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  1. Article ; Online: Molecular and Metabolic Analysis of Arsenic-Exposed Humanized AS3MT Mice.

    Todero, Jenna / Douillet, Christelle / Shumway, Alexandria J / Koller, Beverly H / Kanke, Matt / Phuong, Daryl J / Stýblo, Miroslav / Sethupathy, Praveen

    Environmental health perspectives

    2023  Volume 131, Issue 12, Page(s) 127021

    Abstract: Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a ... ...

    Abstract Background: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new "humanized" mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure.
    Objectives: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure.
    Methods: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic
    Results: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice.
    Discussion: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. https://doi.org/10.1289/EHP12785.
    MeSH term(s) Female ; Male ; Mice ; Humans ; Animals ; Arsenic/analysis ; Blood Glucose/analysis ; Diabetes Mellitus, Type 2/chemically induced ; Arsenicals ; Insulin Resistance ; Insulin ; Obesity ; Methyltransferases/genetics
    Chemical Substances Arsenic (N712M78A8G) ; Blood Glucose ; Arsenicals ; Insulin ; AS3MT protein, human (EC 2.1.1.137) ; Methyltransferases (EC 2.1.1.-) ; AS3MT protein, mouse (EC 2.1.1.137)
    Language English
    Publishing date 2023-12-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 195189-0
    ISSN 1552-9924 ; 0091-6765 ; 1078-0475
    ISSN (online) 1552-9924
    ISSN 0091-6765 ; 1078-0475
    DOI 10.1289/EHP12785
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 1360: Show issues Location:
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    Zs.MO 379: Show issues

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  2. Article ; Online: 14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing.

    Holter, Marlena M / Phuong, Daryl J / Lee, Isaac / Saikia, Mridusmita / Weikert, Lisa / Fountain, Samantha / Anderson, Elizabeth T / Fu, Qin / Zhang, Sheng / Sloop, Kyle W / Cummings, Bethany P

    Science advances

    2022  Volume 8, Issue 29, Page(s) eabn3773

    Abstract: Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β ...

    Abstract Recent studies demonstrate that α cells contribute to glucose-stimulated insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β cell paracrine interactions in the effects of GLP-1R agonists is undefined. We previously found that increased β cell GLP-1R signaling activates α cell GLP-1 expression. Here, we characterized the bidirectional paracrine cross-talk by which α and β cells communicate to mediate the effects of the GLP-1R agonist, liraglutide. We find that the effect of liraglutide to enhance GSIS is blunted by α cell ablation in male mice. Furthermore, the effect of β cell GLP-1R signaling to activate α cell GLP-1 is mediated by a secreted protein factor that is regulated by the signaling protein, 14-3-3-zeta, in mouse and human islets. These data refine our understanding of GLP-1 pharmacology and identify 14-3-3-zeta as a potential target to enhance α cell GLP-1 production.
    Language English
    Publishing date 2022-07-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abn3773
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of an Antiretroviral Small Molecule That Appears To Be a Host-Targeting Inhibitor of HIV-1 Assembly.

    Reed, Jonathan C / Solas, Dennis / Kitaygorodskyy, Anatoliy / Freeman, Beverly / Ressler, Dylan T B / Phuong, Daryl J / Swain, J Victor / Matlack, Kent / Hurt, Clarence R / Lingappa, Vishwanath R / Lingappa, Jaisri R

    Journal of virology

    2021  Volume 95, Issue 3

    Abstract: Given the projected increase in multidrug-resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life cycle stages not targeted by drugs currently in use. Host-targeting compounds are of particular interest because ... ...

    Abstract Given the projected increase in multidrug-resistant HIV-1, there is an urgent need for development of antiretrovirals that act on virus life cycle stages not targeted by drugs currently in use. Host-targeting compounds are of particular interest because they can offer a high barrier to resistance. Here, we report identification of two related small molecules that inhibit HIV-1 late events, a part of the HIV-1 life cycle for which potent and specific inhibitors are lacking. This chemotype was discovered using cell-free protein synthesis and assembly systems that recapitulate intracellular host-catalyzed viral capsid assembly pathways. These compounds inhibit replication of HIV-1 in human T cell lines and peripheral blood mononuclear cells, and are effective against a primary isolate. They reduce virus production, likely by inhibiting a posttranslational step in HIV-1 Gag assembly. Notably, the compound colocalizes with HIV-1 Gag
    MeSH term(s) ATP-Binding Cassette Transporters/metabolism ; Anti-Retroviral Agents/pharmacology ; DEAD-box RNA Helicases/metabolism ; HIV Infections/drug therapy ; HIV Infections/pathology ; HIV Infections/virology ; HIV-1/drug effects ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/virology ; Proto-Oncogene Proteins/metabolism ; Small Molecule Libraries/pharmacology ; Virus Assembly/drug effects ; gag Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances ABCE1 protein, human ; ATP-Binding Cassette Transporters ; Anti-Retroviral Agents ; Proto-Oncogene Proteins ; Small Molecule Libraries ; gag Gene Products, Human Immunodeficiency Virus ; DDX6 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2021-01-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00883-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Formation of RNA Granule-Derived Capsid Assembly Intermediates Appears To Be Conserved between Human Immunodeficiency Virus Type 1 and the Nonprimate Lentivirus Feline Immunodeficiency Virus.

