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  • 407 The OGT/O-GlcNAc Axis Regulates Fibrosis Resolution in Idiopathic Pulmonary Fibrosis

  • Part of
  • Shia Vang, Yiming Livelo, Bailey Burpee, Meghan J. Hirsch, Emma L. Matthews, Luke I. Jones, Girish Melkani, Stefanie Krick, Jarrod W. Barnes
  • Journal:
    Journal of Clinical and Translational Science / Volume 8 / Issue s1 / April 2024
    Published online by Cambridge University Press:
    03 April 2024, p. 121
    • Article
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      • Open access
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  • OBJECTIVES/GOALS: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by dysregulated collagen accumulation in the lung parenchyma. Our goal is to investigate the role of O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT) in pulmonary fibrosis to ultimately discover novel therapies for fibrosis resolution. METHODS/STUDY POPULATION: Lung tissue from IPF and non-IPF donors was subjected to immunohistochemistry (IHC) to assess O-GlcNAc levels. Primary human lung fibroblasts were treated with OGT or O-GlcNAcase (OGA) inhibitors followed by transforming growth factor-beta 1 (TGF-β1) stimulation to assess O-GlcNAc regulation of fibroblast-to-myofibroblast transition (FMT) markers [alpha smooth muscle actin (α-SMA) and type 1 and type 3 collagen (COL1α1, COL3α1)] In Drosophila melanogaster, OGT knockdown (KD)/overexpression (OE) was conditionally induced to assess pericardin, a type IV collagen-like protein, regulation by immunofluorescence. Lastly, a mouse model of bleomycin-induced pulmonary fibrosis was examined following OGT KD and assessed for fibrosis resolution via histology, hydroxyproline assay, and western blotting. RESULTS/ANTICIPATED RESULTS: O-GlcNAc staining was increased in IPF lung tissue compared to non-IPF control lungs. In primary human lung fibroblasts, TGF-α1 administration resulted in increased FMT markers (α-SMA, COL1α1, and COL3α1), which were reduced or increased by OGT or OGA inhibition, respectively. Genetic manipulation in the Drosophila models showed decreased pericardin expression with OGT KD compared to the wild-type, whereas OGT OE increased pericardin compared to control. Additionally, OGT KD in bleomycin treated aged mice resulted in reduced collagen levels at the transcript and protein level and concurrent fibrosis resolution as assessed by Masson’s trichrome staining and total hydroxyproline analysis. Collectively, showing OGT/O-GlcNAc regulating collagen in fibrosis resolution. DISCUSSION/SIGNIFICANCE: These data suggest that the OGT/O-GlcNAc axis regulates collagen deposition in pulmonary fibrosis, and we show that O-GlcNAc is implicated in the pathogenesis of IPF. We identified OGT as a therapeutic target to overcome current drug limitations, opening new horizons for biomedical treatment.

  • Thanatotic Infestation: Ekbom’s Syndrome as an Exordium to Cotard’s Delusion

  • Ahmed A. Chaudhry, Jack W. Hirsch
  • Journal:
    CNS Spectrums / Volume 28 / Issue 2 / April 2023
    Published online by Cambridge University Press:
    14 April 2023, p. 214
    • Article
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  • Introduction

    Ekbom’s delusion as a prelude to Cotard’s syndrome, has not heretofore been described.

    Methods

    Case study: A 45-year-old woman with a past diagnosis of bipolar disorder with psychotic features was admitted, having been up all night conversing with spirits, proclaiming that she had made a deal with Satan. Convinced that her grandmother was possessed by the devil, she smashed her grandmother’s head with a two-by-four. Results: Mental Status Examination: self conversing with her eyes darting around the room. Poor hygiene. Behavior: guarded and withdrawn. Oriented x2. Speech: hyperverbal. Insight and judgment: poor. Mood: hostile, aggressive, and angry. Thought process disorganized, incongruent, and tangentiality. She was convinced she was infested with little black bugs crawling around her insides which had been placed there by the devil. After two days of olanzapine she reported the bugs were no longer present, but rather that she herself was dead and that her organs were decomposing, which persisted through the remainder of the hospitalization.

