BACKGROUND:Disruption of biological rhythms(circadian rhythms)is a typical problem associated with aging.Maintaining the normal function of biological rhythms may be a promising anti-aging strategy.Expression of nuclear factor erthroid 2-related factor 2(Nrf2)is biologically regulated.The glycogen synthase kinase 3(GSK3)system represents a"regulatory valve"that controls subtle oscillations in Nrf2 levels.Circadian changes in the transcript levels of antioxidant genes can influence the response of organisms to oxidative stress.However,the specific molecular mechanism of GSK3/Nrf2 in regulating organismal aging is still puzzling. OBJECTIVE:To search for the general pattern of GSK3/Nrf2-regulated biological rhythms in organismal aging by reviewing the literature in this field. METHODS:The bibliographic method was used to search,review and screen the relevant literature using the keywords of"glycogen synthase kinase 3,nuclear factor erthroid 2-related factor 2,biorhythms and aging"to lay a theoretical foundation for the analysis of the whole paper.Comparative analysis method,through reading and analyzing the obtained literature,was performed to compare the similarities and differences between the literature,thereby providing reasonable theoretical support for the argument.Further comparative analysis of the literature was conducted to clarify the relationship between the relevant indicators as well as the ideas for analysis throughout the text. RESULTS AND CONCLUSION:GSK3 can indirectly regulate Nrf2 expression through the regulation of rhythm genes.GSK3 and Nrf2 are components of anti-aging programs and are associated with biological rhythms.In addition,GSK3/Nrf2 is involved in several metabolic pathways,including those associated with age-related diseases(type 2 diabetes and cancer)and neurodegenerative diseases.

Objective:To investigate the impact of receptor-interacting protein kinase 3 (RIPK3) on major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), as well as the predictive performance of RIPK3 combined with traditional cardiovascular risk factors.Methods:This study was a single-center prospective cohort study. It included patients with AMI who underwent PCI at Peking Union Medical College Hospital between September 2017 and November 2017. Baseline clinical data were collected, and plasma samples were obtained 6 hours after PCI to measure RIPK3 levels. Follow-up was conducted via outpatient visits or phone calls to record the occurrence of MACE, including cardiovascular death, hospitalization for heart failure, and vascular events (recurrent AMI or stroke). The predictive performance of RIPK3, traditional cardiovascular risk factors and their combination for MACE was compared using receiver operating characteristic (ROC) curves. Patients were divided into low- and high-RIPK3 level groups based on the optimal cutoff value of RIPK3. Multivariate Cox proportional hazards regression analysis was used to assess the impact of RIPK3 levels on MACE after PCI in AMI patients. Kaplan-Meier survival curves were plotted, and the log-rank test was used to compare MACE incidence between the low-and high-RIPK3 groups.Results:A total of 103 AMI patients who underwent PCI were included, aged 63.0 (56.0, 69.0) years, and 83 (80.6%) were male. The follow-up time was 5.17 (2.81, 5.17) years, during which 44 patients (42.7%) experienced MACE. The ROC curve analysis showed that the area under the curve ( AUC) for traditional cardiovascular risk factors was 0.68 (95% CI: 0.58-0.78), while the AUC for plasma RIPK3 was 0.72 (95% CI: 0.62-0.82). The combined AUC for traditional risk factors and RIPK3 was 0.75 (95% CI: 0.65-0.85). Multivariate Cox proportional hazards regression analysis indicated that plasma RIPK3 level is greater than or equal to the optimal cutoff value of 440.9 μg/L ( HR=3.31, 95% CI: 1.53-8.30, P=0.005) was an independent risk factor for MACE in AMI patients after PCI. Kaplan-Meier survival analysis demonstrated that the high-RIPK3 group had a significantly higher risk of MACE after PCI compared to the low-RIPK3 group (log-rank P=0.006). Conclusions:Elevated plasma RIPK3 level is an independent risk factor for MACE in AMI patients after PCI. Plasma RIPK3 combined with traditional cardiovascular risk factors can more effectively predict the occurrence of MACE in AMI patients after PCI. AMI patients with RIPK3≥440.9 μg/L have a higher risk of MACE after PCI.

