Krabbe Disease (KD) is a lysosomal leukodystrophy characterized by the production of psychosine in oligodendrocytes, leading to neurodegeneration and ultimately death. The only treatment modality currently available for this disease is hematopoietic stem cell transplantation (HSCT), a procedure with high morbidity, highlighting the need for further therapies to be developed. In this study, we established and characterized GALC knockout MO3.13 cells, a cell line derived from human oligodendrocytes, as a model for KD. Clonal MO3.13 cells with GALC KO were obtained via CRISPR/Cas9-mediated gene editing. GALC activity was measured by a 4-methylumbellyferyl (4-MU)-based assay, and morphology analyses were performed using light microscopy and transmission electron microscopy. Psychosine was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The GALC KO cells have elevated levels of psychosine and an increased number of autophagosomes, autolysosomes, and cytoplasmic granules on transmission electron microscopy. Glycogen abundance was decreased in GALC KO cells compared to controls. After administration of BMN-S202, a ceramide galactosyltransferase inhibitor, psychosine levels in GALC KO cells were reduced back to WT levels. In conclusion, we demonstrated that the GALC KO MO3.13 cell line recapitulates the KD phenotype and biochemical response to SRT and may be a useful KD model for mechanistic studies and therapeutic development for KD.

Necroptosis, a form of programmed, inflammatory necrosis, plays an important role in viral-host defense and inflammation. The receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway mediates necroptosis. Yet, the mechanisms that control necroptosis to limit immunopathology are poorly understood. Here, we report that interferon-stimulated gene 15 (ISG15) negatively regulates RIPK3-mediated cell death, including necroptosis, and limits immunopathology during chikungunya virus (CHIKV) infection. ISG15-deficient mice infected with CHIKV display increased levels of necroptosis, resulting in elevated proinflammatory cytokine and chemokine production, leading to increased lethality. This dysregulated host response is fully prevented when MLKL or RIPK3 is ablated in Isg15-/- mice. Mechanistically, ISG15 non-covalently associates with the RIPK3 necrosome in an RIP homotypic interaction motif (RHIM)-dependent manner, regulating necroptosis downstream of CHIKV infection, tumor necrosis factor (TNF), lipopolysaccharide (LPS), and poly(I:C) stimulation. These results demonstrate a role for ISG15 in limiting immunopathology during infection by modulating necroptosis-dependent inflammation and pathogenesis.

Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing Adamtsl1, Cldn14, and Pmp2 (a.k.a. PMP2+ SCs) that preferentially myelinate large-caliber motor axons. PMP2+ SCs are decreased in both amyotrophic lateral sclerosis (ALS) model mice and ALS patient nerves. Thus, PMP2+ SC dysfunction could contribute to motor-selective neuropathies. We engineered a tamoxifen-inducible Pmp2-CreERT2 mouse and expressed diphtheria toxin in PMP2+ SCs to assess the consequences of ablating this SC subtype in male and female mice. Loss of PMP2+ SCs led to significant loss of large-caliber motor axons with concomitant behavioral, electrophysiological, and ultrastructural defects. Subsequent withdrawal of tamoxifen restored both PMP2+ SCs and large-caliber motor axons and improved behavioral and electrophysiological readouts. Together, our findings highlight that the survival of large-caliber motor axons relies on PMP2+ SCs, demonstrating that malfunction of a specific SC subtype can lead to selective neuronal vulnerability.

Modulation of immune tone at mucosal surfaces is critical to maintain homeostasis while facilitating the handling of emerging threats. One dynamic component of immune modulation is the phagocytosis and clearance of apoptotic bodies known as efferocytosis that inhibits inflammation by promoting its resolution. Here, we evaluated the effects of apoptotic body phagocytosis by intestinal epithelial stem and progenitor cells (ISCs). Unexpectedly, instead of immunomodulation through efferocytosis, this process elevated local immune system activity. To achieve this result, ISCs actively engaged apoptotic bodies in a unique fashion, leading to their engulfment and ultimate delivery to lysosomes for processing. We found that ISCs were capable of actively recruiting inert material such as apoptotic bodies by using actin-based intrinsic biomechanical processes. Uptake of apoptotic bodies was facilitated by complement factor C3 produced by apoptotic bodies themselves. ISCs in turn generated signals heightening T cell activity that was driven in part by ISC-generated TNF. Taken together, uptake of apoptotic bodies by ISCs produced a local inflammatory alert to specific immune cells. This altered paradigm for the response to phagocytosed apoptotic bodies fits the needs of active mucosal surfaces and demonstrates that efferocytosis as currently defined is not a universal response of all cell types.

