Alzheimer’s disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depressionlike behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer’s disease and depression.Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.

OBJECTIVE To provide direction and reference for the adjustment of the discount rate （DR） in China’s pharmacoeconomic guidelines. METHODS Search was conducted on the official websites of the International Society for Pharmacoeconomics and Outcomes Research， health technology assessment agencies in various countries/regions， as well as relevant websites of other upper-middle-income or high-income countries/regions. The recommended DR， adjustment trends， and setting rationales in pharmacoeconomic evaluation guidelines across different countries/regions were then summarized and compared. Based on theoretical derivation and literature analysis， the effects of different DR on the incremental cost-effectiveness ratio （ICER） were examined. RESULTS & CONCLUSIONS Among the 40 included guidelines， the base-case DR ranged from 1.5% to 5%， with 5% being the most common value； the range for sensitivity analysis was 0 to 12%. Thirty-six countries/regions applied the same DR to both costs and health outcomes， while in the Netherlands， Belgium， Poland and Czech Republic， DR for costs was higher than for health outcomes. In recent years， Korea， France and Ireland had lowered their DR in response to economic changes， whereas the Netherlands and Czech Republic had raised their DR for cost. The setting of the DR was primarily based on the public project investment interest rate or referred to recommendations from internationally authoritative institutions and other relevant guidelines. The direction and magnitude of the impact of different DR on the ICER largely depended on the distribution of costs and health outcomes between the intervention and reference measure. The setting and adjustment of DR were closely associated with the economic environment. Based on international experience, the DR in China can be lowered by 0.5% to 1.5%， and localized empirical research can be conducted using internationally common estimation methods.

Objective To investigate the effect of dorsal repulsive axon guidance protein(Draxin)on the migration of trunk neural crest cells during the early development of embryonic mouse spinal cord.Methods Immunohistochemistry and in situ hybridization were used to detect the expression characteristics of Draxin in early embryonic spinal cord(8 mice each group);In situ hybridization was used to detect the change of migration characteristics of trunk neural crest cells in early embryonic spinal cord of different types of mouse(5 mice each group);in vitro culture method was used to check the effect of Draxin on the migration characteristics of embryonic mouse trunk neural crest cells(16 mice each group).Resultsβ-galactosidase gene Z(LacZ)gene was introduced when Draxin gene was knocked out to produce Draxin gene knockout mice.β-galactosidase staining was used to detect LacZ gene expression in Draxin knockout embryonic mice,and the result showed that Draxin expression was observed in the spinal cord of early embryonic mice since 9.5 days(E9.5).Draxin expression was obvious in the embryonic mice spinal cord in E10.5 period.In situ hybridization was used to detect the expression of Draxin gene in the spinal cord of wild type embryonic mice,and the result further verified the obvious expression of Draxin in the early embryonic mice spinal cord in El0.5 period.Sox10 in situ hybridization was used to detect neural crest cell migration in the spinal cord of embryonic mice in E10.5 period.The result showed that segmental migration of neural crest cells in the early embryonic spinal cord of some Draxin knockout mice was delayed compared with the wild type mice.The effect of Draxin on the migration of wild type early embryonic mice trunk neural crest cells in vitro was tested.The result showed that Draxin reduced the migration distance of neural crest cells in vitro.Conclusion In the early developmental stage of embryonic spinal cord(E9.5-E10.5),neural crest cells migrated exuberant.At the same time,Draxin plays an important inhibitory function in the formation of the specific migration pathways of trunk neural crest cells by promoting neural crest cells migrating away from Draxin expressing regions.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Suicidal cases involving sodium nitrite have been reported worldwide. However, postmortem features, such as brownish or grayish livor mortis, remain difficult to interpret, especially as decomposition advances. Here, we present three fatal cases (2020-2023) presumably caused by sodium nitrite ingestion. In these cases, characteristic nitrite-induced changes were inconsistent or obscured by decomposition, but ingestion traces (cup or bottle near the decedents) were observed at each scene. Additionally, containers labeled “sodium nitrite” were found in two cases; however, since sodium nitrite is designated a suicide-hazardous material in South Korea, future scenes may rarely reveal such clear labeling. Although autopsy, including methemoglobin testing, can confirm the cause of death, any delay in the investigative process risks the loss of critical evidence about the ingestion process and other factors. This underscores the importance of focusing on early scene evidence, particularly ingestion traces, and conducting thorough chemical and forensic examinations. Our findings illustrate that timely detection of ingestion-related evidence and subsequent forensic analysis, in conjunction with autopsy results, can elucidate a decedent’s cause and manner of death and clarify any criminal implications.

Under the new situation of establishing the new standard system for pharmaceutical packaging materials in the 2025 edition of the Chinese Pharmacopoeia and promulgating the appendix on pharmaceutical packaging ma-terials in the Good Manufacturing Practice for Drugs,it is urgently necessary to introduce relevant standards for quality agreements on pharmaceutical packaging materials.This article focuses on analyzing the development of group standards for pharmaceutical packaging materials under the new situation,the role and significance of quality agreements for pharmaceutical packaging materials,as well as the interpretation of key parts of the"Guidelines for the Management of Quality Agreements for Pharmaceutical Packaging Materials",in order to help enterprises quick-ly shift from the original"standard-only"approach to strengthening the quality management of the entire product life cycle through quality agreements.

