Objective In response to the clinical needs for personalized wrist orthoses,a topological optimization design method was proposed to achieve an integrated macro-and micro-structural optimization of a personalized,lightweight,and comfortable wrist orthosis.Methods A composite biomechanical finite element model of the wrist orthosis and upper limb was established to quantify the effects of the orthosis geometry on its fixation performance and comfort.A multi-condition topological optimization and microstructure design approach was employed to optimize the non-load-bearing areas of the orthosis.The orthosis was manufactured using three-dimensional(3D)-printed polyether ether ketone(PEEK),and the feasibility of the design was validated.Results While maintaining mechanical strength,the weight of the 3D-printed PEEK orthosis was reduced by 28％compared to the traditional orthoses.Both the pressure at the skin contact interface and the results of a subjective questionnaire indicated that test subjects experienced a high level of comfort wearing the orthosis.Conclusions The orthosis design achieved personalization,lightweight structure,and high comfort while ensuring mechanical strength and fixation performance.

Objective In response to the clinical needs for personalized wrist orthoses,a topological optimization design method was proposed to achieve an integrated macro-and micro-structural optimization of a personalized,lightweight,and comfortable wrist orthosis.Methods A composite biomechanical finite element model of the wrist orthosis and upper limb was established to quantify the effects of the orthosis geometry on its fixation performance and comfort.A multi-condition topological optimization and microstructure design approach was employed to optimize the non-load-bearing areas of the orthosis.The orthosis was manufactured using three-dimensional(3D)-printed polyether ether ketone(PEEK),and the feasibility of the design was validated.Results While maintaining mechanical strength,the weight of the 3D-printed PEEK orthosis was reduced by 28％compared to the traditional orthoses.Both the pressure at the skin contact interface and the results of a subjective questionnaire indicated that test subjects experienced a high level of comfort wearing the orthosis.Conclusions The orthosis design achieved personalization,lightweight structure,and high comfort while ensuring mechanical strength and fixation performance.

Objective To explore the regulatory role of hederagenin(HG)on glutamate(Glu)-in-duced ferroptosis and corresponding inflammatory responses in mouse hippocampal neuron HT22 cells and investigate its potential mechanisms.Methods HT22 cells were randomly divided into control,Glu and HG groups(n=3).The cells of the control group received no treatment,the cells of the Glu group were treated with 35 mmol/L Glu for 24 h to establish a cellular model of ferroptosis in Alzheimer's disease,and the cells of the HG group were treated with 0.5 μmol/L HG and 35 mmol/L Glu for 24 h simultaneously.FerroOrange fluorescent probe was used to de-tect intracellular Fe2+.The production of reactive oxygen species(ROS),mitochondrial membrane potential,and levels of inflammatory factors TNF-α,IL-1β and IL-6 in the cells were assessed.Finally,the expression of the key regulator of iron death,glutathione peroxidase 4(GPX4)was measured.Results Compared to the control group,the levels of intracellular Fe2+,ROS,TNF-α,IL-1β,and IL-6 were significantly elevated,while the mitochondrial membrane potential was obvi-ously reduced in the Glu group(P＜0.05,P＜0.01).The HG group had significantly decreased Fe2+,ROS,TNF-α,IL-1β,and IL-6 and enhanced mitochondrial membrane potential than the Glu group(P＜0.05,P＜0.01).The GPX4 expression was significantly lower in the Glu group than the control group(1.00±0.02 vs 0.46±0.04,P＜0.01),and was notably higher in the 0.5 and 1.0 μmol/L HG groups when compared to the Glu group(0.64±0.03 and 0.59±0.05 vs 0.46±0.04,P＜0.01).Conclusion HG inhibits ferroptosis by regulating GPX4 expression,and thereby effec-tively alleviates the inflammatory response.

