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 construct Pseudomonas aeruginosa(PA)strain with deletion of the pyocyanin synthesis gene PAOⅡ and investigate its drug resistance.Methods By analyzing the ge-nome of the PAOⅡ genotype strain of PA,the distribution of genes/gene clusters related to pyocyanin synthesis in the genome was explored.A strain with deletion of the pyocyanin synthesis gene phzM was constructed using homologous recombination-based seamless gene knockout technology.The growth and drug tolerance of the wild-type and mutant strains were compared.Results Kyoto Encyclopedia of Genes and Genomes(KEGG)clustering analysis was performed on the website https://www.kegg.jp/.The results revealed a gene cluster composed of 9 genes(including PhzA,PhzB,PhzC,PhzD,PhzE,PhzF,PhzG,phzM and PhzS),which was completely consistent with the KEGG PATHWAY:Phenazine biosynthesis-M00835 Pyocyanine biosynthesis pathway.The key gene phzM for pyocyanin synthesis was knocked out via homologous recombination.After the exchange,monoclonal strains growing on M9-citrate medium were verified using primers phzM-AF and phzM-BR.The shuttle plasmid pK18mobSacB-phzM-AB was successfully transfected into the PAOⅡ genotype strain.After gene ex-change,monoclonal strains capable of growing on antibiotic-free plates were selected,and polymerase chain reaction(PCR)was performed to obtain strains with successful scarless knockout of the phzM gene.At 3 and 6 days of culture,the biofilm formation thickness of the PAOⅡ genotype strain was greater than that of the PAOⅡ-△phzM strain,with a statistically significant difference(P＜0.05).Conclusion The biofilm synthesis capacity of the pyocyanin synthesis-deficient strain is reduced,and its resistance to cephalosporins(ceftazidime)is also decreased.

Objective To investigate the effect of lower limb rehabilitation robot combined with mirror therapy on gait control in stroke patients with hemiplegia.Methods A total of 84 stroke patients with hemiplegia admitted to Suzhou Beno Hospital from May 2019 to December 2021 were randomly assigned to group A,group B,or combination group,with 28 cases in each group.All of them were given routine rehabilitation training.On this basis,group A was given lower limb robot-assisted rehabilitation training,group B was given mirror therapy,and the combined group was given lower limb robot-assisted rehabilitation training plus mirror therapy.The spatio-temporal parameters of walking,Holden walking function grade,ankle dorsiflexion angle,varus angle,Berg balance function scale score,and Barthel index were observed before and after rehabilitation training.Results The step width of the three groups 4 weeks after treatment was significantly lower than that before treatment(P<0.05),and the step width of the combination group was significantly lower than that of groups A and B(P<0.05).The step speed,step frequency,and step length of the three groups 4 weeks after treatment were significantly higher than those before treatment(P<0.05),and these three parameters of the combination group was significantly higher than those of groups A and B(P<0.05).Holden walking function grade,ankle dorsiflexion angle,Berg balance function scale score,and Barthel index of the three groups 4 weeks after treatment were significantly higher than those before treatment(P<0.05),and the above-mentioned parameters the combined group were higher than those in groups A and B(P<0.05).After treatment,the varus angle decreased in the 3 groups,and the varus angle in the combined group was significantly lower than that in groups A and B(P<0.05).There were no significant differences in the spatio-temporal parameters of walking,Holden walking function grade,ankle dorsiflexion angle,varus angle,Berg balance function scale score,or Barthel index between group A and group B four weeks after treatment(P>0.05).Conclusion Lower limb rehabilitation robot combined with mirror therapy is effective in stroke patients with hemiplegia,and it can improve walking ability and quality of life.

Objective To study dynamic compression performance of adipose tissues, so as to further reveal the damage mechanism, and provide references for medical treatment.Methods Based on the improved split Hopkinson pressure bar (SHPB) experimental device, the adipose tissue dynamic compression experiment was conducted. The stress-strain curves of adipose tissues at different strain rates were obtained. Then the numerical model of SHPB was established, and the experimental process was simulated and analyzed. The numerical simulation for penetration process of 32 mm diameter rubber non-lethal projectile into the simulated target in human abdomen was carried out.Results Adipose tissues had a noticeable strain rate effect. The stress-strain curves at two high strain rates were approximately straight lines. The slope was similar, and the elastic modulus was 3.25 MPa, which was about 6 times of that under a quasi-static state. The simulation curves of fat SHPB were consistent with the experimental curves, which verified correctness of the constitutive model. In the process of non-lethal projectile penetrating human abdomen, an annular convex area similar to water wave appeared on skin surface, and the fat layer absorbed about 67% of the impact kinetic energy.Conclusions The experimental data of adipose tissues are very accurate. Numerical simulation can reproduce the penetration process well, and provide references for studying the damaging effect of non-lethal weapons on human body.