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  1. Article ; Online: Special issue on the human microbiome

    Amit Sharma / Sin-Hyeog Im

    Experimental and Molecular Medicine, Vol 52, Iss 9, Pp 1361-

    from symbiosis to therapy

    2020  Volume 1363

    Keywords Medicine ; R ; Biochemistry ; QD415-436
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Drug approval prediction based on the discrepancy in gene perturbation effects between cells and humansResearch in context

    Minhyuk Park / Donghyo Kim / Inhae Kim / Sin-Hyeog Im / Sanguk Kim

    EBioMedicine, Vol 94, Iss , Pp 104705- (2023)

    2023  

    Abstract: Summary: Background: Poor translation between in vitro and clinical studies due to the cells/humans discrepancy in drug target perturbation effects leads to safety failures in clinical trials, thus increasing drug development costs and reducing patients’ ...

    Abstract Summary: Background: Poor translation between in vitro and clinical studies due to the cells/humans discrepancy in drug target perturbation effects leads to safety failures in clinical trials, thus increasing drug development costs and reducing patients’ life quality. Therefore, developing a predictive model for drug approval considering the cells/humans discrepancy is needed to reduce drug attrition rates in clinical trials. Methods: Our machine learning framework predicts drug approval in clinical trials based on the cells/humans discrepancy in drug target perturbation effects. To evaluate the discrepancy to predict drug approval (1404 approved and 1070 unapproved drugs), we analysed CRISPR-Cas9 knockout and loss-of-function mutation rate-based gene perturbation effects on cells and humans, respectively. To validate the risk of drug targets with the cells/humans discrepancy, we examined the targets of failed and withdrawn drugs due to safety problems. Findings: Drug approvals in clinical trials were correlated with the cells/humans discrepancy in gene perturbation effects. Genes tolerant to perturbation effects on cells but intolerant to those on humans were associated with failed drug targets. Furthermore, genes with the cells/humans discrepancy were related to drugs withdrawn due to severe side effects. Motivated by previous studies assessing drug safety through chemical properties, we improved drug approval prediction by integrating chemical information with the cells/humans discrepancy. Interpretation: The cells/humans discrepancy in gene perturbation effects facilitates drug approval prediction and explains drug safety failures in clinical trials. Funding: S.K. received grants from the Korean National Research Foundation (2021R1A2B5B01001903 and 2020R1A6A1A03047902) and IITP (2019-0-01906, Artificial Intelligence Graduate School Program, POSTECH).
    Keywords Machine learning ; Drug approval ; Drug safety ; Clinical translation ; Gene perturbation effect ; Discrepancy ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 610
    Language English
    Publishing date 2023-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Of men in mice

    John Chulhoon Park / Sin-Hyeog Im

    Experimental and Molecular Medicine, Vol 52, Iss 9, Pp 1383-

    the development and application of a humanized gnotobiotic mouse model for microbiome therapeutics

    2020  Volume 1396

    Abstract: Gut microbiome: making a human model in mice Gut microbiota play important roles in health and disease, and now the effects of specific microbes sourced from humans can be tested in germ-free mice, which have no microbiome of their own. Many factors can ... ...

    Abstract Gut microbiome: making a human model in mice Gut microbiota play important roles in health and disease, and now the effects of specific microbes sourced from humans can be tested in germ-free mice, which have no microbiome of their own. Many factors can affect how well the transplanted microbiome will reflect the human microbiome it is meant to mimic. Sin-Hyeog Im and John Chulhoon Park of POSTECH in South Korea have reviewed key factors that affect donor microbiomes and how well they transplant to mouse models. Diet, socioeconomic background, ethnicity, and exercise regime affect the human source microbiome. Differences in mouse and human anatomies, murine genetic and immunological backgrounds, and the conditions under which the mice are reared can affect how faithfully the transplanted microbiome reflects its human source. This review will help in designing more translatable animal models to test microbial-based therapies.
    Keywords Medicine ; R ; Biochemistry ; QD415-436
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Effect of IRT5 probiotics on dry eye in the experimental dry eye mouse model.

