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.

Objective:To comprehensively evaluate the medical service capacity of 50 first batch county medical sub-centers in Guizhou Province,it provides the basis and references for further research on the construction of county medical sub-centers in Guizhou province and improvement of the medical service capacity of township health centers(community health service centers)in Guizhou Province.Methods:Through TOPSIS method,RSR method and the fuzzy combination method,the medical service capacity of the primary medical institutions in the county medical sub-center was evaluated.Results:Among the first batch of 50 county-level secondary medical centers,the top three in terms of medical service capabilities were G18,G6,and G36,while the last three were G27,G15,and G22.Conclusion:There were significant differences in the medical and health service capacity among the 50 sub-centers.It is suggested to continue to increase the support for sub-centers,formulate relevant policies according to local conditions and time conditions,and improve the medical service capacity of sub-centers.

Objective:To observe the morphological characteristics of dome-shaped macula (DSM) and macular hole (MH) in high myopia by optical coherence tomography (OCT), to further explore the correlation between DSM and MH.Methods:A retrospective case-control study. From April 2021 to December 2023, 963 eyes of 503 patients with high myopia (myopic diopter ≥6.00 D) in Department of Ophthalmology of the Fourth Hospital of Hebei Medical University were enrolled in the study. The age of patients ranged from 5 to 89 years old, with the mean age of (48.91±16.69) years. Diopter was -6.00 to -26.00 (-10.49±3.15) D. All eyes were examined by OCT. The width and height of DSM, subfoveal choroidal thickness (SFCT), inner port diameter and base diameter of MH were measured by software on OCT. According to the OCT image features, DSM was divided into horizontal and vertical oval-shaped DSM, and symmetrical round DSM. According to the presence or absence of DSM, the eyes were divided into DSM group and non-DSM group. Then, the affected eyes with MH were divided into DSM with MH group and non-DSM with MH group. The incidence of DSM, the incidence of MH in the DSM group and the non-DSM group, the inner port diameter of MH, the base diameter of MH, SFCT, and the location of retinoschisis (RS) in the DSM with MH group and the non-DSM with MH group were observed. Independent sample t test or non-parametric Mann-Whitney U test was used for comparison between groups. Pearson correlation analysis was used to analyze the related factors of MH inner port diameter, base diameter and DSM width, height, height/width ratio. Results:Among the 963 eyes, the DSM group and the non-DSM group were 266 (27.6%, 266/963) and 697 (72.4%, 697/963) eyes. Compared with the non-DSM group, patients in the DSM group were older ( Z=-11.302), had higher degree of myopia ( Z=-8.944), thinner SFCT ( Z=-16.244), and higher incidence of MH ( χ2=8.828), and the differences were statistically significant ( P<0.05). Compared with non-DSM with MH group, the patients in DSM with MH group were older ( t=2.610), higher myopia diopter ( t=3.593), and thinner SFCT ( t=3.505), the differences were statistically significant ( P<0.05). There was no significant difference in the number of eyes in the epiretinal membrane between the two groups ( χ2=0.119, P=0.730). In the DSM with MH group, RS mostly occurred in the outer retina with a large range, while in the non-DSM with MH group, RS mostly occurred in the outer and inner retina with a small range. There was a statistically significant difference in the number of eyes at different positions of RS between the two groups ( χ2=25.131, P<0.05). The results of correlation analysis showed that there was no correlation between the inner port and base diameter of MH and the width, height, height/width ratio of DSM ( P>0.05). Conclusions:Compared with high myopia patients without DSM, patients with DSM are older, have more severe myopia and thinner SFCT. In DSM patients with MH, RS often occurs in the outer retina and has a large range. There was no significant association between DSM morphology and MH size.

Objective:To comprehensively evaluate the medical service capacity of 50 first batch county medical sub-centers in Guizhou Province,it provides the basis and references for further research on the construction of county medical sub-centers in Guizhou province and improvement of the medical service capacity of township health centers(community health service centers)in Guizhou Province.Methods:Through TOPSIS method,RSR method and the fuzzy combination method,the medical service capacity of the primary medical institutions in the county medical sub-center was evaluated.Results:Among the first batch of 50 county-level secondary medical centers,the top three in terms of medical service capabilities were G18,G6,and G36,while the last three were G27,G15,and G22.Conclusion:There were significant differences in the medical and health service capacity among the 50 sub-centers.It is suggested to continue to increase the support for sub-centers,formulate relevant policies according to local conditions and time conditions,and improve the medical service capacity of sub-centers.

