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.

BACKGROUND:Based on the principle of vertical tooth movement,a personalized orthodontic appliance is created through digital design combined with 3D printing,so that the personalized orthodontic appliance forms a support system with the individual incisors.With the help of the absolute support of the micro-implant,the single tooth is precisely controlled in a three-dimensional direction.OBJECTIVE:To design personalized orthodontic appliances with 11,12,21,and 22 intrusion and extrusion based on biomechanical principles,and analyze the safety of the personalized orthodontic appliances in terms of their movement effect on the teeth by means of the three-dimensional finite element method.METHODS:Three-dimensional finite element models of alveolar bone-periodontium-maxillary incisors-personalized cantilever micro-implant-connecting plates-personalized brackets in the maxillary anterior region(teeth numbers 11,12,21,and 22)were established using Mimics,Geomagic Wrap,SolidWorks,and Ansys Workbench software,respectively.Personalized orthodontic appliances with low pressure movement and extended movement were set up at each tooth position.The stress level of each component of the personalized orthodontic appliances was analyzed,and the tooth displacement and periodontal stress distribution were calculated under loading of 300 g tensile or thrust force.RESULTS AND CONCLUSION:(1)The maximum equivalent force on the personalized intrusion mobile orthodontic appliance was 162.90 MPa,and the maximum equivalent force on the personalized extrusion mobile orthodontic appliance was 239.57 MPa.The maximum equivalent stress on both devices was located in the vertical portion of the personalized bracket loading attachment.The equivalent stresses on each part of the personalized orthodontic appliance were all within the yield strength,and they had good safety.(2)The initial displacement of the teeth under the action of the personalized orthodontic appliances showed a tendency towards overall intrusion or extrusion,with the displacement in the vertical direction far exceeding that in the horizontal and sagittal directions.The equivalent stress peak appeared at the root tip or neck of the periodontal membrane,and the equivalent stress concentration area appeared in the periodontal membrane of the root apical region.(3)The results show that the personalized orthodontic appliance allows 11,12,21,and 22 to approximate either intrusion movement or extrusion movement,initially confirming the effectiveness of the personalized vertical movement orthodontic appliance.

BACKGROUND:Currently,the mandibular joint prosthesis manufactured at home and abroad needs to rely on screws to fix the condylar part of the prosthesis during the replacement process,and the retention hole is reserved to facilitate the operation during the operation.However,due to the lack of personalized jaw design,the reattachment plate may not fit the jaw,resulting in screw loosening and dislocation.Therefore,personalized condylar prosthesis replacement is of great value in the repair of the temporomandibular joint.OBJECTIVE:To design a personalized condylar prosthesis with an internal GYROID for mandibular condylar repair and reconstruction.METHODS:The GYROID structure was selected in the Rhinoceros 7 software with the single cell size of 6 mm and the wall thickness of 0.2,0.3,0.4,0.5,0.6,0.7,0.8 mm.The mechanical properties of the GYROID structure were analyzed by finite element method.3D printing of GYROID structural test specimens with different wall thickness(0.2,0.3,0.4,0.5,0.6,0.7,and 0.8 mm)was performed to test the mechanical properties of the specimens through room temperature compression experiments.A wall thickness value conforming to the range of mandibular mechanical properties was selected through finite element analysis and room temperature compression test results.An adult male mandibular CT data were used for inverse modeling to design a condylar prosthesis with an internal GYROID.Finite element analysis was used to simulate the movement of the apical staggered position and the opposite-blade jaw position after condylar prosthesis replacement.RESULTS AND CONCLUSION:(1)The results of finite element analysis and room temperature compression experiment showed that the elastic modulus of the GYROID structure increased with the increase of wall thickness.The elastic modulus of the GYROID structure with wall thickness of 0.5-0.7 mm was within the range of the elastic modulus of the mandible(1.5-4.0 GPa).Therefore,the 6 mm monocellular GYROID structural model with a wall thickness of 0.6 mm was selected for the design of the condylar prosthesis.(2)The results of finite element analysis showed that the stress distribution of mandibular model was symmetrical.The stress distribution of the two types of occlusion was roughly the same,and the stress peak was not significantly different.The stress concentrated in the neck of the condylar prosthesis,and the stress on the replacement side was slightly larger than that on the healthy side.The maximum equivalent stress of the whole internal fixation model was 269.34 MPa,and the maximum equivalent stress of the screw was 20.14 MPa.The equivalent stress and equivalent strain values of the prosthesis were greater than that of the opposite edge jaw position when the tooth tip was interlaced.The equivalent stress and equivalent strain values of the screw were smaller than that of the opposite edge jaw position when the tooth tip was interlaced.(3)The results showed that the design and retention of the personalized GYROID condylar prosthesis were good,which was consistent with the mechanical conduction of the mandible.