    Jayoon Moon / Jin Suk Ryu / Jun Yeop Kim / Sin-Hyeog Im / Mee Kum Kim

    PLoS ONE, Vol 15, Iss 12, p e

    2020  Volume 0243176

    Abstract: Objective To investigate the clinical effects of IRT5 probiotics in the environmental dry eye model. Methods Eight week old male C57BL/6 mice were randomly divided into two groups; control group (n = 16) received oral gavage of 300 μL phosphate-buffered ... ...

    Abstract Objective To investigate the clinical effects of IRT5 probiotics in the environmental dry eye model. Methods Eight week old male C57BL/6 mice were randomly divided into two groups; control group (n = 16) received oral gavage of 300 μL phosphate-buffered saline (PBS) alone once daily, IRT5 group (n = 9) received oral gavage of 1 x 109 CFU IRT5 probiotics powder in 300 μL PBS once daily, both groups for 11 to 12 days. Simultaneously, all mice underwent dry eye induction. Tear secretion, corneal staining and conjunctival goblet cell density were evaluated. Quantative real-time polymerase chain reaction (RT-PCR) for inflammation-related markers was performed. 16S ribosomal RNA of fecal microbiome was analyzed and compositional difference, alpha and beta diversities were assessed. Results There was no difference in NEI score but significant increase in tear secretion was observed in IRT5 group (p < 0.001). There was no significant difference in goblet cell density between groups. Quantative RT-PCR of cornea and conjunctiva revealed increased TNF-α expression in IRT5 group (p < 0.001) whereas other markers did not significantly differ from control. IRT5 group had significantly increased species diversity by Shannon index (p = 0.041). Beta diversity of genus by UniFrac principle coordinates analysis showed significant distance between groups (p = 0.001). Compositional differences between groups were observed and some were significantly associated with tear secretion. Multivariate linear regression analysis revealed Christensenellaceae (p = 0.009), Lactobacillus Helveticus group (p = 0.002) and PAC001797_s (p = 0.011) to strongly influence tear secretion. Conclusion In experimental dry eye model, IRT5 probiotics treatment partially improves experimental dry eye by increasing tear secretion which was associated with and influenced by the change in intestinal microbiome. Also, intestinal microbiome may affect the lacrimal gland through a different mechanism other than regulating inflammation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 630
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: NFAT1 and NFκB regulates expression of the common γ-chain cytokine receptor in activated T cells

    Ju A Shim / So Min Lee / Jin Woo Jeong / Hyori Kim / Woo Jae Son / Jun Hong Park / Parkyong Song / Sin-Hyeog Im / Sangsu Bae / Jung-Hyun Park / Yuna Jo / Changwan Hong

    Cell Communication and Signaling, Vol 21, Iss 1, Pp 1-

    2023  Volume 19

    Abstract: Abstract Introduction Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc ... ...

    Abstract Abstract Introduction Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood. Objective This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation. Methods The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling. Results We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis. Conclusion Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies. Video Abstract
    Keywords Common gamma chain ; TCR signaling ; NFAT1 ; NFκB ; T cell activation ; Medicine ; R ; Cytology ; QH573-671
    Subject code 570
    Language English
    Publishing date 2023-10-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons

    Sang-Hyeon Mun / Chang-Seok Lee / Hyun Jin Kim / Jiye Kim / Haena Lee / Jihye Yang / Sin-Hyeog Im / Joung-Hun Kim / Je Kyung Seong / Cheol-Sang Hwang

    Cell Reports, Vol 42, Iss 7, Pp 112746- (2023)

    2023  

    Abstract: Summary: The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment ... ...