Objective To observe the alterations in functional complexity of brain regions in autism spectrum disorder(ASD)patients and correlations with the predicted brain age.Methods Open brain resting-state functional MRI(rs-MRI)data of 93 ASD patients and 96 typically developing adolescents(healthy subjects)were downloaded.The functional complexity in brain regions were extracted with self-developed virtual digital brain software,and the alterations in functional complexity of brain regions in ASD patients and correlations with their ages were analyzed.Two networks were prospectively trained with data of 65 ASD patients and 67 healthy subjects as the training set to predict brain age,and the results were evaluated,and the predicting errors were compared using test set,i.e.the other 28 ASD patients and 29 healthy subjects.Results Compared to healthy subjects,on the basis of anatomical automatic labeling(AAL)atlas,ASD patients exhibited significantly reduced functional complexity based on Shannon entropy in the left precuneus,left cuneus and right parahippocampal gyrus.Conversely,functional complexity of ASD patients based on permutation entropy significantly increased in the left cuneus and right cerebellar Crus Ⅱ region.The left hippocampus showed reduced functional complexity based on Pearson correlation coefficient,while the left middle temporal gyrus showed increased functional complexity based on Pearson correlation coefficient.The functional complexity in brain regions of ASD patients were not closely correlated with ages(all|r|＜0.4).According to the trained fully connected network,the predicted brain ages of ASD patients and healthy subjects in test set were all lower than their physiological ages,but no significant difference was found between the prediction errors of ASD patients and healthy subjects(P=0.283).Conclusion Functional complexity changed in some brain region functions in ASD patients.The predicted brain ages of ASD patients based on the obtained fully connected network were on the low side,but not obviously affected by the alterations of functional complexity in brain regions.

Objective To explore the molecular mechanisms of resistance to phosphatidyl inositol 3?kinase ( PI3K) inhibitors in triple?negative breast cancer ( TNBC) cells. Methods HCC70 cells ( TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β?catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF?7 ( ER?positive ) and SK?BR3 ( HER2?positive ) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations ( IC50 ) were calculated. The altered activities of WNT/β?catenin and PI3K/AKT/mTOR proteins were detected by Western blot and luciferase report gene assay, respectively. The nuclear translocation of β?catenin protein was examined by immunofluorescence assay. Xenograft nude mouse model was used to evaluate the tumorigenicity of breast cancer cells treated with BKM120 in vivo. The expression levels of p?LRP6, p?4EBP1 and β?catenin proteins in the tumor tissues were determined by immunohistochemical staining. Results The expression levels of FZD7, WANT5B and GSK3 proteins were significantly reduced in the HCC70 cells transfected with the target siRNAs. Meanwhile, the activity of WNT/β?catenin was enhanced and PI3K/AKT/mTOR pathway was inhibited. PI3K/AKT/mTOR inhibitors suppressed MCF?7 and SK?BR3 cell proliferation. The IC50 of GDC?094, BKM120, XL147, perifosine, everolimus, and BEZ235 in MCF?7 cells were 0. 46 mmol/L, 1. 44 mmol/L, 4. 34 mmol/L, 11.35 μmol/L, 53. 71 μmol/L and 12. 87 μmol/L respectively, and 0. 63 mmol/L, 0. 58 mmol/L, 3. 74 mmol/L, 13.22μmol/L, 60.00μmol/L and 11.38μmol/L in the SK?BR3 cells, respectively. The results of luciferase report gene assay showed that the luciferase activities in HCC70, MCF?7 and SK?BR3 cells treated with BKM120 were 1.75±0.05, 1.13±0.02 and 0.43±0.01, respectively. The luciferase activities in HCC70 and SK?BR3 cells were significantly different from that of the control cells (1.00±0.02, P<0.05). The immunohistochemical analysis showed that BKM120 inhibited mTOR activity, and the enhanced WNT/β?catenin activity reversed the phenotype of inhibitory mTOR induced by BKM120. BKM120 suppressed the tumorigenic ability of MCF?7 and SK?BR3 cells in vivo, but had no effect on cultured HCC70 cells. The immunohistochemical analysis showed nuclear translocation of β?catenin protein and increased expression level of p?LRP?6 protein in transplanted tumor tissues from HCC70 cells treated with BKM120, increased the level of p?LRP?6 protein, and no changes of p?4EBP1 protein expression. However, no nuclear translocation of β?catenin protein and no decrease of p?LRP6 and p?4EBP1 protein levels in the transplanted tumor tissue of MCF?7 cells after treatment with BKM120. Conclusions The triple?negative breast cancer HCC70 cells have drugs?resistance to PI3K inhibitors. The WNT/β?catenin signaling pathway may regulate the PI3K/AKT/mTOR pathway, therefore, inducing the drug?resistance of TNBC cells to PI3K inhibitors.

