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  1. Article ; Online: Genomic characterization and therapeutic utilization of IL-13-responsive sequences in asthma.

    Koh, Kyung Duk / Bonser, Luke R / Eckalbar, Walter L / Yizhar-Barnea, Ofer / Shen, Jiangshan / Zeng, Xiaoning / Hargett, Kirsten L / Sun, Dingyuan I / Zlock, Lorna T / Finkbeiner, Walter E / Ahituv, Nadav / Erle, David J

    Cell genomics

    2022  Volume 3, Issue 1, Page(s) 100229

    Abstract: Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a ... ...

    Abstract Epithelial responses to the cytokine interleukin-13 (IL-13) cause airway obstruction in asthma. Here we utilized multiple genomic techniques to identify IL-13-responsive regulatory elements in bronchial epithelial cells and used these data to develop a CRISPR interference (CRISPRi)-based therapeutic approach to downregulate airway obstruction-inducing genes in a cell type- and IL-13-specific manner. Using single-cell RNA sequencing (scRNA-seq) and acetylated lysine 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) in primary human bronchial epithelial cells, we identified IL-13-responsive genes and regulatory elements. These sequences were functionally validated and optimized via massively parallel reporter assays (MPRAs) for IL-13-inducible activity. The top secretory cell-selective sequence from the MPRA, a novel, distal enhancer of the sterile alpha motif pointed domain containing E-26 transformation-specific transcription factor (
    Language English
    Publishing date 2022-12-07
    Publishing country United States
    Document type Journal Article
    ISSN 2666-979X
    ISSN (online) 2666-979X
    DOI 10.1016/j.xgen.2022.100229
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Fluorogenic reporter enables identification of compounds that inhibit SARS-CoV-2.

    Yang, Junjiao / Xiao, Yinghong / Lidsky, Peter V / Wu, Chien-Ting / Bonser, Luke R / Peng, Shiming / Garcia-Knight, Miguel A / Tassetto, Michel / Chung, Chan-I / Li, Xiaoquan / Nakayama, Tsuguhisa / Lee, Ivan T / Nayak, Jayakar V / Ghias, Khadija / Hargett, Kirsten L / Shoichet, Brian K / Erle, David J / Jackson, Peter K / Andino, Raul /
    Shu, Xiaokun

    Nature microbiology

    2023  Volume 8, Issue 1, Page(s) 121–134

    Abstract: The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic ... ...

    Abstract The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.
    MeSH term(s) Chlorocebus aethiops ; Mice ; Humans ; Animals ; SARS-CoV-2/metabolism ; COVID-19 ; Vero Cells ; Angiotensin-Converting Enzyme 2 ; Peptidyl-Dipeptidase A/metabolism ; Antiviral Agents/pharmacology
    Chemical Substances bruceine A (25514-31-2) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Antiviral Agents
    Language English
    Publishing date 2023-01-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2058-5276
    ISSN (online) 2058-5276
    DOI 10.1038/s41564-022-01288-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

    Inter-library loan at ZB MED

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