Objectives:Comparative analysis of the beagles acute-phase electrocardiographic,hemodynamic,left ventricular flow field status,and energy consumption characteristics of pacing at different sites of conduction system may help to elucidate the scientific mechanism of left bundle branch pacing(LBBP)as a option of physiological pacing therapy.Methods:Eight healthy adult beagles were used in this study.Initially,an active fixation lead was implanted in the right atrial appendage,followed by implantation of another active fixation lead at the right ventricular apex,distal His bundle,and left bundle septal branch,respectively.After connecting a dual-chamber pacemaker,electrocardiographic and acute phase hemodynamic parameters under sinus rhythm,right ventricular apex pacing(RVAP),distal His bundle pacing(DHBP),and LBBP states were collected and analyzed.Three complete cardiac cycles of standard apical three-chamber color Doppler dynamic images were acquired under vector flow mapping(VFM)mode.Offline analysis was performed on obtained parameters including isovolumic contraction period,rapid ejection period,isovolumic relaxation period,rapid filling period,atrial contraction period,and left ventricular intracavitary energy consumption.These parameters were compared under pacing at different sites and the linear correlations of major parameters were analyzed.Results:The QRS duration of baseline intrinsic sinus rhythm,RVAP,DHBP and LBBP were(45.0±4.0)ms,(98.4±6.2)ms,(50.0±4.5)ms and(62.0±4.7)ms,respectively.The LBBP-QRS duration was significantly wider than intrinsic sinus rhythm and DHBP,but significantly narrower than RVAP(all P<0.01).Compared with baseline AOO mode(the pacing rate was performed at 10 beats/min above the intrinsic heart rate),the change of acute phase maximum left ventricular pressure rise rate(LVdP/dtmax)in RVAP,DHBP and LBBP was([-7.89±5.67]% ),([0.74±2.05]% )and([-0.14±3.59]% ),respectively.There was no significant difference in LVdP/dtmax changes between DHBP and LBBP(P=0.667),but both pacing modalities were significantly better than RVAP(all P<0.01).The average energy consumption of the left ventricle under RVAP was significantly higher than that of intrinsic sinus rhythm,DHBP,and LBBP in isovolumic contraction period,rapid ejection period,isovolumic relaxation period,rapid filling period,and atrial contraction period(all P<0.01).However,there was no statistically significant difference in energy consumption among intrinsic sinus rhythm,DHBP,and LBBP during the above five phases(all P>0.05).DHBP and LBBP did not show a significant increase in the number of left ventricular vortices,vortex area,and circulation intensity compared to intrinsic sinus rhythm,and LBBP did not show a significant increase in vortex area and circulation intensity compared to DHBP.Conclusions:Although LBBP canines significantly prolonged the paced QRS duration,it showed no significant differences in acute phase left ventricular hemodynamics,left ventricular flow field status,and energy consumption compared to intrinsic sinus rhythm and DHBP.Performance of LBBP was superior to RVAP.This study may contribute to revealing the theoretical basis of LBBP as a feasible physiological pacing therapy.

Aim To construct and analyze the genotype of G protein-coupled receptor kinase 2(GRK2)conditional knockout mice in synoviocytes,and to provide an animal model for stud-ying the function of GRK2 in synoviocytes.Methods Grk2flox/+mice were bred to generate Grk2flox/flox mice,Grk2flox/flox mice were bred to Col1a1-iCre+mice,Grk2flox/+Col1a1-iCre+mice were bred to Grk2flox/flox mice.Grk2flox/flox Col1a1-iCre+mice were ob-tained as target mice.DNA was extracted and amplified by PCR to identify the genotype.Western blot was used to verify the effect of Grk2 knockout in synovium,liver and kidney tissues.HE staining was used to detect the effects of Grk2 conditional knockout in synovial cells on ankle synovium,liver and kidney tissues.Multiple immunofluorescence was used to detect GRK2 expression in synovial cells.Results The results of gene iden-tification showed that Grk2flox/flox Col1a1-iCre+mice had both Flox and Col1a1-iCre genotypes.Western blot results showed that GRK2 expression decreased in synovial tissues of Grk2flox/flox Col1a1-iCre+mice,but there was no significant change in the expression of GRK2 in liver and kidney tissues.HE staining showed that Grk2flox/flox Col1a1-iCre+mice had no significant pathological changes in the ankle synovium,liver and kidney.The results of multiple immunofluorescence showed that GRK2 expression in synovial cells of Grk2flox/flox Col1a1-iCre+mice de-creased.Conclusion Grk2 conditional knockout mice in syno-viocytes are successfully constructed and identified,which pro-vides an animal model for further study of the role of GRK2 in synovial-related diseases.