Objective The purpose of the study is to breed homozygous interferon-γ knockout(IFN-γ-/-)mice and optimize the breeding strategies to achieve continuous and stable reproduction of IFN-γ-/-mice,which could be used as an ideal animal model for fundamental research.Methods Initially,heterozygous IFN-γ knockout(IFN-γ+/-)C57BL/6J mice were used as the parental generation for breeding.Subsequently,3 breeding strategies were employed using the offspring:(1)female heterozygotes mated with male heterozygotes;(2)male homozygotes mated with female heterozygotes;(3)female homozygotes mated with male homozygotes.The number and survival rate of IFN-γ-/-mice were compared across the three breeding strategies to determine the optimal breeding strategy.Under the optimal strategy,the effects of female mating age and diet type on the reproductive performance of IFN-γ-/-mice were further evaluated.Data from the first three litters of 60 IFN-γ-/-female mice,including litter size,number of weaning survivors,and weaning survival rate,were recorded and analyzed.In addition,the effects of dietary supplementation of pregnant mice and environmental optimization measures,such as the provision of shelters,were evaluated.Results Under conditions where the nutritional needs of pregnant mice were adequately met by supplementation with egg yolk and sunflower seeds,mating of female and male IFN-γ-/-mice result ed in a litter size of five to eight IFN-γ-/-mice,demonstrating higher efficiency compared to other breeding strategies.In addition,diet type and mating age significantly influenced female reproductive performance.When 7～9 weeks old female IFN-γ-/-mice were mated to male IFN-γ-/-mice and fed a high-protein breeding diet,litter size(6.9±1.7),weaning survival number(6.5％±2.0％)and weaning survival rate(93.2％±17.8％)were higher than those under other conditions.In addition,providing shelters to prevent fighting between breeding pairs further improved reproductive outcomes.Conclusions By adopting an optimized breeding strategy,combined with a high-protein diet,nutritional supplementation,and standardized mating age management,the breeding efficiency and stability of IFN-γ-/-mice can be significantly improved.This provides a reliable animal model for related research.

Objective The purpose of the study is to breed homozygous interferon-γ knockout(IFN-γ-/-)mice and optimize the breeding strategies to achieve continuous and stable reproduction of IFN-γ-/-mice,which could be used as an ideal animal model for fundamental research.Methods Initially,heterozygous IFN-γ knockout(IFN-γ+/-)C57BL/6J mice were used as the parental generation for breeding.Subsequently,3 breeding strategies were employed using the offspring:(1)female heterozygotes mated with male heterozygotes;(2)male homozygotes mated with female heterozygotes;(3)female homozygotes mated with male homozygotes.The number and survival rate of IFN-γ-/-mice were compared across the three breeding strategies to determine the optimal breeding strategy.Under the optimal strategy,the effects of female mating age and diet type on the reproductive performance of IFN-γ-/-mice were further evaluated.Data from the first three litters of 60 IFN-γ-/-female mice,including litter size,number of weaning survivors,and weaning survival rate,were recorded and analyzed.In addition,the effects of dietary supplementation of pregnant mice and environmental optimization measures,such as the provision of shelters,were evaluated.Results Under conditions where the nutritional needs of pregnant mice were adequately met by supplementation with egg yolk and sunflower seeds,mating of female and male IFN-γ-/-mice result ed in a litter size of five to eight IFN-γ-/-mice,demonstrating higher efficiency compared to other breeding strategies.In addition,diet type and mating age significantly influenced female reproductive performance.When 7～9 weeks old female IFN-γ-/-mice were mated to male IFN-γ-/-mice and fed a high-protein breeding diet,litter size(6.9±1.7),weaning survival number(6.5％±2.0％)and weaning survival rate(93.2％±17.8％)were higher than those under other conditions.In addition,providing shelters to prevent fighting between breeding pairs further improved reproductive outcomes.Conclusions By adopting an optimized breeding strategy,combined with a high-protein diet,nutritional supplementation,and standardized mating age management,the breeding efficiency and stability of IFN-γ-/-mice can be significantly improved.This provides a reliable animal model for related research.