BACKGROUND:Porous structures based on triple periodic minimal surfaces are one of the most promising orthopedic biostructures,among which the Gyroid structure is characterized by high specific surface area,high permeability,and zero mean curvature.OBJECTIVE:To screen the wall thickness interval of TC4 bionic bone scaffolds with 4 mm single-cell Gyroid structure matching the elastic modulus range of cancellous bone of the mandible through finite element analysis combined with mechanical compression test testing.METHODS:The finite element model of the 4 mm single-cell Gyroid structure with different wall thickths(0.1,0.2,0.3,0.4,0.5,0.6,0.7,and 0.8 mm)was established.The equivalent elastic modulus of the Gyroid structure was analyzed,and the wall thickness interval of the Gyroid structure matching the elastic modulus range of the maxillary resinous bone was selected with different wall thicknesses of 0.2,0.3,0.4,0.5,0.6,and 0.7 mm,respectively.According to finite element analysis screening results,the material selected was Ti6Al4V.Selective laser melting was used to prepare 3D printed Gyroid structure specimens.The surface treatment was carried out by large-grained sand blasting and acid etching.The elastic modulus and compressive strength of the specimen were tested by mechanical compression experiment.RESULTS AND CONCLUSION:(1)The finite element analysis results showed that the equivalent elastic modulus of the Gyroid structure increased with the increase of wall thickness,and the equivalent elastic modulus of the Gyroid structure with wall thickness of 0.2-0.7 mm was within the range of the elastic modulus of the spongy bone of the mandible(1.5-4.0 GPa),which was used for 3D printing of the Gyroid structure specimen.(2)The mechanical compression test results showed that the elastic modulus and compressive strength of the Gyroid structural specimen increased with the increase of wall thickness,and the elastic modulus of the Gyroid structural specimen with wall thickness of 0.3-0.5 mm was within the range of the elastic modulus of the cancellous bone of the mandible.The compressive strength of the Gyroid specimen with 0.3-0.7 mm wall thickness was consistent with the mechanical properties of the mandible.(3)The results show that the Gyroid structure of 0.3-0.5 mm wall thickness is compatible with the range of elastic modulus of the mandible.

Objective Exploring the behavioral changes induced by quinpirole in obsessive-compulsive disorder(OCD)mouse,investigating the activation of neurons in different brain regions,and identifying differentially expressed genes(DEGs)and enriched biological pathways through transcriptome sequencing technology to elucidate the pathogenesis of OCD.Methods Randomly assign 32 male C57BL/6J mice,aged two months,to an OCD group and a control group(n=16).Administering quinpirole(0.75 mg/kg)via subcutaneous injection to the OCD group mice every other day for a total of 19 injections,while the control group mice received an equivalent volume of saline solution.Following the completion of the model construction,open field testing,elevated plus maze testing,and marble burying tests were conducted.After the completion of behavioral studies,tissue samples were collected.Neuronal damage was assessed using Nissl staining,while the expression of c-Fos and Iba1 proteins was examined through immunofluorescence staining.Transcriptome sequencing technology was utilized to screen for differentially expressed genes and to enrich relevant signaling pathways.The expression of inflammatory cytokines,including TNF-α,NF-κB p65,phosphorylated NF-κB p65(p-NF-κB p65),and IL-6,was detected using Western Blot analysis.Results Mouse induced with OCD by quinpirole exhibit anxiety-like behaviors and compulsive-like behaviors.Neurons in the hippocampal and hypothalamic regions exhibit signs of damage.The expression of c-Fos and Iba1 proteins is increased in the cortex,striatum,hypothalamus,and other brain regions.Western Blot result indicate a significant increase in the expression of pro-inflammatory cytokines such as TNF-α,p-NF-κB p65,and IL-6.Conclusions In OCD mouse,neurons in multiple brain regions are abnormally activated,microglia exhibit dysfunction,and neuroinflammation induced by the activation of the NF-κB signaling pathway accompanies the development of OCD.

