Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
Ti-10V-2Fe-3Al alloy with fine-grainedβphases was fabricated by friction stir processing with opti-mized processing parameters.The superplastic behavior of the specimens was investigated by tensile deformation at dif...Ti-10V-2Fe-3Al alloy with fine-grainedβphases was fabricated by friction stir processing with opti-mized processing parameters.The superplastic behavior of the specimens was investigated by tensile deformation at different strain rates and temperatures,and an optimal superplastic elongation of 634%was achieved at 700℃ and 3×10^(-4)/s.An annealing treatment at 650℃ for 60 min showed a mi-crostructure withαprecipitates distributed in theβmatrix in the friction stir specimen.Such pre-heat treatment improves the superplasticity of the specimen,achieving an elongation of up to 807%at 750℃ and 3×10^(-4)/s.The influences of tensile temperatures and strain rates on the microstructural evolution,such as grain size variation,grain morphology,and phase transformations,were discussed.The super-plastic deformation behavior of fine-grained Ti-10V-2Fe-3Al alloy is controlled by grain boundary sliding and accompanied by dynamic phase transformation and recrystallization.展开更多
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
基金financially supported by the National Natural Science Foundation of China(No.52105373)the China Scholarship Council(No.202106020094).
文摘Ti-10V-2Fe-3Al alloy with fine-grainedβphases was fabricated by friction stir processing with opti-mized processing parameters.The superplastic behavior of the specimens was investigated by tensile deformation at different strain rates and temperatures,and an optimal superplastic elongation of 634%was achieved at 700℃ and 3×10^(-4)/s.An annealing treatment at 650℃ for 60 min showed a mi-crostructure withαprecipitates distributed in theβmatrix in the friction stir specimen.Such pre-heat treatment improves the superplasticity of the specimen,achieving an elongation of up to 807%at 750℃ and 3×10^(-4)/s.The influences of tensile temperatures and strain rates on the microstructural evolution,such as grain size variation,grain morphology,and phase transformations,were discussed.The super-plastic deformation behavior of fine-grained Ti-10V-2Fe-3Al alloy is controlled by grain boundary sliding and accompanied by dynamic phase transformation and recrystallization.