Objective:To investigate the impact of receptor-interacting protein kinase 3 (RIPK3) on major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), as well as the predictive performance of RIPK3 combined with traditional cardiovascular risk factors.Methods:This study was a single-center prospective cohort study. It included patients with AMI who underwent PCI at Peking Union Medical College Hospital between September 2017 and November 2017. Baseline clinical data were collected, and plasma samples were obtained 6 hours after PCI to measure RIPK3 levels. Follow-up was conducted via outpatient visits or phone calls to record the occurrence of MACE, including cardiovascular death, hospitalization for heart failure, and vascular events (recurrent AMI or stroke). The predictive performance of RIPK3, traditional cardiovascular risk factors and their combination for MACE was compared using receiver operating characteristic (ROC) curves. Patients were divided into low- and high-RIPK3 level groups based on the optimal cutoff value of RIPK3. Multivariate Cox proportional hazards regression analysis was used to assess the impact of RIPK3 levels on MACE after PCI in AMI patients. Kaplan-Meier survival curves were plotted, and the log-rank test was used to compare MACE incidence between the low-and high-RIPK3 groups.Results:A total of 103 AMI patients who underwent PCI were included, aged 63.0 (56.0, 69.0) years, and 83 (80.6%) were male. The follow-up time was 5.17 (2.81, 5.17) years, during which 44 patients (42.7%) experienced MACE. The ROC curve analysis showed that the area under the curve ( AUC) for traditional cardiovascular risk factors was 0.68 (95% CI: 0.58-0.78), while the AUC for plasma RIPK3 was 0.72 (95% CI: 0.62-0.82). The combined AUC for traditional risk factors and RIPK3 was 0.75 (95% CI: 0.65-0.85). Multivariate Cox proportional hazards regression analysis indicated that plasma RIPK3 level is greater than or equal to the optimal cutoff value of 440.9 μg/L ( HR=3.31, 95% CI: 1.53-8.30, P=0.005) was an independent risk factor for MACE in AMI patients after PCI. Kaplan-Meier survival analysis demonstrated that the high-RIPK3 group had a significantly higher risk of MACE after PCI compared to the low-RIPK3 group (log-rank P=0.006). Conclusions:Elevated plasma RIPK3 level is an independent risk factor for MACE in AMI patients after PCI. Plasma RIPK3 combined with traditional cardiovascular risk factors can more effectively predict the occurrence of MACE in AMI patients after PCI. AMI patients with RIPK3≥440.9 μg/L have a higher risk of MACE after PCI.

Objective To explore the efficacy of repeated transcranial magnetic stimulation(rTMS)combined with flupentixol and melitracen tablets on post-stroke depression(PSD)and to evaluate the predictive value of depressive symptom dimensions on the efficacy.Methods PSD patients diagnosed and treated in the department of rehabilitation medicine of Jiaozhou Central Hospital of Qingdao from January 2021 to December 2023 were selected as the research subjects,all patients were treated with rTMS combined with flupentixol and melitracen tablets.The National Institutes of Health Stroke Scale(NIHSS),Hamilton Depression(HAMD),and Barthel Index(BI)of PSD patients before and after treatment were evaluated and compared.PSD patients were divided into the effective group and the ineffective group based on treatment effectiveness,and Logistic regression was used to explore the relationship between depression symptom dimensions and treatment outcomes.Using the receiver operating characteristic(ROC)curve to explore the predictive value of depression symptom dimensions on the efficacy of PSD patients.Results A total of 80 PSD patients were included in this study,of which 68 cases were effective in treatment and 12 cases were ineffective in treatment.Compared with before treatment,PSD patients showed a significant decrease in HAMD score,NIHSS score(P＜0.05),and BI score was significant increased(P＜0.05).The observed mood(OM)score,cognitive score,and neurological symptom(NS)score of PSD patients in the effective group were higher than those in the ineffective group,and the differences were statistically significant(P＜0.05).Logistic regression analysis showed that high-level OM score,cognitive score,and NS score were independent protective factors for effective PSD treatment.ROC analysis showed that the baseline OM score,cognitive score,and NS score for ineffective treatment were 0.744[95％CI(0.568,0.921)],0.734[95％CI(0.572,0.896)],and 0.709[95％CI 0.534,0.884)],respectively.Conclusion rTMS combined with flupentixol and melitracen tablets can significantly improve depression symptoms and neurological impairment,and improve the ability of daily living.Moreover,depressive symptom dimensions at baseline can predict the treatment effects of PSD patients.