Objective Exploring the behavioral changes induced by quinpirole in obsessive-compulsive disorder(OCD)mouse,investigating the activation of neurons in different brain regions,and identifying differentially expressed genes(DEGs)and enriched biological pathways through transcriptome sequencing technology to elucidate the pathogenesis of OCD.Methods Randomly assign 32 male C57BL/6J mice,aged two months,to an OCD group and a control group(n=16).Administering quinpirole(0.75 mg/kg)via subcutaneous injection to the OCD group mice every other day for a total of 19 injections,while the control group mice received an equivalent volume of saline solution.Following the completion of the model construction,open field testing,elevated plus maze testing,and marble burying tests were conducted.After the completion of behavioral studies,tissue samples were collected.Neuronal damage was assessed using Nissl staining,while the expression of c-Fos and Iba1 proteins was examined through immunofluorescence staining.Transcriptome sequencing technology was utilized to screen for differentially expressed genes and to enrich relevant signaling pathways.The expression of inflammatory cytokines,including TNF-α,NF-κB p65,phosphorylated NF-κB p65(p-NF-κB p65),and IL-6,was detected using Western Blot analysis.Results Mouse induced with OCD by quinpirole exhibit anxiety-like behaviors and compulsive-like behaviors.Neurons in the hippocampal and hypothalamic regions exhibit signs of damage.The expression of c-Fos and Iba1 proteins is increased in the cortex,striatum,hypothalamus,and other brain regions.Western Blot result indicate a significant increase in the expression of pro-inflammatory cytokines such as TNF-α,p-NF-κB p65,and IL-6.Conclusions In OCD mouse,neurons in multiple brain regions are abnormally activated,microglia exhibit dysfunction,and neuroinflammation induced by the activation of the NF-κB signaling pathway accompanies the development of OCD.

Objective To investigate the mechanism by which cancer-associated fibroblast(CAF)in the tumor microenvironment regulate key pathways in prostate cancer stem cells(PCSCs).Methods An in vitro co-culture system of CAF and PCSC was established to observe the effects of CAF on PCSC proliferation and sphere formation.Prostate cancer stem cells were treated with CAF conditioned medium pre-treated with Wnt inhibitor DKK-1 and SDF-1 neutralizing anti-body(MAB310).Western blot was used to detect the expression of β-catenin,CXCR4,CD133 and CD44 in PCSCs.And PCR was used to detect the expression of β-catenin,CXCR4,TCF,and LEF mRNA.TOPflash/FOPflash dual-luciferase reporter assays were conducted to detect the effects of SDF-1 on Wnt/β-catenin signaling activity in PCSCs.Results ELISA results showed that the secretion of Wnt3a and SDF-1 in CAF supernatant was significantly higher than that in WPMY-1 cells(P＜0.05).The A value of PCSCs co-cultured with CAF at a 1∶6 ratio was significantly higher than that of the PCSC-only group(P＜0.0 1),and CAF promoted sphere formation in PCSCs(P＜0.05).Western blot results showed that CAF-CM significantly increased the relative expression of β-catenin,CXCR4,CD133 and CD44 in PCSCs(P＜0.01).Compared to CAF-CM,CAFanti-Wnt-CM significantly reduced the expression of β-catenin,CD133 and CD44(P＜0.01).CAFanti-SDF-1-CM also significantly inhibited the expression of CXCR4,β-catenin,CD133 and CD44(P＜0.01).PCR results showed that CAFanti-SDF-1-CM inhibited the expression of β-catenin,CXCR4 and downstream Wnt signaling effectors TCF and LEF(P＜0.01).Dual-luciferase reporter assay results showed that luciferase activity in the CAFanti-SDF-1-CM group was significantly lower than that in the CAF-CM group(P＜0.05).Conclusion CAF reg-ulates the stemness of PCSCs through the Wnt/β-catenin and SDF-1/CXCR4 pathways.CXCR4 may enhance the mainte-nance of stemness by activating β-catenin.

