A, Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency, JHEP Reports (2022), doi: https://doi.org/10.1016/j.jhepr.2022.100446. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by inheritance of the SERPINA1-Z genetic variant (PiZ) leading to protein misfolding and liver toxicity. There remain no approved medicines for this disease. Here we report the results of a small molecule screen performed in patient-derived iPSC hepatocytes that identified Leucine-rich repeat kinase-2 (LRRK2), as a potentially new therapeutic target. Genetic deletion of LRRK2 in PiZ mice reduced both intrahepatic misfolded polymers and fibrosis leading us to test a library of commercially available LRRK2 inhibitors across several cell models. One of these molecules, CZC-25146, a candidate with favourable pharmacokinetic properties, reduced polymer load, increased normal AAT secretion and reduced inflammatory cytokines in both cells and the PiZ mouse. Mechanistically, this effect was achieved via inhibition of LRRK2 kinase activity and autophagy induction. These findings support the use of CZC-25146 (and potentially LRRK2 inhibitors more broadly) in hepatic proteinopathy disease research and as potential new therapies.
Defrosting is an important controlled event of variable refrigerant flow air conditioning system (VRF AC). The whole course includes defrosting preparation phase, defrosting execution phase, defrosting end preparation phase and pump-down residual running phase. The defrosting control function can make a great influence on the performance of variable refrigerant flow air conditioning system, whose elements are composed of a certain controlled event, controlled components, executed conditions, controlled time, controlled courses and control logic. A sequence diagram is adopted to express the defrosting dynamic process and the control models of execution conditions on defrosting arrival, defrosting end and pump-down residual running end have been built. Thus, the defrosting control function has been formed based on the model and sequence diagram. The defrosting experiments demonstrate that the built model and sequence diagram can scientifically and accurately express the defrosting control function.
Practical application: Defrosting is an important controlled event of variable refrigerant flow air conditioning system. It is difficult to describe the complex controlled course, which is composed of defrosting preparation phase, defrosting execution phase, defrosting end preparation phase and pump-down residual running phase. A sequence diagram can be adopted to express the defrosting dynamic process and the control models of executed conditions on defrosting arrival, defrosting end and pump-down residual running end have been built. Thus, the defrosting control function has been formed based on model and sequence diagram.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.