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  1. Article ; Online: Learning Spectral Fractional Anisotropy and Mean Diffusivity Features as Neuroimaging Biomarkers for Tracking White Matter Integrity Changes in Myotonic Dystrophy Type 1 Patients using Deep Convolutional Neural Networks.

    Kamali, Tahereh / Day, John W / Deutsch, Gayle K / Sampson, Jacinda B / Murad, Alejandro / Chaufty, Jeremy / Parker, Dana / Wozniak, Jeffrey R

    Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

    2023  Volume 2023, Page(s) 1–4

    Abstract: Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social ...

    Abstract Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular progressive multisystem disease that results in a broad spectrum of clinical central nervous system (CNS) involvement, including problems with memory, attention, executive functioning, and social cognition. Fractional anisotropy and mean diffusivity along-tract data calculated using diffusion tensor imaging techniques play a vital role in assessing white matter microstructural changes associated with neurodegeneration caused by DM1. In this work, a novel spectrogram-based deep learning method is proposed to characterize white matter network alterations in DM1 with the goal of building a deep learning model as neuroimaging biomarkers of DM1. The proposed method is evaluated on fractional anisotropies and mean diffusivities along-tract data calculated for 25 major white matter tracts of 46 DM1 patients and 96 unaffected controls. The evaluation data consists of a total of 7100 spectrogram images. The model achieved 91% accuracy in identifying DM1, a significant improvement compared to previous methods.Clinical relevance- Clinical care of DM1 is particularly challenging due to DM1 multisystem involvement and the disease variability. Patients with DM1 often experience neurological and psychological symptoms, such as excessive sleepiness and apathy, that greatly impact their quality of life. Some of DM1 CNS symptoms may be responsive to treatment. The goal of this research is to gain a deeper understanding of the impact of DM1 on the CNS and to develop a deep learning model that can serve as a biomarker for the disease, with the potential to be used in future clinical trials as an outcome measure.
    MeSH term(s) Humans ; White Matter/diagnostic imaging ; Myotonic Dystrophy/diagnostic imaging ; Myotonic Dystrophy/complications ; Myotonic Dystrophy/psychology ; Diffusion Tensor Imaging ; Anisotropy ; Quality of Life ; Neuroimaging
    Language English
    Publishing date 2023-12-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2694-0604
    ISSN (online) 2694-0604
    DOI 10.1109/EMBC40787.2023.10340468
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Intracellular amyloid precursor protein sorting and amyloid-β secretion are regulated by Src-mediated phosphorylation of Mint2.

    Chaufty, Jeremy / Sullivan, Sarah E / Ho, Angela

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2012  Volume 32, Issue 28, Page(s) 9613–9625

    Abstract: Mint adaptor proteins bind to the membrane-bound amyloid precursor protein (APP) and affect the production of pathogenic amyloid-β (Aβ) peptides related to Alzheimer's disease (AD). Previous studies have shown that loss of each of the three Mint proteins ...