Objective To explore the molecular mechanisms of resistance to phosphatidyl inositol 3?kinase ( PI3K) inhibitors in triple?negative breast cancer ( TNBC) cells. Methods HCC70 cells ( TNBC) were transfected with siFZD7, siWANT5B or siGSK3 using lipofectamine 2000 transfection reagent. The expression levels of key proteins of WNT/β?catenin and PI3K/AKT/mTOR pathways were determined by Western blot analysis. After HCC70, MCF?7 ( ER?positive ) and SK?BR3 ( HER2?positive ) cells were treated with PI3K/AKT/mTOR inhibitors, the inhibition rates of cell proliferation were measured by MTT assay, and half maximal inhibitory concentrations ( IC50 ) were calculated. The altered activities of WNT/β?catenin and PI3K/AKT/mTOR proteins were detected by Western blot and luciferase report gene assay, respectively. The nuclear translocation of β?catenin protein was examined by immunofluorescence assay. Xenograft nude mouse model was used to evaluate the tumorigenicity of breast cancer cells treated with BKM120 in vivo. The expression levels of p?LRP6, p?4EBP1 and β?catenin proteins in the tumor tissues were determined by immunohistochemical staining. Results The expression levels of FZD7, WANT5B and GSK3 proteins were significantly reduced in the HCC70 cells transfected with the target siRNAs. Meanwhile, the activity of WNT/β?catenin was enhanced and PI3K/AKT/mTOR pathway was inhibited. PI3K/AKT/mTOR inhibitors suppressed MCF?7 and SK?BR3 cell proliferation. The IC50 of GDC?094, BKM120, XL147, perifosine, everolimus, and BEZ235 in MCF?7 cells were 0. 46 mmol/L, 1. 44 mmol/L, 4. 34 mmol/L, 11.35 μmol/L, 53. 71 μmol/L and 12. 87 μmol/L respectively, and 0. 63 mmol/L, 0. 58 mmol/L, 3. 74 mmol/L, 13.22μmol/L, 60.00μmol/L and 11.38μmol/L in the SK?BR3 cells, respectively. The results of luciferase report gene assay showed that the luciferase activities in HCC70, MCF?7 and SK?BR3 cells treated with BKM120 were 1.75±0.05, 1.13±0.02 and 0.43±0.01, respectively. The luciferase activities in HCC70 and SK?BR3 cells were significantly different from that of the control cells (1.00±0.02, P<0.05). The immunohistochemical analysis showed that BKM120 inhibited mTOR activity, and the enhanced WNT/β?catenin activity reversed the phenotype of inhibitory mTOR induced by BKM120. BKM120 suppressed the tumorigenic ability of MCF?7 and SK?BR3 cells in vivo, but had no effect on cultured HCC70 cells. The immunohistochemical analysis showed nuclear translocation of β?catenin protein and increased expression level of p?LRP?6 protein in transplanted tumor tissues from HCC70 cells treated with BKM120, increased the level of p?LRP?6 protein, and no changes of p?4EBP1 protein expression. However, no nuclear translocation of β?catenin protein and no decrease of p?LRP6 and p?4EBP1 protein levels in the transplanted tumor tissue of MCF?7 cells after treatment with BKM120. Conclusions The triple?negative breast cancer HCC70 cells have drugs?resistance to PI3K inhibitors. The WNT/β?catenin signaling pathway may regulate the PI3K/AKT/mTOR pathway, therefore, inducing the drug?resistance of TNBC cells to PI3K inhibitors.