Objective:To observe the morphological characteristics of dome-shaped macula (DSM) and macular hole (MH) in high myopia by optical coherence tomography (OCT), to further explore the correlation between DSM and MH.Methods:A retrospective case-control study. From April 2021 to December 2023, 963 eyes of 503 patients with high myopia (myopic diopter ≥6.00 D) in Department of Ophthalmology of the Fourth Hospital of Hebei Medical University were enrolled in the study. The age of patients ranged from 5 to 89 years old, with the mean age of (48.91±16.69) years. Diopter was -6.00 to -26.00 (-10.49±3.15) D. All eyes were examined by OCT. The width and height of DSM, subfoveal choroidal thickness (SFCT), inner port diameter and base diameter of MH were measured by software on OCT. According to the OCT image features, DSM was divided into horizontal and vertical oval-shaped DSM, and symmetrical round DSM. According to the presence or absence of DSM, the eyes were divided into DSM group and non-DSM group. Then, the affected eyes with MH were divided into DSM with MH group and non-DSM with MH group. The incidence of DSM, the incidence of MH in the DSM group and the non-DSM group, the inner port diameter of MH, the base diameter of MH, SFCT, and the location of retinoschisis (RS) in the DSM with MH group and the non-DSM with MH group were observed. Independent sample t test or non-parametric Mann-Whitney U test was used for comparison between groups. Pearson correlation analysis was used to analyze the related factors of MH inner port diameter, base diameter and DSM width, height, height/width ratio. Results:Among the 963 eyes, the DSM group and the non-DSM group were 266 (27.6%, 266/963) and 697 (72.4%, 697/963) eyes. Compared with the non-DSM group, patients in the DSM group were older ( Z=-11.302), had higher degree of myopia ( Z=-8.944), thinner SFCT ( Z=-16.244), and higher incidence of MH ( χ2=8.828), and the differences were statistically significant ( P<0.05). Compared with non-DSM with MH group, the patients in DSM with MH group were older ( t=2.610), higher myopia diopter ( t=3.593), and thinner SFCT ( t=3.505), the differences were statistically significant ( P<0.05). There was no significant difference in the number of eyes in the epiretinal membrane between the two groups ( χ2=0.119, P=0.730). In the DSM with MH group, RS mostly occurred in the outer retina with a large range, while in the non-DSM with MH group, RS mostly occurred in the outer and inner retina with a small range. There was a statistically significant difference in the number of eyes at different positions of RS between the two groups ( χ2=25.131, P<0.05). The results of correlation analysis showed that there was no correlation between the inner port and base diameter of MH and the width, height, height/width ratio of DSM ( P>0.05). Conclusions:Compared with high myopia patients without DSM, patients with DSM are older, have more severe myopia and thinner SFCT. In DSM patients with MH, RS often occurs in the outer retina and has a large range. There was no significant association between DSM morphology and MH size.

OBJECTIVE To pr ovide theoretic support for Guiyang to scientifically guide the development of drug retail industry and implement national health policies . METHODS The data were collected through statistical yearbook ，data cloud ， coordinate acquisition device of Application Programming Interface of Baidu map and so on. The spatial distribution characteristics and accessibility of medical insurance designated retail pharmacies （shorted for “designated pharmacies ”）in Guiyang were analyzed by spatial analysis based on Geographic Information System. The related factors for the distribution of designated pharmacies in Guiyang were analyzed by statistical method. RESULTS The number of designated pharmacies ，designated pharmacies per thousand people and designated pharmacies per 10 km2 in Guiyang increased from 2 018，0.41 and 2.51 in 2020 to 2 500，0.42 and 3.11 in 2021，with growth rates of 23.89％，2.44％ and 23.90％ respectively. The service area of the designated pharmacies that residents of Guiyang reached within 15 minutes on foot was 10.27％ of the total service area of designated pharmacies in Guiyang. The results of correlation analysis showed that the correlation coefficients between the regional gross regional production ，total retail sales of consumer goods ，population，urban per capita disposable income and the number of designated pharmacies in Guiyang were 0.999，0.999，0.977 and 0.992，respectively （all P＜0.05）. CONCLUSIONS The distribution of designated pharmacies is insufficient in Guiyang ，the development of designated pharmacies in various administrative regions is uneven ，and the layout of pharmacies is significantly affected by economic and demographic factors. It is suggested that the local government should explore the strategy of scientifically and reasonably expanding the coverage of designated pharmacies in urban and rural areas，promote the rational layout of pharmacies with appropriate economic and demographic policies ，and pay attention to improving the service capacity of designated pharmacies ，so as to improve the quality of life of the people and guide the healthy and high-quality development of drug retail industry.

