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  1. Article ; Online: A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

    Richter, Felix / Rutherford, Kayleigh D / Cooke, Anisha J / Meshkati, Malorie / Eddy-Abrams, Vanessa / Greene, Daniel / Kosowsky, Jordana / Park, Yeaji / Aggarwal, Surabhi / Burke, Rebecca J / Chang, Weili / Connors, Jillian / Giannone, Peter J / Hays, Thomas / Khattar, Divya / Polak, Mark / Senaldi, Liana / Smith-Raska, Matthew / Sridhar, Shanthy /
    Steiner, Laurie / Swanson, Jonathan R / Tauber, Kate A / Barbosa, Mafalda / Guttmann, Katherine F / Turro, Ernest

    American journal of kidney diseases : the official journal of the National Kidney Foundation

    2024  

    Abstract: The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide ... ...

    Abstract The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.
    Language English
    Publishing date 2024-01-10
    Publishing country United States
    Document type Case Reports
    ZDB-ID 604539-x
    ISSN 1523-6838 ; 0272-6386
    ISSN (online) 1523-6838
    ISSN 0272-6386
    DOI 10.1053/j.ajkd.2023.12.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1669: Show issues Location:
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    Zs.MO 468: Show issues

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  2. Article: The Transcription Factor Zfx Regulates Peripheral T Cell Self-Renewal and Proliferation.

    Smith-Raska, Matthew R / Arenzana, Teresita L / D'Cruz, Louise M / Khodadadi-Jamayran, Alireza / Tsirigos, Aristotelis / Goldrath, Ananda W / Reizis, Boris

    Frontiers in immunology

    2018  Volume 9, Page(s) 1482

    Abstract: Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further ... ...

    Abstract Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC have long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of
    Language English
    Publishing date 2018-07-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2606827-8
    ISSN 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2018.01482
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes.

    Arenzana, Teresita L / Smith-Raska, Matthew R / Reizis, Boris

    Blood

    2009  Volume 113, Issue 23, Page(s) 5857–5867

    Abstract: The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of ... ...

    Abstract The development, homeostasis, and function of B lymphocytes involve multiple rounds of B-cell receptor (BCR)-controlled proliferation and prolonged maintenance. We analyzed the role of transcription factor Zfx, a recently identified regulator of hematopoietic stem cell maintenance, in B-cell development and homeostasis. Panhematopoietic or B cell-specific deletion of Zfx in the bone marrow blocked B-cell development at the pre-BCR selection checkpoint. Zfx deficiency in peripheral B cells caused accelerated B-cell turnover, depletion of mature recirculating B cells, and delayed T-dependent antibody responses. In addition, the numbers and function of B-1 cell lineage were reduced. Zfx-deficient B cells showed normal proximal BCR signaling, but impaired BCR-induced proliferation and survival in vitro. This was accompanied by aberrantly enhanced and prolonged integrated stress response and by delayed induction of cyclin D2 and Bcl-xL proteins. Thus, Zfx restrains the stress response and couples antigen receptor signaling to cell expansion and maintenance during B-cell development and peripheral homeostasis. These results identify a novel transcriptional regulator of the B-cell lineage and highlight the common genetic control of stem cell maintenance and lymphocyte homeostasis.
    MeSH term(s) Animals ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Differentiation/immunology ; Cell Proliferation ; Cell Survival/immunology ; Homeostasis/immunology ; Kruppel-Like Transcription Factors/deficiency ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Mice, Knockout ; Receptors, Antigen, B-Cell/immunology ; T-Lymphocytes/immunology
    Chemical Substances Kruppel-Like Transcription Factors ; Receptors, Antigen, B-Cell ; zinc finger protein, X-linked
    Language English
    Publishing date 2009-03-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2008-11-188888
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
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    Zs.MO 364: Show issues

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  4. Article: Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen.

    Caton, Michele L / Smith-Raska, Matthew R / Reizis, Boris

    The Journal of experimental medicine

    2007  Volume 204, Issue 7, Page(s) 1653–1664

    Abstract: Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch-RBP-J pathway in ... ...

    Abstract Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch-RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8(-) DC subset and reduced the frequency of cytokine-secreting CD8(-) DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J-deficient splenic CD8(-) DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8(-) DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch-RBP-J signaling controls the maintenance of CD8(-) DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
    MeSH term(s) Animals ; CD11c Antigen/genetics ; CD8-Positive T-Lymphocytes/immunology ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Flow Cytometry ; Homeostasis ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/deficiency ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/physiology ; Integrases/genetics ; Lipopolysaccharides/pharmacology ; Mice ; Mice, Transgenic ; Polymerase Chain Reaction ; Receptors, Notch/physiology ; Signal Transduction ; Spleen/immunology ; Toll-Like Receptors/physiology
    Chemical Substances CD11c Antigen ; Immunoglobulin J Recombination Signal Sequence-Binding Protein ; Lipopolysaccharides ; Receptors, Notch ; Toll-Like Receptors ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
    Language English
    Publishing date 2007-07-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20062648
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.107: Show issues Location:
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    Zs.MG 45: Show issues

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  5. Article ; Online: ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia.