    Reed, Jonathan C / Westergreen, Nick / Barajas, Brook C / Ressler, Dylan T B / Phuong, Daryl J / Swain, John V / Lingappa, Vishwanath R / Lingappa, Jaisri R

    Journal of virology

    2018  Volume 92, Issue 9

    Abstract: During immature capsid assembly in cells, human immunodeficiency virus type 1 (HIV-1) Gag co-opts a host RNA granule, forming a pathway of intracellular assembly intermediates containing host components, including two cellular facilitators of assembly, ... ...

    Abstract During immature capsid assembly in cells, human immunodeficiency virus type 1 (HIV-1) Gag co-opts a host RNA granule, forming a pathway of intracellular assembly intermediates containing host components, including two cellular facilitators of assembly, ABCE1 and DDX6. A similar assembly pathway has been observed for other primate lentiviruses. Here we asked whether feline immunodeficiency virus (FIV), a nonprimate lentivirus, also forms RNA granule-derived capsid assembly intermediates. First, we showed that the released FIV immature capsid and a large FIV Gag-containing intracellular complex are unstable during analysis, unlike for HIV-1. We identified harvest conditions, including
    MeSH term(s) ATP-Binding Cassette Transporters/metabolism ; Animals ; COS Cells ; Capsid/metabolism ; Capsid Proteins/genetics ; Capsid Proteins/metabolism ; Cats ; Cell Line ; Chlorocebus aethiops ; DEAD-box RNA Helicases/metabolism ; Endoribonucleases/metabolism ; Gene Products, gag/genetics ; HIV-1/genetics ; HIV-1/metabolism ; Immunodeficiency Virus, Feline/genetics ; Immunodeficiency Virus, Feline/metabolism ; RNA-Binding Proteins/biosynthesis ; Virus Assembly/genetics
    Chemical Substances ATP-Binding Cassette Transporters ; Capsid Proteins ; Gene Products, gag ; RNA-Binding Proteins ; Endoribonucleases (EC 3.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2018-04-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.01761-17
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 609: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Identifying the assembly intermediate in which Gag first associates with unspliced HIV-1 RNA suggests a novel model for HIV-1 RNA packaging.

    Barajas, Brook C / Tanaka, Motoko / Robinson, Bridget A / Phuong, Daryl J / Chutiraka, Kasana / Reed, Jonathan C / Lingappa, Jaisri R

    PLoS pathogens

    2018  Volume 14, Issue 4, Page(s) e1006977

    Abstract: During immature capsid assembly, HIV-1 genome packaging is initiated when Gag first associates with unspliced HIV-1 RNA by a poorly understood process. Previously, we defined a pathway of sequential intracellular HIV-1 capsid assembly intermediates; here ...

