z=0.675, P=0.500], oxygen therapy duration [32.0(14.0, 96.3) h vs.39.0 (24.0, 83.2) h, Z=0.094, P=0.925], the recovery rate from clinical symptoms during treatment [(105/106, 99.1%) vs.(96/101, 95.0%)], and recurrence rate [(0/106, 0) vs.(2/101, 2.0%)] between the 2 groups (all P>0.05).However, the above-mentioned four indicators in the experimental group showed a trend of clinical benefits.The quantitative virus detection results showed that the RSV viral load in both groups decreased after treatment compared to before treatment.After 2 days of treatment, the decline rate of RSV viral load from the baseline was 0.90 lg copies/(mL·d) in the experimental group and 0.25 lg copies/(mL·d)in the control group, with a statistically significant difference ( P<0.05).Furthermore, there was no statistically significant difference in the incidence of adverse reactions between the 2 groups ( P>0.05).Importantly, no drug-related serious adverse reactions occurred in both groups. Conclusions:The nebulized inhalation therapy of IFN α1b demonstrates efficacy and safety in treating pediatric RSV associated lower respiratory tract infections.It particularly offers outstanding clinical therapeutic value for severe children.

Objective:To explore the impact of Cullin5 on the radiosensitivity of glioblastoma multiforme cell and its underlying mechanisms.Methods:Glioblastoma U251 cells were transfected with flag-NC plasmids and overexpression plasmids (flag-Cullin5), and divided into the flag-NC group and flag-Cullin5 group. The expression levels of Cullin5 and programmed death ligand 1 (PD-L1) mRNA and protein were assessed using real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. After exposing U251 cells to 0, 2, 4, and 8 Gy X-ray radiation, cell viability was evaluated via the CCK-8 assay, and apoptosis rates were measured using flow cytometry. Co-immunoprecipitation was used to detect the interaction between Cullin5 and PD-L1, and ubiquitination assays were conducted to investigate the ubiquitination effect of Cullin5 on PD-L1. Cells were further transfected with PD-L1 overexpression (oe-PD-L1) and flag-Cullin5 and assigned into the flag-Cullin5 group, flag-Cullin5+oe-NC group, and flag-Cullin5+oe-PD-L1 group. qRT-PCR and Western blot were used to measure the expression levels of Cullin5 and PD-L1 mRNA and protein post-X-ray radiation in these groups. Cell survival rates and apoptosis rates were measured following radiation. Statistical differences between two or among multiple groups were analyzed using LSD- t test or one-way ANOVA. Results:Compared with the flag-NC group, the flag-Cullin5 group showed increased expression levels of Cullin5 mRNA and protein, and decreased PD-L1 protein expression (all P<0.05). Following radiation doses of 4 and 8 Gy, there was a reduction in cell survival rates and an increase in apoptosis rates (both P<0.05). Co-immunoprecipitation assay revealed the presence of PD-L1 in the Cullin5 immunoprecipitate and vice versa. Ubiquitination levels of PD-L1 protein were higher in the flag-Cullin5 group compared to those in the flag-NC group. Additionally, compared to the flag-Cullin5 group, the flag-Cullin5+oe-PD-L1 group exhibited increased PD-L1 mRNA and protein levels (both P<0.05), and following radiation doses of 4 and 8 Gy, these cells showed higher survival rates and lower apoptosis rates (both P<0.05). Conclusion:Cullin5 enhances the radiosensitivity of glioblastoma multiforme cells to radiation therapy through mediating the ubiquitination degradation of PD-L1.

ObjectiveTo investigate the protective effect of salidroside against nonalcoholic fatty liver disease （NAFLD） and its mechanism of action. MethodsA total of 24 male KM mice were randomly divided into normal group， HFD group， HFD+blank control group， and HFD+salidroside group， with 6 mice in each group. The mice in the normal group were given normal diet， and those in the other groups were given high-fat diet. After 14 weeks of modeling， the mice were given salidroside 100 mg/kg/day by gavage， and related samples were collected at the end of week 22. Enzyme-linked immunosorbent assay was used to measure the serum levels of related biochemical parameters including alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， triglyceride （TG）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C）； HE staining and NAFLD activity score （NAS） were used to observe the liver histopathology of mice； Western blot was used to measure the changes in the expression of NAMPT， Sirt1， AMPKα， and SREBP1 in liver tissue. A one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the normal group， the HFD group had obvious steatosis and extensive large lipid droplets in liver tissue， with significant increases in NAS score （P<0.01） and the content of AST， ALT， TG， TC， and LDL-C in peripheral blood （all P<0.05） and a significant reduction in the content of HDL-C （P<0.05）， as well as significant reductions in the expression levels of NAMPT， AMPKα， and Sirt1 in liver tissue （all P<0.05） and a significant increase in the expression level of SERBP1 （P<0.01）. Compared with the HFD group and the HFD+blank control group， the HFD+salidroside group had reductions in the distribution of vacuolar lipid droplets and intralobular inflammation in liver tissue， alleviation of the ballooning degeneration of hepatocytes， significant reductions in NAS score （P<0.01） and the content of AST， ALT， TG， and LDL-C in peripheral blood （all P<0.05）， and a significant increase in the content of HDL-C （P<0.05）， as well as significant increases in the expression levels of NAMPT， AMPKα， and Sirt1 in liver tissue （all P<0.05） and a significant reduction in the expression level of SERBP1 （P<0.01）. ConclusionSalidroside can significantly improve the pathological state of mice with NAFLD induced by high-fat diet and exert a protective effect against NAFLD by increasing the expression of NAMPT， Sirt1， and AMPKα and reducing the expression of SERBP1.