    Abstract Mint adaptor proteins bind to the membrane-bound amyloid precursor protein (APP) and affect the production of pathogenic amyloid-β (Aβ) peptides related to Alzheimer's disease (AD). Previous studies have shown that loss of each of the three Mint proteins delays the age-dependent production of amyloid plaques in transgenic mouse models of AD. However, the cellular and molecular mechanisms underlying Mints effect on amyloid production are unclear. Because Aβ generation involves the internalization of membrane-bound APP via endosomes and Mints bind directly to the endocytic motif of APP, we proposed that Mints are involved in APP intracellular trafficking, which in turn, affects Aβ generation. Here, we show that APP endocytosis was attenuated in Mint knock-out neurons, revealing a role for Mints in APP trafficking. We also show that the endocytic APP sorting processes are regulated by Src-mediated phosphorylation of Mint2 and that internalized APP is differentially sorted between autophagic and recycling trafficking pathways. A Mint2 phosphomimetic mutant favored endocytosis of APP along the autophagic sorting pathway leading to increased intracellular Aβ accumulation. Conversely, the Mint2 phospho-resistant mutant increased APP localization to the recycling pathway and back to the cell surface thereby enhancing Aβ42 secretion. These results demonstrate that Src-mediated phosphorylation of Mint2 regulates the APP endocytic sorting pathway, providing a mechanism for regulating Aβ secretion.
    MeSH term(s) Adaptor Proteins, Signal Transducing/metabolism ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Analysis of Variance ; Animals ; Biotinylation/methods ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cells, Cultured ; Cerebral Cortex/pathology ; Chlorocebus aethiops ; Disease Models, Animal ; Endocytosis/genetics ; Endocytosis/physiology ; Gene Expression Regulation/genetics ; Gene Expression Regulation/physiology ; Green Fluorescent Proteins/genetics ; Humans ; Mice ; Mice, Transgenic ; Mutation/genetics ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Peptide Fragments/metabolism ; Phosphorylation/genetics ; Presenilin-1/genetics ; Protein Transport/genetics ; Transfection ; src-Family Kinases/genetics ; src-Family Kinases/metabolism
    Chemical Substances Adaptor Proteins, Signal Transducing ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Apba1 protein, mouse ; Apba2 protein, mouse ; Apba3 protein, mouse ; Carrier Proteins ; Nerve Tissue Proteins ; PSEN1 protein, human ; Peptide Fragments ; Presenilin-1 ; amyloid beta-protein (1-40) ; amyloid beta-protein (1-42) ; Green Fluorescent Proteins (147336-22-9) ; src-Family Kinases (EC 2.7.10.2)
    Language English
    Publishing date 2012-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.0602-12.2012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: SIDL interacts with the dendritic targeting motif of Shal (K(v)4) K+ channels in Drosophila.

    Diao, Fengqiu / Chaufty, Jeremy / Waro, Girma / Tsunoda, Susan

    Molecular and cellular neurosciences

    2010  Volume 45, Issue 1, Page(s) 75–83

    Abstract: Shal K(+) (K(v)4) channels in mammalian neurons have been shown to be localized exclusively to somato-dendritic regions of neurons, where they function as key determinants of dendritic excitability. To gain insight into the mechanisms underlying ... ...

    Abstract Shal K(+) (K(v)4) channels in mammalian neurons have been shown to be localized exclusively to somato-dendritic regions of neurons, where they function as key determinants of dendritic excitability. To gain insight into the mechanisms underlying dendritic localization of K(v)4 channels, we use Drosophila melanogaster as our model system. We show that Shal K(+) channels display a conserved somato-dendritic localization in vivo in Drosophila. From a yeast-2-hybrid screen, we identify the novel interactor, SIDL (for Shal Interactor of Di-Leucine Motif), as the first target protein reported to bind the highly conserved di-leucine motif (LL-motif) implicated in dendritic targeting. We show that SIDL is expressed primarily in the nervous system, co-localizes with GFP-Shal channels in neurons, and interacts specifically with the LL-motif of Drosophila and mouse Shal channels. We disrupt the Shal-SIDL interaction by mutating the LL-motif on Shal channels, and show that Shal K(+) channels are then mislocalized to some, but not all, axons in vivo. These results suggest that there are multiple mechanisms underlying Shal K(+) channel targeting, one of which depends on the LL-motif. The identification of SIDL may provide the first step for future investigation into the molecular machinery regulating the LL-motif-dependent targeting of K(+) channels.
    MeSH term(s) Animals ; Dendrites/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/anatomy & histology ; Drosophila melanogaster/embryology ; Drosophila melanogaster/metabolism ; Humans ; Mice ; Neurons/cytology ; Neurons/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Shal Potassium Channels/genetics ; Shal Potassium Channels/metabolism ; Two-Hybrid System Techniques
    Chemical Substances Drosophila Proteins ; Recombinant Fusion Proteins ; Shal Potassium Channels
    Language English
    Publishing date 2010-06-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1046640-x
    ISSN 1095-9327 ; 1044-7431
    ISSN (online) 1095-9327
    ISSN 1044-7431
    DOI 10.1016/j.mcn.2010.06.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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