Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly, and BuChE has emerged as a potential therapeutic target. In this study, we reported the development of compound 8e, a selective reversible BuChE inhibitor (eqBuChE IC₅₀ = 0.049 μmol/L, huBuChE IC₅₀ = 0.066 μmol/L), identified through extensive virtual screening and lead optimization. Compound 8e demonstrated favorable blood-brain barrier permeability, good drug-likeness property and pronounced neuroprotective efficacy. Additionally, 8e exhibited significant therapeutic effects in zebrafish AD models and scopolamine-induced cognitive impairments in mice. Further, 8e significantly improved cognitive function in APP/PS1 transgenic mice. Proteomics analysis demonstrated that 8e markedly elevated the expression levels of very low-density lipoprotein receptor (VLDLR), offering valuable insights into its potential modulation of the Reelin-mediated signaling pathway. Thus, compound 8e emerges as a novel and potent BuChE inhibitor for the treatment of AD, with significant implications for further exploration into its mechanisms of action and therapeutic applications.

Background::Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors.Methods::The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25-70 years old from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020.Results::The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy.Conclusions::We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

Objective:To systematically evaluate the qualitative research on rehabilitation experience of patients after hip and knee arthroplasty, so as to provide theoretical reference for nursing workers to scientifically and reasonably carry out nursing services.Methods:The research is a Meta-synthesis of qualitative research. Computer retrieval of PubMed, Web of Science, Embase, CINAHL, Cochrane Library, China National Knowledge Infrastructure, VIP, WanFang and China Biology Medicine disc was conducted to collect articles on qualitative research of patients' experience in rehabilitation after artificial joint replacement. The retrieval time limit was from the establishment of the database to February 27, 2022. The quality of article was evaluated using the quality evaluation criteria for qualitative research of the Australian Joanna Briggs Institute Evidence-Based Health Care Center. The results were integrated and analyzed using the pooled integration method.Results:A total of 17 articles were included, including 8 phenomenological studies, 3 rooted theoretical studies, and 6 descriptive studies. The quality evaluation of 17 articles were all Grade B. Finally, 3 integration results were obtained, forming 8 new categories, namely, the challenge of "returning to normality" (category 1: recovery of individual physical and mental state; category 2: return to normal life; category 3: return to family and social roles) , desire for multi-dimensional support (category 1: desire for continuous medical information support; category 2: emotional social support was of great significance) , changing self-coping styles (category 1: positive behavioral coping strategies; category 2: positive psychological adjustment strategies; category 3: reliance on spirit and belief) .Conclusions:The rehabilitation experience of patients after arthroplasty mainly includes the challenge of "returning to normality", the desire for multi-dimensional support and the changing self-coping styles. Medical staff should pay attention to the physical and mental changes, information and emotional needs of patients after joint replacement, and provide targeted support and help to accelerate the progress of patients' postoperative rehabilitation, improve their quality of life, and deepen their social integration.

Objective:To explore the role of blended learning in the undergraduate teaching of Clinical Biochemistry. Methods:The Batch 2017 medical laboratory technology undergraduates ( n=134) were selected as research objects, and the effect and opinions of blended learning were statistically analyzed by questionnaire survey and online-offline platform data. SPSS 23.0 was used to conduct rank sum test. Results:The application of blended learning in the Clinical Biochemistry teaching affected the learning effect in an all-round way. The average score increased from 70 (64, 76) to 79 (71, 85), with statistical difference ( Z=6.69, P<0.001). Conclusion:The combined application of blended learning, problem-based learning, flipped classroom and formative assessment is conducive to teaching students in accordance with their aptitude and cultivating students' clinical thinking ability.

Objective To analyze clinicopathological characteristics and the potential risk-related factors of female breast hyperplasia in different age groups.Method From Jan 2015 to Dec 2016,patients diagnosed with breast hyperplasia in 12 hospitals were evaluated.All patients completed the self-designed questionnaires on women'health,including basic demographic information,clinic examination information,radiologic information and pathologic results.The patients were divided into a young group (＜ 45 years old) and an elderly group (from 45 to 75 years old).Results There were 3 684 cases of breast hyperplasia,including 2 291 cases in young group and 1 393 cases in elder group,respectively Clinically breast pain type were most commonly observed in both young and older groups (50.3％ vs.42.7％,P ＜ 0.001).While pathological research based on biopsy showed that breast adenopathy were the most common changes in both groups (67.9％ vs.61.7％,P ＜0.001).More breast cancer cases were identified in elder group than that in young group,especially in clinically lump type patients (9.4％ vs.4.2％,P ＜ 0.001).Compared with elder group,patients in young group have different distribution characteristics regarding to fertility factors,lifestyle factors and psychology scale including anxiety and depression.Conclusion Distributions of clinicopathological characteristics and risk factors of female breast hyperplasia differ across different age groups.

Objective: To investigate the correlation between the expression of PD-1, PD-L1 and clinicopathologic parameters in triple negative breast carcinoma (TNBC). Methods: Samples from 151 patients with TNBC and 65 cases of other breast carcinomas (non-TNBC) were examined for PD-L1 and PD-1 expression by immunohistochemical staining on tissue microarray. Results: The expression of PD-L1 and PD-1 in the tumor cells and interstitial lymphocytes in TNBC was significantly (P<0.05)higher than that in non-TNBC.In TNBC, the expression rates of PD-L1 in the cancer nests and stroma were 16.6%(25/151) and 25.2%(38/151)respectively.The former was positively correlated with tumor histological grade and lymph node metastasis (P<0.05), and the latter only with tumor histological grade (P<0.05). The expression rate of PD-1 was 27.2% (41/151), and correlated with PD-L1 expression in stromal tumor-infiltrating lymphocytes (P<0.05). Conclusion The expression of PD-L1 in TNBC is significantly correlated with high-grade histology, lymph node metastasis and PD-L1 expression in stromal tumor-infiltrating lymphocytes.

