Browsing by Author "Kim, Minsu"

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    Coordination of bacterial proteome with metabolism by cyclic AMP signalling
    (Springer Nature, 2013) You, Conghui; Okano, Hiroyuki; Hui, Sheng; Zhang, Zhongge; Kim, Minsu; Gunderson, Carl W.; Wang, Yi-Ping; Lenz, Peter; Yan, Dalai; Hwa, Terence; Microbiology and Immunology, School of Medicine
    The cyclic AMP (cAMP)-dependent catabolite repression effect in Escherichia coli is among the most intensely studied regulatory processes in biology. However, the physiological function(s) of cAMP signalling and its molecular triggers remain elusive. Here we use a quantitative physiological approach to show that cAMP signalling tightly coordinates the expression of catabolic proteins with biosynthetic and ribosomal proteins, in accordance with the cellular metabolic needs during exponential growth. The expression of carbon catabolic genes increased linearly with decreasing growth rates upon limitation of carbon influx, but decreased linearly with decreasing growth rate upon limitation of nitrogen or sulphur influx. In contrast, the expression of biosynthetic genes showed the opposite linear growth-rate dependence as the catabolic genes. A coarse-grained mathematical model provides a quantitative framework for understanding and predicting gene expression responses to catabolic and anabolic limitations. A scheme of integral feedback control featuring the inhibition of cAMP signalling by metabolic precursors is proposed and validated. These results reveal a key physiological role of cAMP-dependent catabolite repression: to ensure that proteomic resources are spent on distinct metabolic sectors as needed in different nutrient environments. Our findings underscore the power of quantitative physiology in unravelling the underlying functions of complex molecular signalling networks.
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    Identifying intragenic functional modules of genomic variations associated with cancer phenotypes by learning representation of association networks
    (Springer Nature, 2022-07-06) Kim, Minsu; Huffman, Jennifer E.; Justice, Amy; Goethert, Ian; Agasthya, Greeshma; VA Million Veteran Program; Danciu, Ioana; Medicine, School of Medicine
    Background: Genome-wide Association Studies (GWAS) aims to uncover the link between genomic variation and phenotype. They have been actively applied in cancer biology to investigate associations between variations and cancer phenotypes, such as susceptibility to certain types of cancer and predisposed responsiveness to specific treatments. Since GWAS primarily focuses on finding associations between individual genomic variations and cancer phenotypes, there are limitations in understanding the mechanisms by which cancer phenotypes are cooperatively affected by more than one genomic variation. Results: This paper proposes a network representation learning approach to learn associations among genomic variations using a prostate cancer cohort. The learned associations are encoded into representations that can be used to identify functional modules of genomic variations within genes associated with early- and late-onset prostate cancer. The proposed method was applied to a prostate cancer cohort provided by the Veterans Administration's Million Veteran Program to identify candidates for functional modules associated with early-onset prostate cancer. The cohort included 33,159 prostate cancer patients, 3181 early-onset patients, and 29,978 late-onset patients. The reproducibility of the proposed approach clearly showed that the proposed approach can improve the model performance in terms of robustness. Conclusions: To our knowledge, this is the first attempt to use a network representation learning approach to learn associations among genomic variations within genes. Associations learned in this way can lead to an understanding of the underlying mechanisms of how genomic variations cooperatively affect each cancer phenotype. This method can reveal unknown knowledge in the field of cancer biology and can be utilized to design more advanced cancer-targeted therapies.
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    Peripheral blood-derived mesenchymal stem cells demonstrate immunomodulatory potential for therapeutic use in horses
    (PLOS, 2019-03-14) Longhini, Ana Leda F.; Salazar, Tatiana E.; Vieira, Cristiano; Trinh, Thao; Duan, Yaqian; Pay, Louise M.; Li Calzi, Sergio; Losh, Megan; Johnston, Nancy A.; Xie, Huisheng; Kim, Minsu; Hunt, Robert J.; Yoder, Mervin C.; Santoro, Domenico; McCarrel, Taralyn M.; Grant, Maria B.; Ophthalmology, School of Medicine
    Previously, we showed that mesenchymal stem cells (MSC) can be mobilized into peripheral blood using electroacupuncture (EA) at acupoints, LI-4, LI-11, GV-14, and GV-20. The purpose of this study was to determine whether EA-mobilized MSC could be harvested and expanded in vitro to be used as an autologous cell therapy in horses. Peripheral blood mononuclear cells (PBMC) isolated from young and aged lame horses (n = 29) showed a marked enrichment for MSCs. MSC were expanded in vitro (n = 25) and administered intravenously at a dose of 50 x 106 (n = 24). Treatment resulted in significant improvement in lameness as assessed by the American Association of Equine Practitioners (AAEP) lameness scale (n = 23). MSCs exhibited immunomodulatory function by inhibition of lymphocyte proliferation and induction of IL-10. Intradermal testing showed no immediate or delayed immune reactions to MSC (1 x 106 to 1 x 104). In this study, we demonstrated an efficient, safe and reproducible method to mobilize and expand, in vitro, MSCs in sufficiently high concentrations for therapeutic administration. We confirm the immunomodulatory function of these cells in vitro. This non-pharmacological and non-surgical strategy for stem cell harvest has a broad range of biomedical applications and represents an improved clinically translatable and economical cell source for humans.