Canine degenerative myelopathy (DM) is a human amyotrophic lateral sclerosis (ALS)-like neurodegenerative disease. It is a unique, naturally occurring animal model of human ALS. Canine DM is associated with the aggregation of canine superoxide dismutase 1 (cSOD1), which is similar to human ALS. Almost 100% of cases in dogs are familial, and the E40K mutation in cSOD1 is a major causative mutation of DM. Therefore, it is important to understand the molecular mechanisms underlying cSOD1(E40K) aggregation. To address this, we first analyzed the structural model of wild type cSOD1. Interactions were evident between amino acid E40 and K91. Therefore, the mutation at residue E40 causes loss of the interaction and may destabilize the native structure of cSOD1. Differential scanning fluorimetry revealed that the E40K mutant was less stable than the wild type. Moreover, stability could be recovered by the E40K and K91E double mutation. Acceleration of amyloid fibril formation in vitro and aggregate formation in cells of cSOD1(E40K) was also suppressed by the introduction of this double mutation in thioflavin T fluorescence assay results and in transfectant cells, respectively. These results clearly show the importance of the interaction between amino acid residues E40 and K91 in cSOD1 for the stability of the native structure and aggregation.
This paper developed a new framework for better knowledge management through computational simulations, enabling both human knowledge creation and updating simulation models. The framework was developed based on the concepts of the socialization, externalization, combination, and internalization (SECI) model, and it contains a structured workshop that includes the four types of Ba the model requires. To evaluate this framework, the planning of post-disaster restoration of water distribution networks was employed as a case study. In addition, a new optimization method was developed using empirical heuristics obtained from practitioners, aiming for meaningful feedback from the practitioners working in a water management company. Based on our simulation, three workshops were conducted to create new knowledge, and new features were added to the simulation. In these workshops, practitioners performed simulation-based training in planning the restoration and then discussed their decisions. Afterward, it was concluded that the proposed framework was sufficient for updating the simulation. However, it required additional methods to provide practitioners with opportunities to obtain new insights.
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