The role of ubiquitin carboxyl-terminal hydrolase isozyme L1/UCHL1 in human lung diseases:environmental exposure, epigenetics and epigenetic editing

Environmental exposure to cigarette smoke or toxic metal cadmium is closely associated with various airway diseases, including lung cancer and chronic lung diseases. Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) is a member of the ubiquitin-proteasome system and involved in protein turnover, and its dysregulation has been associated with airway diseases. The thesis first examines the molecular mechanisms of chronic cadmium-induced adaptation and carcinogenesis. In this part, epiproteome (proteomic analysis of histone marks) and subproteome (proteomic analysis of subcellular proteins) approaches were used to interrogate cadmium-transformed human bronchial epithelial cells, and we found that these cadmium-adapted cells exhibit epithelial-mesenchymal transition (EMT) and enhanced cell migration. Through subproteome profiling, we found that UCHL1 was the top downregulated protein upon chronic cadmium exposure and its lower expression was closely associated with EMT. In the second part of the thesis, we continued to explore the role of UCHL1 in smoking-related disease through transcription modulation of UCHL1 in different lung cell lines. We first confirmed that UCHL1 was highly expressed in current smokers. As UCHL1 plays a crucial role in EMT and fibrosis, we further checked whether UCHL1 also functions on extra cellular matrix (ECM) production and airway remodeling. We increased the expression of UCHL1 by a CRISPR/dCas9-based artificial transcription activator and demonstrated a subsequent increase in the expression of the ECM gene COL1A1. Downregulation of UCHL1 was obtained via writing of the repressive histone mark H3K27 methylation and indirectly resulted in a decreased expression of ECM genes COL1A1 and fibronectin. Overall, these results suggest that UCHL1 is a mediator in the synthesis of ECM proteins and may be involved in smoking-induced airway remodeling

Concept Extraction and Clustering for Topic Digital Library Construction

This paper is to introduce a new approach to build topic digital library using concept extraction and document clustering. Firstly, documents in a special domain are automatically produced by document classification approach. Then, the keywords of each document are extracted using the machine learning approach. The keywords are used to cluster the documents subset. The clustered result is the taxonomy of the subset. Lastly, the taxonomy is modified to the hierarchical structure for user navigation by manual adjustments. The topic digital library is constructed after combining the full-text retrieval and hierarchical navigation function

Uniqueness of a pre-generator for C0C_0-semigroup on a general locally convex vector space

The main purpose is to generalize a theorem of Arendt about uniqueness of $C_0$-semigroups from Banach space setting to the general locally convex vector spaces, more precisely, we show that cores are the only domains of uniqueness for $C_0$-semigroups on locally convex spaces. As an application, we find a necessary and sufficient condition for that the mass transport equation has one unique $L^1(\R^d,dx)$ weak solution