    Abstract During immature capsid assembly, HIV-1 genome packaging is initiated when Gag first associates with unspliced HIV-1 RNA by a poorly understood process. Previously, we defined a pathway of sequential intracellular HIV-1 capsid assembly intermediates; here we sought to identify the intermediate in which HIV-1 Gag first associates with unspliced HIV-1 RNA. In provirus-expressing cells, unspliced HIV-1 RNA was not found in the soluble fraction of the cytosol, but instead was largely in complexes ≥30S. We did not detect unspliced HIV-1 RNA associated with Gag in the first assembly intermediate, which consists of soluble Gag. Instead, the earliest assembly intermediate in which we detected Gag associated with unspliced HIV-1 RNA was the second assembly intermediate (~80S intermediate), which is derived from a host RNA granule containing two cellular facilitators of assembly, ABCE1 and the RNA granule protein DDX6. At steady-state, this RNA-granule-derived ~80S complex was the smallest assembly intermediate that contained Gag associated with unspliced viral RNA, regardless of whether lysates contained intact or disrupted ribosomes, or expressed WT or assembly-defective Gag. A similar complex was identified in HIV-1-infected T cells. RNA-granule-derived assembly intermediates were detected in situ as sites of Gag colocalization with ABCE1 and DDX6; moreover these granules were far more numerous and smaller than well-studied RNA granules termed P bodies. Finally, we identified two steps that lead to association of assembling Gag with unspliced HIV-1 RNA. Independent of viral-RNA-binding, Gag associates with a broad class of RNA granules that largely lacks unspliced viral RNA (step 1). If a viral-RNA-binding domain is present, Gag further localizes to a subset of these granules that contains unspliced viral RNA (step 2). Thus, our data raise the possibility that HIV-1 packaging is initiated not by soluble Gag, but by Gag targeted to a subset of host RNA granules containing unspliced HIV-1 RNA.
    MeSH term(s) ATP-Binding Cassette Transporters/genetics ; ATP-Binding Cassette Transporters/metabolism ; Animals ; COS Cells ; Cell Membrane/metabolism ; Chlorocebus aethiops ; Cytoplasm/metabolism ; DEAD-box RNA Helicases/genetics ; DEAD-box RNA Helicases/metabolism ; HIV Infections/genetics ; HIV Infections/virology ; HIV-1/genetics ; Humans ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; RNA Splicing ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Virion ; Virus Assembly ; gag Gene Products, Human Immunodeficiency Virus/genetics ; gag Gene Products, Human Immunodeficiency Virus/metabolism
    Chemical Substances ABCE1 protein, human ; ATP-Binding Cassette Transporters ; Proto-Oncogene Proteins ; RNA, Viral ; gag Gene Products, Human Immunodeficiency Virus ; DDX6 protein, human (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2018-04-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1006977
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: GLP-1 receptor signaling increases PCSK1 and β cell features in human α cells.

    Saikia, Mridusmita / Holter, Marlena M / Donahue, Leanne R / Lee, Isaac S / Zheng, Qiaonan C / Wise, Journey L / Todero, Jenna E / Phuong, Daryl J / Garibay, Darline / Coch, Reilly / Sloop, Kyle W / Garcia-Ocana, Adolfo / Danko, Charles G / Cummings, Bethany P

    JCI insight

    2021  Volume 6, Issue 3

    Abstract: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for ... ...

    Abstract Glucagon-like peptide-1 (GLP-1) is an incretin hormone that potentiates glucose-stimulated insulin secretion. GLP-1 is classically produced by gut L cells; however, under certain circumstances α cells can express the prohormone convertase required for proglucagon processing to GLP-1, prohormone convertase 1/3 (PC1/3), and can produce GLP-1. However, the mechanisms through which this occurs are poorly defined. Understanding the mechanisms by which α cell PC1/3 expression can be activated may reveal new targets for diabetes treatment. Here, we demonstrate that the GLP-1 receptor (GLP-1R) agonist, liraglutide, increased α cell GLP-1 expression in a β cell GLP-1R-dependent manner. We demonstrate that this effect of liraglutide was translationally relevant in human islets through application of a new scRNA-seq technology, DART-Seq. We found that the effect of liraglutide to increase α cell PC1/3 mRNA expression occurred in a subcluster of α cells and was associated with increased expression of other β cell-like genes, which we confirmed by IHC. Finally, we found that the effect of liraglutide to increase bihormonal insulin+ glucagon+ cells was mediated by the β cell GLP-1R in mice. Together, our data validate a high-sensitivity method for scRNA-seq in human islets and identify a potentially novel GLP-1-mediated pathway regulating human α cell function.
    MeSH term(s) Animals ; Female ; Gene Knockdown Techniques ; Glucagon-Like Peptide-1 Receptor/agonists ; Glucagon-Like Peptide-1 Receptor/deficiency ; Glucagon-Like Peptide-1 Receptor/genetics ; Glucagon-Like Peptide-1 Receptor/metabolism ; Glucagon-Secreting Cells/drug effects ; Glucagon-Secreting Cells/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; In Vitro Techniques ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Liraglutide/pharmacology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Proprotein Convertase 1/metabolism ; RNA-Seq ; Signal Transduction
    Chemical Substances GLP1R protein, human ; Glp1r protein, mouse ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents ; Liraglutide (839I73S42A) ; PCSK1 protein, human (EC 3.4.21.93) ; Proprotein Convertase 1 (EC 3.4.21.93)
    Language English
    Publishing date 2021-02-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.141851
    Database MEDical Literature Analysis and Retrieval System OnLINE

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