ABSTRACT
Carboxy terminal fragments (CTFs) of TDP-43 contain an intrinsically disordered region (IDR) and form cytoplasmic condensates containing amyloid fibrils. Such condensates are toxic and associated with pathogenicity in amyotrophic lateral sclerosis. However, the molecular details of how the domain of TDP-43 CTFs leads to condensation and cytotoxicity remain elusive. Here, we show that truncated RNA/DNA-recognition motif (RRM) at the N-terminus of TDP-43 CTFs leads to the structural transition of the IDR, whereas the IDR itself of TDP-43 CTFs is difficult to assemble even if they are proximate intermolecularly. Hetero-oligomers of TDP-43 CTFs that have recruited other proteins are more toxic than homo-oligomers, implicating loss-of-function of the endogenous proteins by such oligomers is associated with cytotoxicity. Furthermore, such toxicity of TDP-43 CTFs was cell-nonautonomously affected in the nematodes. Therefore, misfolding and oligomeric characteristics of the truncated RRM at the N-terminus of TDP-43 CTFs define their condensation properties and toxicity.
Subject(s)
DNA-Binding Proteins , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Humans , Animals , Protein Multimerization , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/metabolism , Intrinsically Disordered Proteins/geneticsABSTRACT
The creation of highly effective oral drug delivery systems (ODDSs) has long been the main objective of pharmaceutical research. Multidisciplinary efforts involving materials, electronics, control, and pharmaceutical sciences encourage the development of robot-enabled ODDSs. Compared with conventional rigid robots, soft robots potentially offer better mechanical compliance and biocompatibility with biological tissues, more versatile shape control and maneuverability, and multifunctionality. In this paper, we first describe and highlight the importance of manipulating drug release kinetics, i.e. pharmaceutical kinetics. We then introduce an overview of state-of-the-art soft robot-based ODDSs comprising resident, shape-programming, locomotive, and integrated soft robots. Finally, the challenges and outlook regarding future soft robot-based ODDS development are discussed.
Subject(s)
Robotics , Delayed-Action Preparations , Drug CompoundingABSTRACT
Millimeter-scale animals such as Caenorhabditis elegans, Drosophila larvae, zebrafish, and bees serve as powerful model organisms in the fields of neurobiology and neuroethology. Various methods exist for recording large-scale electrophysiological signals from these animals. Existing approaches often lack, however, real-time, uninterrupted investigations due to their rigid constructs, geometric constraints, and mechanical mismatch in integration with soft organisms. The recent research establishes the foundations for 3-dimensional flexible bioelectronic interfaces that incorporate microfabricated components and nanoelectronic function with adjustable mechanical properties and multidimensional variability, offering unique capabilities for chronic, stable interrogation and stimulation of millimeter-scale animals and miniature tissue constructs. This review summarizes the most advanced technologies for electrophysiological studies, based on methods of 3-dimensional flexible bioelectronics. A concluding section addresses the challenges of these devices in achieving freestanding, robust, and multifunctional biointerfaces.
