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  1. Article ; Online: Prediction of alternative pre-mRNA splicing outcomes.

    Najjar, Rayan / Mustelin, Tomas

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 20000

    Abstract: To understand the biological impact of alternative pre-mRNA splicing, it is vital to know which exons are involved, what protein domains they encode, and how the translated isoforms differ. Therefore, we developed a computational pipeline (RiboSplitter) ... ...

    Abstract To understand the biological impact of alternative pre-mRNA splicing, it is vital to know which exons are involved, what protein domains they encode, and how the translated isoforms differ. Therefore, we developed a computational pipeline (RiboSplitter) focused on functional effect prediction. It builds on event-based alternative splicing detection with additional filtering steps leading to more efficient statistical testing, and with detection of isoform-specific protein changes. A key methodological advance is reading frame prediction by translating exonic DNA in all possible frames, then finding a single open reading frame, or a single frame with matches to known proteins of the gene. This allowed unambiguous translation in 93.9% of alternative splicing events when tested on RNA-sequencing data of B cells from Sjögren's syndrome patients. RiboSplitter does not depend on reference annotations and translates events even when one or both isoform(s) are novel (unannotated). RiboSplitter's visualizations illustrate each event with translation outcomes, show event location within the gene, and align exons to protein domains.
    MeSH term(s) Humans ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA, Messenger/genetics ; RNA Splicing/genetics ; Alternative Splicing ; Protein Isoforms/metabolism
    Chemical Substances RNA Precursors ; RNA, Messenger ; Protein Isoforms
    Language English
    Publishing date 2023-11-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-47348-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus.

    Ukadike, Kennedy C / Mustelin, Tomas

    Journal of clinical medicine

    2021  Volume 10, Issue 4

    Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A ... ...

    Abstract Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.
    Language English
    Publishing date 2021-02-19
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm10040856
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book: Src family tyrosine kinases in leukocytes

    Mustelin, Tomas

    (Molecular biology intelligence unit)

    1994  

    Author's details Tomas Mustelin
    Series title Molecular biology intelligence unit
    Keywords Leukocytes / physiology ; Protein-Tyrosine Kinase / metabolism ; Genes, src / genetics
    Language English
    Size V, 155 S. : Ill.
    Publisher Landes
    Publishing place Austin
    Publishing country United States
    Document type Book
    HBZ-ID HT006570173
    ISBN 1-57059-113-X ; 978-1-57059-113-6
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    1995 A 1674 order for loan Magazin

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  4. Article ; Online: Implications of Endogenous Retroelements in the Etiopathogenesis of Systemic Lupus Erythematosus

    Kennedy C. Ukadike / Tomas Mustelin

    Journal of Clinical Medicine, Vol 10, Iss 4, p

    2021  Volume 856

    Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A ... ...

    Abstract Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. While its etiology remains elusive, current understanding suggests a multifactorial process with contributions by genetic, immunologic, hormonal, and environmental factors. A hypothesis that combines several of these factors proposes that genomic elements, the L1 retrotransposons, are instrumental in SLE pathogenesis. L1 retroelements are transcriptionally activated in SLE and produce two proteins, ORF1p and ORF2p, which are immunogenic and can drive type I interferon (IFN) production by producing DNA species that activate cytosolic DNA sensors. In addition, these two proteins reside in RNA-rich macromolecular assemblies that also contain well-known SLE autoantigens like Ro60. We surmise that cells expressing L1 will exhibit all the hallmarks of cells infected by a virus, resulting in a cellular and humoral immune response similar to those in chronic viral infections. However, unlike exogenous viruses, L1 retroelements cannot be eliminated from the host genome. Hence, dysregulated L1 will cause a chronic, but perhaps episodic, challenge for the immune system. The clinical and immunological features of SLE can be at least partly explained by this model. Here we review the support for, and the gaps in, this hypothesis of SLE and its potential for new diagnostic, prognostic, and therapeutic options in SLE.
    Keywords systemic lupus erythematosus ; retroelements ; L1 ; LINE-1 ; reverse transcriptase ; type I interferons ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: How Retroviruses and Retrotransposons in Our Genome May Contribute to Autoimmunity in Rheumatological Conditions.

    Mustelin, Tomas / Ukadike, Kennedy C

    Frontiers in immunology

    2020  Volume 11, Page(s) 593891

    Abstract: More than 200 human disorders include various manifestations of autoimmunity. The molecular events that lead to these diseases are still incompletely understood and their causes remain largely unknown. Numerous potential triggers of autoimmunity have ... ...