Objective:To explore the risk factors of pressure injury (PI) in postoperative coma patients with severe brain injury (SBI) .Methods:From June 2018 to April 2022, 300 postoperative coma patients with SBI admitted to Henan Provincial People's Hospital were selected as the study subject by convenience sampling. Patients were divided into PI group ( n=35) and non-PI group ( n=265) based on whether PI occurred 7 days after surgery, and the clinical data of the two groups of patients were compared. Logistic regression was used to analyze the risk factors for postoperative PI in coma patients with SBI. Results:Among 300 postoperative coma patients with SBI, the incidence of PI during hospitalization was 11.67% (35/300), with a total of 54 occurrences of PI. Logistic regression analysis showed that age, diabetes, malnutrition, urinary and fecal incontinence, respiratory mode and postoperative hyperthermia were all the influencing factors of PI in coma patients with SBI after surgery ( P<0.05) . Conclusions:Age, diabetes, malnutrition, urinary and fecal incontinence, mechanical ventilation and postoperative high fever are all risk factors for PI in coma patients with SBI. Nurses should actively evaluate the risk of PI and provide targeted preventive measures.

Humans ; Depressive Disorder, Major ; Motor Cortex ; Magnetic Resonance Imaging

Objective To analyze the etiological characteristics and the variation of pathogens spectrum in hospitalized children with a-cute respiratory tract infection(ARTI)before and after COVID-19 under"the level B of management for class B"of infectious diseases(Level B for Class B)in Shenzhen,in order to provide reference for the clinical diagnosis,treatment and prevention of ARTI.Meth-ods The ARTI cases from January 8,2022 to July 30,2022 were selected as before"Level B for Class B",and the cases from Janu-ary 8,2023 to July 30,2023 were selected as after"Level B for Class B".The pharyngeal swab samples submitted for analyzing 11 common pathogens,such as COVID-19,influenza virus(Ⅳ),respiratory syncytial virus(RSV)and mycoplasma pneumoniae(MP)in the children with ARTI admitted to Shenzhen Children's Hospital.Results SARS-CoV-2 were detected as positive in 347 cases,a-mong which 225 cases were before"Level B for Class B"including 29 cases combined with other pathogens(12.89％,29/225)and human parainfluenza viruses(HPIV)was the most common(31.03％,9/29).After"Level B for Class B",SARS-CoV-2 were detec-ted as positive in 122 cases,including 28 cases combined with other pathogens(22.95％,28/122),and RSV was the most common(28.57％,8/28).There was a statistical difference between the positive rate of SARS-CoV-2 combined with other pathogens before and after"Level B for Class B"(X2=5.834,P=0.016).After"Level B for Class B",the total pathogen detection rate(positive for at least one pathogen)was 60.82％(2 864/4 709)in the spring(January 8,2023 to April 30,2023),and influenza virus A(IVA)(22.64％,1 066/4 709),rhinovirus(HRV)(19.86％,935/4 709)and RSV(13.29％,626/4 709)were the main pathogens,and there were 301 cases(6.39％,301/4 709)of mixed infections.In the summer(May 1,2023 to July 30,2023),the total detection rate of pathogens was 70.26％(4 012/5 710),among which RSV(21.63％,1 235/5 710),MP(13.91％,794/5 710),HPIV(10.05％,574/5 710)were the main pathogens,and there were 710 cases(12.43％,710/5 710)of mixed infections,all of which were significantly higher than the same period before"Level B for Class B".The difference was statistically significant(P＜0.05).Conclusion After"Level B for Class B"for COVID-19,the detection rate of 11 common pathogens increased significantly and the pathogen spectrum of ARTI changed significantly.