Objective:To investigate the association between relative mitochondrial DNA copy number (mtDNA-CN) and coal-burning-borne endemic fluorosis (abbreviated as coal-burning-borne fluorosis).Methods:From June 2018 to March 2019, using cross-sectional study, 482 patients with coal-burning-borne fluorosis were selected as the case group in Bijie City, a typical coal-burning-borne fluorosis area of Guizhou Province; meanwhile, 212 healthy individuals from Changshun County, a non-coal-burning-borne fluorosis area in Guizhou Province, were selected as the control group. Questionnaire survey and physical examination were used to collect general condition such as basic information and living habits of the two groups, peripheral venous blood samples were collected, and real-time fluorescence quantitative PCR was used to detect the relative mtDNA-CN in peripheral blood. The correlation between relative mtDNA-CN and coal-burning-borne fluorosis was analyzed by binary and unordered multi-class logistic regression.Results:There were significant differences in the body mass index (BMI), and the distribution of gender rario, marital status and education level between the control group and the case group ( t = 7.91, χ 2 = 5.11, 13.33, 34.32, P < 0.05). The relative mtDNA-CN in the control group was higher than that in the case group [median (quartile): 202 (138, 292) vs 131 (96, 217), Z = - 7.80, P < 0.001]. The results of binary logistic regression analysis [odds ratio (95% confidence interval)] showed that educational level [primary school: 0.572 (0.377 - 0.868), junior high school and above: 0.292 (0.174 - 0.493)], relative mtDNA-CN [131 - < 217: 0.265 (0.144 - 0.488), ≥217: 0.183 (0.100 - 0.335)] and BMI [1.222 (1.142 - 1.307)] were the influencing factors for the risk of coal-burning-borne fluorosis( P < 0.05). In subgroups with different BMI and educational levels, the relative mtDNA-CN was significantly negatively correlated with the risk of coal-burning-borne fluorosis( Ptrend < 0.05), and there was no interaction between mtDNA-CN and BMI and educational levels ( Pinteraction > 0.05). The results of unordered multi-class logistic regression analysis showed that the relative mtDNA-CN were significantly negatively correlated with the risk of dental fluorosis and skeletal fluorosis ( Ptrend < 0.05). Conclusion:The higher the relative mtDNA-CN, the lower the risk of coal-burning-borne fluorosis, suggesting that mtDNA-CN may be a potential biomarker of coal-burning fluorosis.

Objective:To explore the relationship between children's intelligence and urinary fluoride in Suojia Township of Miao, Yi and Hui Nationalities (referred to as Suojia Township), a coal-burning-borne endemic fluorosis area in Guizhou Province.Methods:In April 2019, 173 children aged 10 to 13 years old were selected from three schools in Suojia Township. According to whether they had dental fluorosis, the children were divided into case group ( n = 104) and control group ( n = 69). Middle segment urine samples of the children were collected and urinary fluoride level was determined by the method of ion-selective electrode. Combined Raven's Test-the Rural in China (CRT-RC2) was used for children's intelligence quotient (IQ) test. Linear regression analysis was used to observe the association between urinary fluoride and IQ, and the results were expressed by regression coefficient ( β) and 95% confidence interval ( CI). Results:Urinary fluoride level of case group was higher than that of control group [(2.14 ± 1.78) vs (1.53 ± 0.98) mg/L], and IQ was lower than that of control group [(92.33 ± 11.68) vs (100.38 ± 11.87) points], and the differences were statistically significant ( t = 2.58, 4.41, P < 0.05). The linear regression equation of urinary fluoride ( X) and IQ ( Y) of case group was Y = 96.99 - 2.86 X. For every 1 mg/L increase in urinary fluoride level, IQ decreased by 2.86 points ( β = - 2.86, 95% CI: - 5.48 - - 0.24). Conclusion:Long-term exposure to fluoride pollution from coal burning may damage children's intelligence, and children's IQ decreases with increase of fluoride level in urine.