    Abstract Summary: The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment develop metabolic disorders. However, the existence, metabolic fate, and functional outcomes of cytosol-retained POMC remain unclear. Here, we show that SP-uncleaved POMC is produced in the cytosol of POMC neuronal cells, thus inducing ER stress and ferroptotic cell death. Mechanistically, the cytosol-retained POMC sequesters the chaperone Hspa5 and subsequently accelerates degradation of the glutathione peroxidase Gpx4, a core regulator of ferroptosis, via the chaperone-mediated autophagy. We also show that the Marchf6 E3 ubiquitin ligase mediates the degradation of cytosol-retained POMC, thereby preventing ER stress and ferroptosis. Furthermore, POMC-Cre-mediated Marchf6-deficient mice exhibit hyperphagia, reduced energy expenditure, and weight gain. These findings suggest that Marchf6 is a critical regulator of ER stress, ferroptosis, and metabolic homeostasis in POMC neurons.
    Keywords CP: Metabolism ; CP: Cell biology ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Inflammation-induced Id2 promotes plasticity in regulatory T cells

    Sung-Min Hwang / Garima Sharma / Ravi Verma / Seohyun Byun / Dipayan Rudra / Sin-Hyeog Im

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Regulatory T (Treg) cells may lose the expression of their master transcription factor, Foxp3, and be converted to pro-inflammatory cells. Here the authors show that this lineage plasticity may be mediated by the enhanced expression of another ... ...

    Abstract Regulatory T (Treg) cells may lose the expression of their master transcription factor, Foxp3, and be converted to pro-inflammatory cells. Here the authors show that this lineage plasticity may be mediated by the enhanced expression of another transcription regulator, Id2, which suppresses the transcription of Foxp3 to alter Treg lineage stability.
    Keywords Science ; Q
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: The transcription factor Foxp1 preserves integrity of an active Foxp3 locus in extrathymic Treg cells

    Sayantani Ghosh / Sinchita Roy-Chowdhuri / Keunsoo Kang / Sin-Hyeog Im / Dipayan Rudra

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 14

    Abstract: Regulatory T (Treg) cells suppress immune cell activation to maintain immune homeostasis, and have their lineage enforced by the master transcription factor Foxp3. Here the authors show that Foxp3 expression is promoted and maintained by a related family ...

    Abstract Regulatory T (Treg) cells suppress immune cell activation to maintain immune homeostasis, and have their lineage enforced by the master transcription factor Foxp3. Here the authors show that Foxp3 expression is promoted and maintained by a related family member, Foxp1, specifically in peripherally induced Treg but not in Treg cells of thymic origin.
    Keywords Science ; Q
    Language English
    Publishing date 2018-10-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Inflammation-induced Id2 promotes plasticity in regulatory T cells

    Sung-Min Hwang / Garima Sharma / Ravi Verma / Seohyun Byun / Dipayan Rudra / Sin-Hyeog Im

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Regulatory T (Treg) cells may lose the expression of their master transcription factor, Foxp3, and be converted to pro-inflammatory cells. Here the authors show that this lineage plasticity may be mediated by the enhanced expression of another ... ...

    Abstract Regulatory T (Treg) cells may lose the expression of their master transcription factor, Foxp3, and be converted to pro-inflammatory cells. Here the authors show that this lineage plasticity may be mediated by the enhanced expression of another transcription regulator, Id2, which suppresses the transcription of Foxp3 to alter Treg lineage stability.
    Keywords Science ; Q
    Language English
    Publishing date 2018-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: The transcription factor Foxp1 preserves integrity of an active Foxp3 locus in extrathymic Treg cells

    Sayantani Ghosh / Sinchita Roy-Chowdhuri / Keunsoo Kang / Sin-Hyeog Im / Dipayan Rudra

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 14

    Abstract: Regulatory T (Treg) cells suppress immune cell activation to maintain immune homeostasis, and have their lineage enforced by the master transcription factor Foxp3. Here the authors show that Foxp3 expression is promoted and maintained by a related family ...

    Abstract Regulatory T (Treg) cells suppress immune cell activation to maintain immune homeostasis, and have their lineage enforced by the master transcription factor Foxp3. Here the authors show that Foxp3 expression is promoted and maintained by a related family member, Foxp1, specifically in peripherally induced Treg but not in Treg cells of thymic origin.
    Keywords Science ; Q
    Language English
    Publishing date 2018-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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