Topology optimization of flexure hinges with a prescribed compliance matrix based on the adaptive spring model and stress constraint

This paper focuses on the configuration design of flexure hinges with a prescribed compliance matrix and preset rotational center position. A new method for the topology optimization of flexure hinges is proposed based on the adaptive spring model and stress constraint. The hinge optimization model is formulated by maximizing the bending displacement with a spring while optimizing the compliance matrix to a prescribed value. To avoid numerical instability, an artificial spring is used as an auxiliary calculation, and a new strategy is developed for adaptively adjusting the spring stiffness according to the prescribed compliance matrix. The maximum stress of flexure hinge is limited by using a normalized P-norm of the effective von Mises stress, and a position constraint of rotational center is proposed to predetermine the position of the rotational center. In addition, to reduce the error of the stress measurement, a simple but effective filtering method is presented to obtain a complete black-and-white design. Numerical examples are used to verify the proposed method. Topology results show that the obtained flexure hinges have the prescribed compliance matrix and preset rotational center position while also meeting the stress requirements.     

Identification of Novel Fragments Binding to the PDZ1-2 Domain of PSD-95

Inhibition of PSD-95 has emerged as a promising strategy for the treatment of ischemic stroke, as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to binding small molecules. We screened 2500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR), including an inhibition counter-test, and found four promising fragments. Three ligand efficient fragments were shown by ¹H,¹⁵N HSQC NMR to bind in the small hydrophobic P⁰ pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.     

Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

Exploration of GH94 Sequence Space for Enzyme Discovery Reveals a Novel Glucosylgalactose Phosphorylase Specificity

The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d -glucosyl-d -galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d -glucosyl-d -galactose and 4-O-β-d -glucosyl-l -arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis.     

Phenotypic Discovery of SB1501, an Anti-obesity Agent,through Modulating Mitochondrial Activity

Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α–UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities.     

Design,Synthesis, and Biological Evaluation of Lysine Demethylase 5 C Degraders

Lysine demethylase 5 C (KDM5C) controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics. KDM5C has emerged as a therapeutic target for anti-prostate cancer agents, and recently we identified triazole 1 as an inhibitor of KDM5C. Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays, but did not show strong anticancer effects. Therefore, a different approach is needed for the development of anticancer agents targeting KDM5C. Here, we attempted to identify KDM5C degraders by focusing on a protein-knockdown strategy. Compound 3 b , which was designed based on compound 1 , degraded KDM5C and inhibited the growth of prostate cancer PC-3 cells more strongly than compound 1 . These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C.     

Reconfigurable topology synthesis for application-specific NoC on partially dynamically reconfigurable systems

In this paper, a four-stage method for synthesizing reconfigurable ASNoC topology is proposed for partially dynamically reconfigurable systems, where the topology is reconfigured dynamically at run-time along with the application's execution. Firstly, a simulated annealing based topology-aware integrated optimization framework is proposed to generate the proper schedule and floorplan of task modules. Secondly, based on the schedule and floorplan of task modules, an Integer Linear Programming (ILP)-based method and a heuristic method, are proposed to partition the communication requirements of the application into $T$ time intervals. Thirdly, we explore the proper positions of switches in the floorplan for global communications. Finally, considering the reconfiguration costs between adjacent time intervals, the routing path allocation problem is solved for time intervals in an iterative procedure to generate fine-grained dynamically reconfigurable ASNoC topologies. Experimental results show that, compared to the random partition of communication requirements, the proposed heuristic method and ILP-based method can achieve 5.4% and 10.0% power consumption improvement, respectively. And, the reconfigurable ASNoC can achieve 31.6% power consumption improvement when compared with static ASNoC.     

Topology optimization for crashworthiness of thin-walled structures under axial crash considering nonlinear plastic buckling and locations of plastic hinges

Although topology optimization is established for linear static problems, more effort is required for solving nonlinear plastic problems. A new topology optimization approach with equivalent static loads (ESLs) is suggested to find the optimum topologies and locations of plastic hinges of thin-walled crash boxes by considering crash-induced deformation, the main crash energy-absorbing mechanism. Together with finite element method crashworthiness analyses, considering all nonlinearities with rate-dependent plasticity, the method was developed using an appropriate time-incremental scheme of ESLs without removing any high values of loads. Analyses show that the crash boxes with optimum topologies have energy-absorbing capabilities equivalent to the original structure. The proposed method is evaluated for two crashes: a crash box at low speed and a double cell subjected to high-speed collision. The results indicate that this method captures nonlinear crushing behaviours and accurate locations of plastic hinges where, if proper reinforcements are made, energy absorption can be enhanced.     

POD-assisted strategies for structural topology optimization

We propose a new numerical tool for structural optimization design. To cut down the computational burden typical of the Solid Isotropic Material with Penalization (SIMP) method, we apply Proper Orthogonal Decomposition on SIMP snapshots computed on a fixed grid to construct a rough structure (predictor) which becomes the input of a SIMP procedure performed on an anisotropic adapted mesh (corrector). The benefit of the proposed design tool is to deliver smooth and sharp layouts which require a contained computational effort before moving to the 3D printing production phase.