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  1. Article ; Online: Rapid Identification of New Biomarkers for the Classification of GM1 Type 2 Gangliosidosis Using an Unbiased 1 H NMR-Linked Metabolomics Strategy

    Benita C. Percival / Yvonne L. Latour / Cynthia J. Tifft / Martin Grootveld

    Cells, Vol 10, Iss 572, p

    2021  Volume 572

    Abstract: Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, ... ...

    Abstract Biomarkers currently available for the diagnosis, prognosis, and therapeutic monitoring of GM1 gangliosidosis type 2 (GM1T2) disease are mainly limited to those discovered in targeted proteomic-based studies. In order to identify and establish new, predominantly low-molecular-mass biomarkers for this disorder, we employed an untargeted, multi-analyte approach involving high-resolution 1 H NMR analysis coupled to a range of multivariate analysis and computational intelligence technique (CIT) strategies to explore biomolecular distinctions between blood plasma samples collected from GM1T2 and healthy control (HC) participants ( n = 10 and 28, respectively). The relationship of these differences to metabolic mechanisms underlying the pathogenesis of GM1T2 disorder was also investigated. 1 H NMR-linked metabolomics analyses revealed significant GM1T2-mediated dysregulations in ≥13 blood plasma metabolites (corrected p < 0.04), and these included significant upregulations in 7 amino acids, and downregulations in lipoprotein-associated triacylglycerols and alanine. Indeed, results acquired demonstrated a profound distinctiveness between the GM1T2 and HC profiles. Additionally, employment of a genome-scale network model of human metabolism provided evidence that perturbations to propanoate, ethanol, amino-sugar, aspartate, seleno-amino acid, glutathione and alanine metabolism, fatty acid biosynthesis, and most especially branched-chain amino acid degradation ( p = 10 −12 −10 −5 ) were the most important topologically-highlighted dysregulated pathways contributing towards GM1T2 disease pathology. Quantitative metabolite set enrichment analysis revealed that pathological locations associated with these dysfunctions were in the order fibroblasts > Golgi apparatus > mitochondria > spleen ≈ skeletal muscle ≈ muscle in general. In conclusion, results acquired demonstrated marked metabolic imbalances and alterations to energy demand, which are consistent with GM1T2 disease pathogenesis mechanisms.
    Keywords GM1 gangliosidosis ; lysosomal storage disorders ; nuclear magnetic resonance (NMR) analysis ; NMR-based metabolomics ; biomarkers ; validation ; Biology (General) ; QH301-705.5
    Subject code 333 ; 572
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation

    Yvonne L. Latour / Kara M. McNamara / Margaret M. Allaman / Daniel P. Barry / Thaddeus M. Smith / Mohammad Asim / Kamery J. Williams / Caroline V. Hawkins / Justin Jacobse / Jeremy A. Goettel / Alberto G. Delgado / M. Blanca Piazuelo / M. Kay Washington / Alain P. Gobert / Keith T. Wilson

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    2023  Volume 11

    Abstract: Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors ... ...

    Abstract Abstract The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors that are highly involved in immune cell adhesion to endothelial cells while in the circulation and help facilitate extravasation into tissues. Here we show that specific deletion of the Tln1 gene encoding the protein talin-1, an integrin-activating scaffold protein, from cells of the myeloid lineage using the Lyz2-cre driver mouse reduces epithelial damage, attenuates colitis, downregulates the expression of macrophage markers, decreases the number of differentiated colonic mucosal macrophages, and diminishes the presence of CD68-positive cells in the colonic mucosa of mice infected with the enteric pathogen Citrobacter rodentium. Bone marrow-derived macrophages lacking expression of Tln1 did not exhibit a cell-autonomous phenotype; there was no impaired proinflammatory gene expression, nitric oxide production, phagocytic ability, or surface expression of CD11b, CD86, or major histocompatibility complex II in response to C. rodentium. Thus, we demonstrate that talin-1 plays a role in the manifestation of infectious colitis by increasing mucosal macrophages, with an effect that is independent of macrophage activation.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570 ; 616
    Language English
    Publishing date 2023-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells

    Justin Jacobse / Rachel E. Brown / Jing Li / Jennifer M. Pilat / Ly Pham / Sarah P. Short / Christopher T. Peek / Andrea Rolong / M. Kay Washington / Ruben Martinez-Barricarte / Mariana X. Byndloss / Catherine Shelton / Janet G. Markle / Yvonne L. Latour / Margaret M. Allaman / James E. Cassat / Keith T. Wilson / Yash A. Choksi / Christopher S. Williams /
    Ken S. Lau / Charles R. Flynn / Jean-Laurent Casanova / Edmond H.H.M. Rings / Janneke N. Samsom / Jeremy A. Goettel

    Cell Reports, Vol 42, Iss 2, Pp 112128- (2023)

    2023  

    Abstract: Summary: The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains ...