Objective:To investigate the safety of selective feticide by radiofrequency ablation (RFA) in dichorionic triamniotic (DCTA) triplets and factors related to the clinical outcome.Methods:A retrospective cohort study was designed to review the clinical records and pregnancy outcome of DCTA triplets patients who underwent RFA for selective feticide performed at the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital from January 1,2016 to January 1,2020. Placentas were collected after delivery for gross examination and perfusion study with the mixture of vinylidene chloride and self-curing denture acrylic.Results:A total of 12 DCTA cases were recruited. Selective feticide by RFA were performed at a mean gestational age of 15.6 weeks, and cases delivered at a mean gestational age of 36.9 weeks (34 +4-38 +2 weeks). Eight of the cases undertook invasive prenatal diagnosis weeks after RFA. The interval between RFA to delivery and gestational ages at delivery were similar between women undertook prenatal diagnosis and those who did not ( P>0.05). Six of the 23 newborns (26%) were small for gestational age. The average birth weight of either monochorionic singleton fetus or the remained co-twin of the monochorionic diamniotic (MCDA) twin as lower than that of singleton pregnancy ( P<0.001). One case of DCTA (8.3%) underwent intrauterine fetal death of the MCDA co-twin 4 h after RFA. Fetal tachycardia and cessation of fetal movement of the co-twin were observed before death. By the time of delivery, placental examination revealed the pale anemia look of the placental part of the co-twin and the reddish appearance of the part of the reduced fetus, which suggested a hypovolemic shock after an uncompleted RFA as the cause of co-twin death. A total of 10 MCDA placentas from cases with a living MCDA co-twins were collected. Various degree of placental perfusion on the reduced fetal side of placenta was noticed in nine cases. The co-twin with the placenta which did not have such kind of perfusion had a birth weight at the lowest percentile. Conclusion:Selective feticide by RFA is a safe procedure for DCTA triplet, and prenatal diagnosis has no adverse impact on pregnancy outcome. Ultrasound monitoring of fetal heart rate and fetal movement of the MCDA co-twin after RFA is helpful for predicting clinical outcome. Postnatal placental examination provides clues for adverse outcome, and the growth potential of the MCDA co-twin might be related to the type of anastomosis between the two fetuses.

Objective:To investigate the safety of selective feticide by radiofrequency ablation (RFA) in dichorionic triamniotic (DCTA) triplets and factors related to the clinical outcome.Methods:A retrospective cohort study was designed to review the clinical records and pregnancy outcome of DCTA triplets patients who underwent RFA for selective feticide performed at the First Affiliated Hospital of Southern University of Science and Technology, Shenzhen People's Hospital from January 1,2016 to January 1,2020. Placentas were collected after delivery for gross examination and perfusion study with the mixture of vinylidene chloride and self-curing denture acrylic.Results:A total of 12 DCTA cases were recruited. Selective feticide by RFA were performed at a mean gestational age of 15.6 weeks, and cases delivered at a mean gestational age of 36.9 weeks (34 +4-38 +2 weeks). Eight of the cases undertook invasive prenatal diagnosis weeks after RFA. The interval between RFA to delivery and gestational ages at delivery were similar between women undertook prenatal diagnosis and those who did not ( P>0.05). Six of the 23 newborns (26%) were small for gestational age. The average birth weight of either monochorionic singleton fetus or the remained co-twin of the monochorionic diamniotic (MCDA) twin as lower than that of singleton pregnancy ( P<0.001). One case of DCTA (8.3%) underwent intrauterine fetal death of the MCDA co-twin 4 h after RFA. Fetal tachycardia and cessation of fetal movement of the co-twin were observed before death. By the time of delivery, placental examination revealed the pale anemia look of the placental part of the co-twin and the reddish appearance of the part of the reduced fetus, which suggested a hypovolemic shock after an uncompleted RFA as the cause of co-twin death. A total of 10 MCDA placentas from cases with a living MCDA co-twins were collected. Various degree of placental perfusion on the reduced fetal side of placenta was noticed in nine cases. The co-twin with the placenta which did not have such kind of perfusion had a birth weight at the lowest percentile. Conclusion:Selective feticide by RFA is a safe procedure for DCTA triplet, and prenatal diagnosis has no adverse impact on pregnancy outcome. Ultrasound monitoring of fetal heart rate and fetal movement of the MCDA co-twin after RFA is helpful for predicting clinical outcome. Postnatal placental examination provides clues for adverse outcome, and the growth potential of the MCDA co-twin might be related to the type of anastomosis between the two fetuses.