An ultra-high performance liquid chromatography-tandem mass spectrometry ( UHPLC-MS/MS ) method was developed and validated for the simultaneous determination of 9 kinds of trace endocrine disrupting chemicals in biological samples using ultrasonic-assisted extraction followed by purification with gel permeation chromatography ( GPC) and silica gel columns. The sample extracts were purified by Bio beads S-X3 GPC columns with cyclohexane/ethyl acetate (1:1, V/V) as mobile phase, and the target compounds were eluted in the fraction of 12-28 mL retention volume. Electrospray ionization source operated in positive mode and atmospheric pressure chemical ionization source operated in negative mode were used for mass spectrometric detection. Data acquisition was carried out in multiple reaction monitoring mode. Recoveries were predominately within 65 . 2%-118 . 0%. Method quantification limits were 0 . 1-9 . 7 ng/g dw ( dry weight ) . This method was successfully applied to the analysis of the target endocrine disrupting chemicals in carps collected from the Pearl River. with the exception of carbanilide and triclocarban, the rest analytes were detected in fish tissue samples, with the concentrations varied within the range of 0. 1-22. 6 ng/g dw.

Objective To observe changes of cell cycle after stable silencing of SNCG gene in human endometrial carcinoma HEC-1A cells.Methods Flow cytometry was used to observe the changes of SNCG stable silencing HEC-1A cell growth cycle.The percentage of G2/M phase of HCE-1A cells after acridine orange staining was observed by laser scanning confocal microscopy.Results Flow cytometry results showed that the group of SNCG stable silencing in G1 and G2/M phase of the cells increased,but the percentage of cells in the S phase were decreased,the difference were both statistically significant (P ＜ 0.05).The results of cells after confocal microscopy observation of acridine orange staining,the group of SNCG stable silencing were observed in G2/M phase high percentage were statistically significant (P ＜ 0.05).Conclusion Two experimental methods commonly validated that the cell cycle of SNCG stable silencing on HEC-1A cells was arrested in G2/M phase,suggesting that SNCG gene is closely related to the cell growth cycle of endometrial carcinoma.

AIM: To investigate the role of renin-angiotensin system (RAS) disequilibrium in hyporeactivity and injury of aorta after tourniquet shock ( TS) by observing the changes of aortic contractile reactivity and RAS components after TS.METHODS:Male C57BL/6 mice (8 months old) were divided into 7 groups including control group and 6 mod-el groups.The mice in model groups were sacrificed at reperfusion of 10 min, 1 h, 2 h, 4 h, 6 h and 12 h.The mice in control group were not subjected to tourniquet ligation .The Doppler flowmetry was used to determine the limb blood flow . The carotid artery catheter was applied to detect the blood pressure .The isolated vascular tension tester was available to measure the reactivity of the aorta .HE staining combined with transmission electron microscopy was used to evaluate the morphology of injured aortas .The protein expression of AT 1 receptor , Mas receptor , ACE and ACE2 was measured by Western blot.The serum contents of Ang Ⅱand Ang (1-7) were detected by ELISA.RESULTS:Compared with control group, the blood flow in model groups decreased gradually with the prolongation of reperfusion time .The blood pressure in-creased at 10 min after reperfusion, and then decreased gradually.Accordingly, vascular reaction to norepinephrine (NE) in-creased at 10 min and then descended .The vascular reactivity reached the lowest level at 4 h.Morphological injury score in-creased gradually .Vascular AT1 receptor and ACE2 proteins were reduced , while Mas receptor and ACE proteins were up-regulated compared with control group .The content of AngⅡin the serum elevated, while the content of Ang (1-7) was re-duced.CONCLUSION:The mechanism of aortic reaction to NE increased temporarily in the early stage of shock and then decreased .It may be related to the morphological injury of aorta and the imbalance of RAS .

Objective To investigate the relationship between renal vascular resistance index( RI) and serum Apelin level in type 2 diabetic mellitus ( T2DM )?Methods Seventeen cases newly diagnosed T2DM patients with RI increased but without microalbuminuraia in Minhang Hospital Affiliated to Fudan University from December 2011 to December 2014 were selected as observation group,17 newly diagnosed T2DM patients with RI normal during the same period were selected as control group?Fasting plasma glucose(FPG),glycosylated hemoglobin A1C(HbAlC),blood lipids and fasting insulin(FINS),hepatic functional and renal function were tested in all the subjects?Serum Apelin level was detected by enzyme?linked immunosorbent assay?Results Compared with control group,serum Apelin level was significantly higher in observation group((179?2±122?4)μg/L vs?(56?7±50?6) μg/L,t=3?814,P<0?05)?Partial correlation analysis showed that the RI was positive correlated with Apelin ( r= 0?364, P= 0?040 )?Conclusion The serum Apelin levels elevated in newly diagnosed T2DM patients with RI increased, and RI is positively correlated with Apelin, which indicate that Apelin play an important role in the pathophysiology of early renal damage in patients with TsDM.