Optimal Design for 3-PSS Flexible Parallel Micromanipulator Based on Kinematic and Dynamic Characteristics

This paper proposes two optimal design schemes for improving the kinematic and dynamic performance of the 3-PSS flexible parallel micromanipulator according to different application requirements and conditions. Firstly, the workspace, dexterity, frequencies, and driving forces of the mechanism are successively analyzed. Then, a progressive optimization design is carried out, in which the scale parameters of this mechanism are firstly optimized to maximize the workspace, combining the constraints of the minimum global dexterity of the mechanism. Based on the optimized scale parameters, the minimum thickness and the cutting radius of the flexure spherical hinge are further optimized for minimizing the required driving forces, combined with constraints of the minimum first-order natural frequency of the mechanism and the maximum stress of the flexure spherical hinge during the movement of the mechanism. Afterward, a synchronous optimization design is proposed, in which the scale parameters are optimized to maximize the first-order natural frequency of the mechanism, combined with the constraints of a certain inscribed circle of the maximum cross-section of the workspace, the maximum stroke of the selected piezoelectric stages, and the maximum ultimate angular displacement of the flexure spherical hinge. The effectiveness of both optimization methods is verified by the comparison of the kinematic and dynamic characteristics of the original and optimized mechanism. The advantage of the progressive optimization method is that both the workspace and the driving forces are optimized and the minimum requirements for global dexterity and first-order natural frequency are ensured. The merit of the synchronous optimization method is that only the scale parameters of the mechanism need to be optimized without changing the structural parameters of the flexible spherical hinge

TIMP1 protects against blood-brain barrier disruption after subarachnoid haemorrhage by inhibiting ubiquitination of astrocytic β1-integrin

Background Astrocytes regulate blood-brain barrier (BBB) integrity, whereas subarachnoid haemorrhage (SAH) results in astrocyte dysregulation and BBB disruption. Here, we explored the involvement of tissue inhibitor of matrix metalloprotease-1 (TIMP1) in astrocyte-mediated BBB protection during SAH, along with its underlying mechanisms.Methods C57BL/6J mice were used to establish a model of SAH. The effects of TIMP1 on SAH outcomes were analysed by intraperitoneal injection of recombinant mouse TIMP1 protein (rm-TIMP1; 250 µg/kg). The roles of TIMP1 and its effector β1-integrin on astrocytes were observed by in vivo transduction with astrocyte-targeted adeno-associated virus carrying TIMP1 overexpression plasmid or β1-integrin RNAi. The molecular mechanisms underlying TIMP1 and β1-integrin interactions were explored in primary cultured astrocytes stimulated with red blood cells (RBCs).Results TIMP1 was upregulated after SAH. Administration of rm-TIMP1 mitigated SAH-induced early brain injury (EBI) in male and female mice. TIMP1 was primarily expressed in astrocytes; its overexpression in astrocytes led to increased β1-integrin expression in astrocytes, along with the preservation of astrocytic endfoot attachment to the endothelium and subsequent recovery of endothelial tight junctions. All of these effects were reversed by the knockdown of β1-integrin in astrocytes. Molecular analysis showed that TIMP1 overexpression decreased the RBC-induced ubiquitination of β1-integrin; this effect was partially achieved by inhibiting the interaction between β1-integrin and the E3 ubiquitin ligase Trim21.Conclusion TIMP1 inhibits the interaction between β1-integrin and Trim21 in astrocytes, thereby rescuing the ubiquitination of astrocytic β1-integrin. It subsequently restores interactions between astrocytic endfeet and the endothelium, as well as BBB integrity, eventually mitigating SAH-induced EBI