Objective To investigate effects of different ventilation methods during pulmonary surfactant(PS) administration on cerebral oxygen metabolism in preterm infants with neonatal respiratory distress syndrome.Methods Newborns met the inclusion criteria were enrolled into this study,and they were randomly divided into manual group and mechanical group.During PS administration,the proximal end of the tracheal tube was connected to a bag valve mask device in the manual group or a mechanical ventilator in the mechanical group.Brain near infrared spectroscopy monitoring was carried out to detect the cerebral oxygen saturation(ScO2),and the mean arterial blood pressure (MABP) was simultaneously recorded.Results For all 49 preterm infants,PS was administered to preterm infants with severe respiratory distress syndrome treated with mechanical ventilation,including 24 cases of manual ventilation and 25 cases of mechanical ventilation.The left cerebral ScO2 and correlation coefficient of ScO2 and MABP(rScO2-MABP) showed no difference in both groups before PS administration.During administration,ScO2 dramatically increased in both groups [manual group:(85.88 ± 5.54) ％ vs.(77.31 ± 5.40) ％,t =5.521,P =0.000;mechanical group:(83.88 ± 3.18) ％ vs.(76.53 ±4.38)％,t =6.741,P =0.000],and gradually decreased after administration,the level of ScO2 didn't return to the baseline till the 2nd 5 minutes after PS administration [manual group:(79.25 ± 3.02) ％ vs.(77.31 ± 5.40) ％,t =1.560,P =0.220;mechanical group:(78.59 ± 3.45) ％ vs.(76.53 ± 4.38) ％,t =1.832,P =0.074].The same trend of ScO2 change rate was shown simultaneously in both groups.The rScO2-MABP markedly increased during administration in both groups (manual group:2.34 ±0.16 vs.1.86 ±0.21,t =9.022,P =0.000;mechanical group:2.12 ± 0.15 vs.1.87 ±0.21,t =4.810,P =0.000).The rScO2-MABt,in mechanical group rapidly decreased to baseline during the 1st5 minutes (1.84 ± 0.18 vs.1.87 ± 0.21,t =0.538,P =0.635) but went back to baseline in manual group during the 2nd 5 minutes(1.84 ±0.19 vs.1.86-0.21,t =0.350,P =0.809).Change rates of rScO2-MABP were markedly higher in manual group than those in mechanical group during the 1 st 5 minutes (1.15 ± 0.13 vs.1.00 ± 0.15,t =4.943,P =0.000).Conclusions ScO2 could be affected transiently by PS administration with different methods of ventilation.The effect on cerebral autoregulation in mechanical group is shorter than that in manual group.

Objective To observe the changes of abdominal oxygen saturation in very low birth weight infants (VLBWI)with feeding intolerance (FI)within 1 4 days after birth monitored by near infrared spectroscopy (NIRS).Methods VLBWI fitting entry criteria were enrolled into this study.NIRS monitoring was carried out to detect cerebral oxygen saturation (ScO2 )and abdominal oxygen saturation (SsO2 ).Data were analyzed between FI infants and feeding tolerance (FT)infants.FI was defined as follows:gastric residual of more than 50% of the previous feeding volume;emesis or abdominal distention or both;decrease,delay or discontinuation of enteral feedings. Results 93 VLBWI were enrolled.52 cases(55.91 %)presented with FI,including 29 cases(31 .1 9%)of gastric residual increasing and 23 cases(24.73%)of emesis with or without abdominal distention within 1 4 days after birth. The levels of SsO2 and SsO2 /ScO2 showed no differences in infants with FT and with FI within 24h after birth (P >0.05).The change rates of the median of SsO2 and SsO2 /ScO2 in FT infants were similar during 1 4 days (P >0.05).While both the change rates of SsO2 and SsO2 /ScO2 were markedly decreased 1 day before and the day of FI (P <0.01 ).The decreasing degree of SsO2 was similar between infants with gastric residual increasing and infants with emesis with or without abdominal distention[(1 6.2 ±5.1 )vs (1 7.4 ±3.6)%,t =0.733,P =0.476]. Conclusion Abdominal oxygen saturation measured by NIRS may be a useful method for infants adjusting the feeding plan.