Alzheimer's disease(AD)is common neurodegenerative diseases that is the main causes of cognitive dysfunction and behavioral abnormalities.Constructing animal models with similar characteristics to human patients is crucial for advancing investigations of AD,and to develop new therapeutic drugs.Combined with the latest research progress,this review classifies animal models of AD according to aging models,genetically modified models,and chemically induced models.This review systematically summarizes the commonly used animal models of AD,and elucidates the modeling mechanisms and pathological changes,and compares their advantages and limitation,with a view to provide method ological references for researchers in selecting appropriate animal model for AD investigation.

Rapid developments in biotechnology have led researchers to seek new method to improve the efficiency and accuracy of biomedical research and drug development,promoting interdisciplinary integration.Recent advancements in artificial intelligence(AI)technologies have brought unprecedented opportunities to this field.The integration of various AI models allows researchers to better utilize multi-omics data,identify disease phenotypes,interpret animal behavior,assess treatment effects,improve experimental designs,reduce the use of experimental animals,enhance animal facility management,and improve animal welfare.This article reviews the advancements in AI biomedical research over the past decade and discusses its contributions to disease phenotype identification,the selection and design of experimental animal models,animal behavior analysis,and animal facility management.It also points out the challenges related to data standardization,AI model selection and interpretability,the extrapolation process from AI models to animal experiments and clinical practice,as well as ethical considerations in using AI in sensitive areas involving human genetics and personalized medicine.This review aims to help researchers and practitioners in relevant fields understand the current state and opportunities of AI development,thus providing support for its broader application.

Objective To investigate the effects of microRNA-34a(miR-34a-5p)on the progression of chronic lymphocytic leukemia(CLL)through the Wnt/β-catenin signaling pathway.Methods Human chronic B-cell leukemia MEC-1 cells were selected for experimentation.MEC cells were divided into two groups,group one:the p53 agonist group and the control group;group two:the control group,the miR-34a-5p mimic group and its corresponding negative control,the miR-34a-5p inhibitor group and its corresponding negative control,as well as the miR-34a-5p inhibitor+Wnt inhibitor XAV-939 group.The expression levels of miR-34a-5p in each group were measured using real-time fluorescence quantitative PCR(qPCR).Cell proliferation was assessed by CCK-8 assay,while cell migration ability was evaluated using Transwell migration assay.Dual-luciferase reporter assay was employed to validate the targeting relationships between p53 and miR-34a-5p,as well as between miR-34a-5p and Wnt1.Western blot analysis was used to detect the protein expressions of β-catenin and Cyclin D1,which were key components of the Wnt/β-catenin signaling pathway.Results In MEC-1 cells:① compared with the control group,there was a increased miR-34a-5p expression and inhibited cell proliferation in the p53 agonist group(P＜0.05).Dual-luciferase reporter assay confirmed a negative regulatory correlation between miR-34a-5p and p53.② the miR-34a-5p mimic group showed significantly upregulated miR-34a-5p expression compared to the control group,leading to suppressed cell proliferation,reduced migration capability and decreased protein expressions of β-catenin and Cyclin D1(P＜0.05).Conversely,the miR-34a-5p inhibitor group demonstrated significantly downregulated miR-34a-5p expression,resulting in enhanced cell proliferation,increased migratory capacity and upregulated protein levels of β-catenin and Cyclin D1 compared to those of the control group(P＜0.05).③ A targeting relationship was observed between miR-34a-5p and Wnt1.④ Compared with the miR-34a-5p inhibitor group,the XAV-939 group exhibited significantly upregulated miR-34a-5p expression,markedly decreased numbers of migrated cells and substantially reduced protein expression levels of β-catenin and Cyclin D1(P＜0.05).Conclusion miR-34a plays the role of a tumor suppressor gene in CLL.Overexpression of miR-34a can inhibit the Wnt/β-catenin signaling pathway,reduce the proliferation activity and migration ability of cells,and promote cell apoptosis.