    Weisberg, Stuart P / Smith-Raska, Matthew R / Esquilin, Jose M / Zhang, Ji / Arenzana, Teresita L / Lau, Colleen M / Churchill, Michael / Pan, Haiyan / Klinakis, Apostolos / Dixon, Jack E / Mirny, Leonid A / Mukherjee, Siddhartha / Reizis, Boris

    Cell reports

    2014  Volume 6, Issue 3, Page(s) 528–540

    Abstract: Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic ... ...

    Abstract Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
    MeSH term(s) Animals ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/pathology ; Clone Cells ; Gene Expression Regulation, Leukemic ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Mice ; Mitochondria/enzymology ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism ; Phenotype ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Proto-Oncogene Proteins c-myc/metabolism ; Receptors, Notch/metabolism
    Chemical Substances Kruppel-Like Transcription Factors ; Proto-Oncogene Proteins c-myc ; Receptors, Notch ; zinc finger protein, X-linked ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; Ptpmt1 protein, mouse (EC 3.1.3.27) ; PTEN Phosphohydrolase (EC 3.1.3.67)
    Language English
    Publishing date 2014-01-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2014.01.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: ZFX Controls Propagation and Prevents Differentiation of Acute T-Lymphoblastic and Myeloid Leukemia

    Stuart P. Weisberg / Matthew R. Smith-Raska / Jose M. Esquilin / Ji Zhang / Teresita L. Arenzana / Colleen M. Lau / Michael Churchill / Haiyan Pan / Apostolos Klinakis / Jack E. Dixon / Leonid A. Mirny / Siddhartha Mukherjee / Boris Reizis

    Cell Reports, Vol 6, Iss 3, Pp 528-

    2014  Volume 540

    Abstract: Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic ... ...

    Abstract Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator.
    Keywords Biology (General) ; QH301-705.5
    Subject code 572 ; 610
    Language English
    Publishing date 2014-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Glycosylation patterns of HIV-1 gp120 depend on the type of expressing cells and affect antibody recognition.

    Raska, Milan / Takahashi, Kazuo / Czernekova, Lydie / Zachova, Katerina / Hall, Stacy / Moldoveanu, Zina / Elliott, Matt C / Wilson, Landon / Brown, Rhubell / Jancova, Dagmar / Barnes, Stephen / Vrbkova, Jana / Tomana, Milan / Smith, Phillip D / Mestecky, Jiri / Renfrow, Matthew B / Novak, Jan

    The Journal of biological chemistry

    2010  Volume 285, Issue 27, Page(s) 20860–20869

    Abstract: Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the interaction between a variably glycosylated envelope glycoprotein (gp120) and host-cell receptors. Approximately half of the molecular mass of gp120 is contributed by N-glycans, which ... ...

    Abstract Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the interaction between a variably glycosylated envelope glycoprotein (gp120) and host-cell receptors. Approximately half of the molecular mass of gp120 is contributed by N-glycans, which serve as potential epitopes and may shield gp120 from immune recognition. The role of gp120 glycans in the host immune response to HIV-1 has not been comprehensively studied at the molecular level. We developed a new approach to characterize cell-specific gp120 glycosylation, the regulation of glycosylation, and the effect of variable glycosylation on antibody reactivity. A model oligomeric gp120 was expressed in different cell types, including cell lines that represent host-infected cells or cells used to produce gp120 for vaccination purposes. N-Glycosylation of gp120 varied, depending on the cell type used for its expression and the metabolic manipulation during expression. The resultant glycosylation included changes in the ratio of high-mannose to complex N-glycans, terminal decoration, and branching. Differential glycosylation of gp120 affected envelope recognition by polyclonal antibodies from the sera of HIV-1-infected subjects. These results indicate that gp120 glycans contribute to antibody reactivity and should be considered in HIV-1 vaccine design.
    MeSH term(s) Acquired Immunodeficiency Syndrome/immunology ; Antibodies/immunology ; Antibody Specificity ; Cell Line ; Cell Line, Tumor ; DNA, Complementary/genetics ; Enzyme-Linked Immunosorbent Assay/methods ; Glycoside Hydrolases/metabolism ; Glycosylation ; HIV Envelope Protein gp120/genetics ; HIV Envelope Protein gp120/immunology ; HIV Envelope Protein gp120/isolation & purification ; HIV Envelope Protein gp120/metabolism ; HIV Seropositivity/immunology ; HIV Seropositivity/metabolism ; HIV-1/immunology ; HIV-1/metabolism ; Hep G2 Cells/metabolism ; Humans ; Jurkat Cells/metabolism ; Mannose/metabolism ; Mannose-Binding Lectin/genetics ; Mass Spectrometry ; Oligosaccharides/chemistry ; Oligosaccharides/isolation & purification ; Plasmids ; Polysaccharides/chemistry ; Polysaccharides/isolation & purification
    Chemical Substances Antibodies ; DNA, Complementary ; HIV Envelope Protein gp120 ; Mannose-Binding Lectin ; Oligosaccharides ; Polysaccharides ; gp120 protein, Human immunodeficiency virus 1 ; Glycoside Hydrolases (EC 3.2.1.-) ; Mannose (PHA4727WTP)
    Language English
    Publishing date 2010-05-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M109.085472
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.108: Show issues Location:
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