    Abstract Summary: The cytokine interleukin-23 (IL-23) is involved in the pathogenesis of inflammatory and autoimmune conditions including inflammatory bowel disease (IBD). IL23R is enriched in intestinal Tregs, yet whether IL-23 modulates intestinal Tregs remains unknown. Here, investigating IL-23R signaling in Tregs specifically, we show that colonic Tregs highly express Il23r compared with Tregs from other compartments and their frequency is reduced upon IL-23 administration and impairs Treg suppressive function. Similarly, colonic Treg frequency is increased in mice lacking Il23r specifically in Tregs and exhibits a competitive advantage over IL-23R-sufficient Tregs during inflammation. Finally, IL-23 antagonizes liver X receptor pathway, cellular cholesterol transporter Abca1, and increases Treg apoptosis. Our results show that IL-23R signaling regulates intestinal Tregs by increasing cell turnover, antagonizing suppression, and decreasing cholesterol efflux. These results suggest that IL-23 negatively regulates Tregs in the intestine with potential implications for promoting chronic inflammation in patients with IBD.
    Keywords CP: Immunology ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Human GLB1 knockout cerebral organoids

    Yvonne L. Latour / Robin Yoon / Sarah E. Thomas / Christina Grant / Cuiling Li / Miguel Sena-Esteves / Maria L. Allende / Richard L. Proia / Cynthia J. Tifft

    Molecular Genetics and Metabolism Reports, Vol 21, Iss , Pp - (2019)

    A model system for testing AAV9-mediated GLB1 gene therapy for reducing GM1 ganglioside storage in GM1 gangliosidosis

    2019  

    Abstract: GM1 gangliosidosis is an autosomal recessive neurodegenerative disorder caused by the deficiency of lysosomal β-galactosidase (β-gal) and resulting in accumulation of GM1 ganglioside. The disease spectrum ranges from infantile to late onset and is ... ...

    Abstract GM1 gangliosidosis is an autosomal recessive neurodegenerative disorder caused by the deficiency of lysosomal β-galactosidase (β-gal) and resulting in accumulation of GM1 ganglioside. The disease spectrum ranges from infantile to late onset and is uniformly fatal, with no effective therapy currently available. Although animal models have been useful for understanding disease pathogenesis and exploring therapeutic targets, no relevant human central nervous system (CNS) model system has been available to study its early pathogenic events or test therapies. To develop a model of human GM1 gangliosidosis in the CNS, we employed CRISPR/Cas9 genome editing to target GLB1 exons 2 and 6, common sites for mutations in patients, to create isogenic induced pluripotent stem (iPS) cell lines with lysosomal β-gal deficiency. We screened for clones with <5% of parental cell line β-gal enzyme activity and confirmed GLB1 knockout clones using DNA sequencing. We then generated GLB1 knockout cerebral organoids from one of these GLB1 knockout iPS cell clones. Analysis of GLB1 knockout organoids in culture revealed progressive accumulation of GM1 ganglioside. GLB1 knockout organoids microinjected with AAV9-GLB1 vector showed a significant increase in β-gal activity and a significant reduction in GM1 ganglioside content compared with AAV9-GFP–injected organoids, demonstrating the efficacy of an AAV9 gene therapy-based approach in GM1 gangliosidosis. This proof-of-concept in a human cerebral organoid model completes the pre-clinical studies to advance to clinical trials using the AAV9-GLB1 vector.
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Hypusination Orchestrates the Antimicrobial Response of Macrophages

    Alain P. Gobert / Jordan L. Finley / Yvonne L. Latour / Mohammad Asim / Thaddeus M. Smith / Thomas G. Verriere / Daniel P. Barry / Margaret M. Allaman / Alberto G. Delagado / Kristie L. Rose / M. Wade Calcutt / Kevin L. Schey / Johanna C. Sierra / M. Blanca Piazuelo / Raghavendra G. Mirmira / Keith T. Wilson

    Cell Reports, Vol 33, Iss 11, Pp 108510- (2020)

    2020  

    Abstract: Summary: Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor ...

    Abstract Summary: Innate responses of myeloid cells defend against pathogenic bacteria via inducible effectors. Deoxyhypusine synthase (DHPS) catalyzes the transfer of the N-moiety of spermidine to the lysine-50 residue of eukaryotic translation initiation factor 5A (EIF5A) to form the amino acid hypusine. Hypusinated EIF5A (EIF5AHyp) transports specific mRNAs to ribosomes for translation. We show that DHPS is induced in macrophages by two gastrointestinal pathogens, Helicobacter pylori and Citrobacter rodentium, resulting in enhanced hypusination of EIF5A. EIF5AHyp was also increased in gastric macrophages from patients with H. pylori gastritis. Furthermore, we identify the bacteria-induced immune effectors regulated by hypusination. This set of proteins includes essential constituents of antimicrobial response and autophagy. Mice with myeloid cell-specific deletion of Dhps exhibit reduced EIF5AHyp in macrophages and increased bacterial burden and inflammation. Thus, regulation of translation through hypusination is a critical hallmark of the defense of eukaryotic hosts against pathogenic bacteria.
    Keywords macrophages ; bacterial infection ; innate immunity ; hypusine ; polyamines ; Helicobacter pylori ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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