Bisecting N-acetylglucosamine(GlcNAc),a GlcNAc linked to the core β-mannose resi-due via a β1,4 linkage,is a special type of N-glycosylation that has been reported to be involved in various biological processes,such as cell adhesion and fetal development.This N-glycan structure is abundant in human trophoblasts,which is postulated to be resistant to natural killer cell-mediated cytotoxicity,enabling a mother to nourish a fetus without rejection.In this study,we hypothesized that the human amniotic membrane,which serves as the last barrier for the fetus,may also express bisected-type glycans.To test this hypothesis,glycomic analysis of the human amniotic membrane was performed,and bisected N-glycans were detected.Furthermore,our pro-teomic data,which have been previously employed to explore human missing proteins,were ana-lyzed and the presence of bisecting GlcNAc-modified peptides was confirmed.A total of 41 glycoproteins with 43 glycopeptides were found to possess a bisecting GlcNAc,and 25 of these gly-coproteins were reported to exhibit this type of modification for the first time.These results provide insights into the potential roles of bisecting GlcNAc modification in the human amniotic membrane,and can be beneficial to functional studies on glycoproteins with bisecting GlcNAc modifications and functional studies on immune suppression in human placenta.

Objective:To investigate the relationship between gene polymorphism of osteoprotegerin (OPG) and coal-burning endemic fluorosis in Guizhou Province.Methods:In 2018 and 2019, a case-control study was conducted in Bijie City, a typical coal-burning endemic fluorosis area in Guizhou Province, and 260 cases of coal-burning endemic fluorosis patients were selected as case group. According to the "Diagnostic Criteria for Endemic Skeletal Fluorosis" (WS 192-2008), the case group was divided into severe group (130 cases) and mild group (130 cases). At the same time, 130 cases without dental fluorosis and skeletal fluorosis symptoms were chosen as control group in Changshun County, a non-coal-burning endemic fluorosis area in Guizhou Province. Whole blood genomic DNA was extracted, and real-time fluorescence quantitative PCR with TaqMan-MGB probe was utilized to type the OPG gene rs2460985, rs2073618, rs6469804 and rs6993813 four single nucleotide polymorphism (SNP) loci of all samples, and genetic model analysis was performed to compare the frequency distribution of its alleles, genotypes and constructed haplotypes in control, mild and severe groups. Results:By Hardy-Weinberg equilibrium test, the genotype frequencies of the four SNP loci all reached genetic balance in control, mild and severe groups ( P > 0.05). There was a statistically significant difference in the genotype frequency of OPG gene rs6469804 locus among the three groups (χ 2 = 10.615, P < 0.05), and the difference in the genotype frequency of this locus between the control group and the severe group was statistically significant (χ 2 = 6.784, P < 0.05). The results of genetic model analysis showed that in comparison between the control group and the severe group, the optimal genetic model of rs6469804 locus was the overdominant genetic model, the frequency distribution of genotypes AA + GG and AG in the control group and the severe group was statistically significant [odds ratio ( OR) = 1.94, 95% confidence interval ( CI): 1.16 - 3.23, P < 0.05], genotype AG was a risk factor for coal-burning endemic fluorosis. In comparison between the control group and the mild group, the optimal genetic model of rs2073618 locus was the recessive genetic model, the frequency distribution of genotypes GG + GC and CC in the control group and the mild group was statistically significant ( OR = 3.17, 95% CI: 1.08 - 9.30, P < 0.05), genotype CC was a risk factor for coal-burning endemic fluorosis. In comparison between the control group and the mild group, haplotypes C-C-G-T and T-G-A-C were risk factors for coal-burning endemic fluorosis (adjusted OR = 2.41, 1.98, 95% CI: 1.29 - 4.50, 1.22 - 3.23, P < 0.05); in comparison between the control group and the severe group, haplotype T-G-A-C was a risk factor for coal-burning endemic fluorosis (adjusted OR = 1.87, 95% CI: 1.14 - 3.07, P < 0.05). Conclusion:OPG gene rs6469804 locus genotype AG and rs2073618 locus genotype CC may be risk factors for coal-burning endemic fluorosis.