Chapter 13 Special Sense Organs Robert E. Schmidt, Robert E. SchmidtSearch for more papers by this authorJason D. Struthers, Jason D. StruthersSearch for more papers by this author Robert E. Schmidt, Robert E. SchmidtSearch for more papers by this authorJason D. Struthers, Jason D. StruthersSearch for more papers by this author Book Editor(s):Robert E. Schmidt, Robert E. Schmidt Independent Avian and Exotic Animal Pathology Consultant, Anthem, AZ, USASearch for more papers by this authorJason D. Struthers, Jason D. Struthers Associate Professor Midwestern University College of Veterinary Medicine, Glendale, AZ, USASearch for more papers by this authorDavid N. Phalen, David N. Phalen Professor Faculty of Veterinary Science University of Sydney, Camden, New South Wales, AustraliaSearch for more papers by this author First published: 26 January 2024 https://doi.org/10.1002/9781119650522.ch13 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary This chapter includes a brief description of the normal avian eye and ear, and describes diseases and morphologic lesions of the eye by anatomic segment, and diseases/lesions of the orbit and outer, middle, and inner ear. Topics covered include congenital disease, infectious disease, noninfectious disease, and neoplasia. Many of the described conditions are illustrated with gross images and photomicrographs. A detailed reading list is included. Additional Reading Alves de Assis JC , Pulido-Murillo E , de Melo AL , et al. 2022 . 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Chapter 9 Lymphatic and Hematopoietic System Helene Pendl, Helene PendlSearch for more papers by this authorRobert E. Schmidt, Robert E. SchmidtSearch for more papers by this author Helene Pendl, Helene PendlSearch for more papers by this authorRobert E. Schmidt, Robert E. SchmidtSearch for more papers by this author Book Editor(s):Robert E. Schmidt, Robert E. Schmidt Independent Avian and Exotic Animal Pathology Consultant, Anthem, AZ, USASearch for more papers by this authorJason D. Struthers, Jason D. Struthers Associate Professor Midwestern University College of Veterinary Medicine, Glendale, AZ, USASearch for more papers by this authorDavid N. Phalen, David N. Phalen Professor Faculty of Veterinary Science University of Sydney, Camden, New South Wales, AustraliaSearch for more papers by this author First published: 26 January 2024 https://doi.org/10.1002/9781119650522.ch9 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary This chapter includes a brief section on the normal structures of the avian lymphoid and hematopoietic systems and describes the characteristics of innate, adaptive, humoral, and cell-mediated immunity in avian species. The subsequent description of pathologic conditions of the immune system includes infectious, noninfectious, and neoplastic diseases of the tissues of the immune system, as well as the range of types of immune-mediated disease events in other organs. The descriptions are illustrated with gross and histologic images of viral, bacterial, fungal, and parasitic infections, as well as noninfectious causes and neoplasms. A detailed list of further reading is included. Additional Reading Aita M , Mazzone AM , Gabrielli F , et al. 1995 . Identification of cells secreting a thymostimulin-like substance and examination of some histoenzymatic pathways in aging avian primary lymphatic organs: I thymus . Eur J Histochem 39 : 289 – 300 . CASPubMedWeb of Science®Google Scholar Amann O , Kik MJ , Passon-Vastenburg MH , et al. 2007 . Chronic pulmonary interstitial fibrosis in a Blue-fronted Amazon parrot ( Amazona aestiva aestiva ) . Avian Dis 51 : 150 – 153 . 10.1637/0005-2086(2007)051[0150:CPIFIA]2.0.CO;2 PubMedWeb of Science®Google Scholar Atoji Y , Yamamoto Y , Suzuki Y . 1999 . Thymic epithelial cysts in the pigeon . 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Gene Fusions identified with INTEGRATE.

Predicted neoantigens generated as described above. This table contains all peptides with predicted ic50 less than 500 and fold-change greater than 1. The list is provided before filtering for expression or presence in the founding clone.

Gene Expression from RNA-sequencing in each of the three tumors.

Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer’s disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aβ pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

Clonal clustering assignments generated from sciClone.

Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease. Failure to remyelinate successfully is common in MS lesions, often with consequent neuronal/axonal dam-age. CNS myelin is normally produced by oligodendroglial cells. Remyelination by Schwann cells (SchC) has been reported in spinal cord demyelination, in which SchCs are in close proximity to CNS myelin. We identified an MS cerebral lesion that was remyelinated by SchCs. This prompted us to query the extent of SchC remyelination in the brain and spinal cords of additional autopsied MS specimens. CNS tissues were obtained from the autopsies of 14 MS cases. Remyelinated lesions were identified by Luxol fast blue-periodic-acid Schiff and solochrome cyanine staining. Depar-affinized sections containing remyelinated lesions were stained with antieglial fibrillary acid protein to identify reactive astrocytes. Glycoprotein P zero (P0) is a protein exclusive to peripheral but not CNS myelin. Areas of SchC remyelination were identified by staining with anti-P0. Myelinated regions in the index case cerebral lesion were confirmed to be of SchC origin using anti-P0 staining. Subsequently, 64 MS lesions from 14 autopsied MS cases were examined, and 23 lesions in 6 cases showed remyelination by SchCs. Lesions from the cerebrum, brainstem, and spinal cord were examined in each case. When present, SchC remyelination was most commonly located adjacent to the venules and associated with a lower surrounding density of glial fibrillary acid protein thorn reactive astrocytes than areas of only oligodendroglial cell remyelination. The dif-ference was significant only for spinal cord and brainstem lesions but not for lesions located in the brain. In conclusion, we demonstrated SchC remyelination in the cerebrum, brainstem, and spinal cord of 6 autopsied MS cases. To our knowledge, this is the first report of supratentorial SchC remyelination in MS.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Somatic SNVs and Indels with transcript annotation, population frequencies, and readcounts appended.

Segmented somatic copy number calls.