    Discussion

    Neuroimaging abnormalities in Ekbom’s syndrome involve the striatum, basal ganglia (putamen and caudate nucleus), insular and cingulate cortices, cortex (prefrontal, right parietal, and temporal lobes), right lingual and orbitofrontal gyri, and thalamus. In Cotard’s syndrome, abnormalities have been identified in the striatum, frontal and temporal lobes, and right-sided and bilateral hemispheres. An overlap between the delusions exists in the striatum, inferior parietal, and temporal lobes. A single lesion in the nondominant inferior parietal lobe may cause both syndromes, due to its substantial interconnection with the temporo-limbic areas. Since the parietal lobe is also involved in somatosensory processing, peradventure distorted sensory perception with associated sensation of formication may have been the nidus for the delusional infestation as well as a nidus for the perception of thanatos habitus. Such misperception may have then been amplified into a delusion because of a hyperconnection between the parietal lobe and the limbic system. This may represent a variant of the two-factor hypothesis of delusions whereby a distorted sensory perception is then misrepresented in a delusion. Dysfunction of the right hemisphere, which normally acts to censor the left, allows the delusion to manifest. A single lesion of the inferior parietal lobule may be sufficient for both sensory distortions and loss of inhibition of delusional interpretation of distorted sensation by the frontal lobe, yclept the sensorialist hypothesis.

    Conclusion

    In those with monothematic delusions, the search for transient fluctuation in delusional states may be revealing.

    Funding

    No Funding

  • 2 - Tradition and Innovation in Schubert’s Lieder

  • from Part I - Schubert’s Winterreise and Its Musical Heritage
  • Edited by Marjorie W. Hirsch, Williams College, Massachusetts, Lisa Feurzeig, Grand Valley State University, Michigan
  • Book:
    The Cambridge Companion to Schubert's ‘Winterreise'
    Published online:
    02 February 2021
    Print publication:
    04 February 2021, pp 24-42

  • Summary

    On August 19, 1815, a dozen years before undertaking Winterreise, Franz Schubert composed a song that treads similar poetic ground. Like the winter wanderer of Wilhelm Müller’s cycle, the protagonist of Johann Wolfgang von Goethe’s “An den Mond” (D259; To the Moon) roams through a natural landscape evoking inner terrain; the moonlit wood and valley conjure the recesses of his (or her) mind, intimating a journey of self-discovery. The protagonist’s present solitude, recollection of joyful and troubled times, glancing reference to faithless love, direct address to a river, allusion to the harshness of winter, mention of his own song, and mysterious closing reference to wandering by night through the labyrinth of the heart all anticipate ways that Müller, in a darker mode, conveys existential isolation and suffering in Winterreise.

  • Introduction: An Endless Winter Journey

  • Edited by Marjorie W. Hirsch, Williams College, Massachusetts, Lisa Feurzeig, Grand Valley State University, Michigan
  • Book:
    The Cambridge Companion to Schubert's ‘Winterreise'
    Published online:
    02 February 2021
    Print publication:
    04 February 2021, pp 1-8

  • Summary

    “I like these songs more than all the rest, and you will come to like them as well,” Franz Schubert reportedly declared upon first singing through his haunting new song cycle Winterreise (D911) to a few close friends. The first half of the statement is remarkable given that by 1827, the year in which this intimate premiere took place, Schubert had already composed over 550 Lieder, including countless gems. His claim to prefer these “horrifying” new songs depicting a solitary wanderer’s alienation, disorientation, and despair suffered amidst a bleak, frigid landscape bespeaks a deep personal attachment to the cycle. Composing the work had been taxing, as indicated by the numerous cross-outs, rewritings, and insertions in portions of the autograph manuscript, and Schubert was plainly proud of his accomplishment. In asserting “I like these songs more than all the rest,” he may have intended to steer his friends toward a positive assessment of the cycle, to reassure them that it was not merely the regrettable creation of a disturbed mind.

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