RESUMEN
Objective:The present study delves into the realm of scientific unknowns, which serve as the primary representation of major scientific challenges and often give rise to subversive, non-consensus, and high-risk scientific problems. Addressing this pivotal aspect, we focus on the development of scientific unknown identification methods and tool platforms to provide essential data support for priority setting of basic research through a problem-oriented approach. Such efforts are imperative for managing the scientific and technological innovation system within the context of demands and problem-solving.Methods:While numerous knowledge bases have been established in the medical field, there remains a notable lack of focus on the unknown base. The paper synthesizes relevant literature and existing research, amalgamating the methodological paradigm of scientific big data research with text mining. This integration facilitates comprehensive interpretations and enlightening insights concerning the concept, identification methods, and construction of an unknown-base.Results:By systematically analyzing the concept of scientific unknowns, we present a recognition method based on cognitive state and logical rules. Furthermore, we discuss a classification framework and realization path for scientific unknowns from the dimensions of attribute, relationship, and disease, thereby providing foundational insights for the construction of a medical unknown database.Conclusions:Notably, the research on unknowns in medical science transcends disciplinary boundaries, encompassing the confluence of information science, data science, medical informatics, and science and technology management. As such, this paper seeks to expound upon the significance and application scenarios of unknown research in science, furnishing valuable ideas and references for scholars in the field.
RESUMEN
Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.