    Abstract More than 200 human disorders include various manifestations of autoimmunity. The molecular events that lead to these diseases are still incompletely understood and their causes remain largely unknown. Numerous potential triggers of autoimmunity have been proposed over the years, but very few of them have been conclusively confirmed or firmly refuted. Viruses have topped the lists of suspects for decades, and it seems that many viruses, including those of the Herpesviridae family, indeed can influence disease initiation and/or promote exacerbations by a number of mechanisms that include prolonged anti-viral immunity, immune subverting factors, and mechanisms, and perhaps "molecular mimicry". However, no specific virus has yet been established as being truly causative. Here, we discuss a different, but perhaps mechanistically related possibility, namely that retrotransposons or retroviruses that infected us in the past and left a lasting copy of themselves in our genome still can provoke an escalating immune response that leads to autoimmune disease. Many of these loci still encode for retroviral proteins that have retained some, or all, of their original functions. Importantly, these endogenous proviruses cannot be eliminated by the immune system the way it can eliminate exogenous viruses. Hence, if not properly controlled, they may drive a frustrated and escalating chronic, or episodic, immune response to the point of a frank autoimmune disorder. Here, we discuss the evidence and the proposed mechanisms, and assess the therapeutic options that emerge from the current understanding of this field.
    MeSH term(s) Alu Elements ; Animals ; Autoimmune Diseases/diagnosis ; Autoimmune Diseases/etiology ; Autoimmune Diseases/metabolism ; Autoimmunity/genetics ; Disease Susceptibility ; Endogenous Retroviruses ; Genome, Human ; Humans ; Immunity ; Long Interspersed Nucleotide Elements ; Proviruses/genetics ; Retroelements ; Rheumatic Diseases/diagnosis ; Rheumatic Diseases/etiology ; Rheumatic Diseases/metabolism
    Chemical Substances Retroelements
    Language English
    Publishing date 2020-11-13
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.593891
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression.

    Najjar, Rayan / Rogel, Noga / Pineda, Jose Mario Bello / Wang, Xiaoxing / Tran, Megan / Bays, Alison / Mustelin, Tomas

    Lupus science & medicine

    2024  Volume 11, Issue 1

    Abstract: Objectives: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar ... ...

    Abstract Objectives: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response.
    Methods: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions.
    Results: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases.
    Conclusions: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.
    MeSH term(s) Humans ; Neutrophils ; Transcriptome ; COVID-19/genetics ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Lupus Erythematosus, Systemic/genetics ; RNA/metabolism ; Interferon Type I/genetics
    Chemical Substances RNA (63231-63-0) ; Interferon Type I
    Language English
    Publishing date 2024-01-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 2779620-6
    ISSN 2053-8790
    ISSN 2053-8790
    DOI 10.1136/lupus-2023-001059
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Book ; Thesis: Transduction of mitogenic signals in T-lymphocytes inositide turnover and rapid activation of ornithine decarboxylase

    Mustelin, Tomas

    1987  

    Author's details Tomas Mustelin
    Keywords Ornithine Decarboxylase ; Stimulation, Chemical ; Mitogens ; T-Lymphocytes ; Transduction, Genetic
    Language English
    Size 78 S. : Ill., graph. Darst.
    Publishing country Finland
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Helsinki, Univ., Diss., 1987
    HBZ-ID HT003191943
    Database Catalogue ZB MED Medicine, Health

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    In stock of ZB MED Cologne/Königswinter

    Shelf markLoan statusLocation
    88 E 2941 order for loan Magazin

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  8. Article ; Online: Role of Neutrophils in Systemic Vasculitides.

    Michailidou, Despina / Mustelin, Tomas / Lood, Christian

    Frontiers in immunology

    2020  Volume 11, Page(s) 619705

    Abstract: Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti- ... ...

    Abstract Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, playing a key role in driving the autoimmune response, the role of neutrophils and NETs in large vessel vasculitis, including giant cell arteritis (GCA), is not well understood. In this review, we summarize the current insight into molecular mechanisms contributing to neutrophil-mediated pathology in small and medium vessel vasculitis, as well as provide potential translational perspectives on how neutrophils, and NETs, may partake in large vessel vasculitis, a rare disease entity of unclear pathogenesis.
    MeSH term(s) Extracellular Traps/immunology ; Humans ; Neutrophils/immunology ; Neutrophils/pathology ; Systemic Vasculitis/immunology ; Systemic Vasculitis/pathology
    Language English
    Publishing date 2020-12-17
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.619705
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Expression of L1 retrotransposons in granulocytes from patients with active systemic lupus erythematosus.

    Ukadike, Kennedy C / Najjar, Rayan / Ni, Kathryn / Laine, Amanda / Wang, Xiaoxing / Bays, Alison / Taylor, Martin S / LaCava, John / Mustelin, Tomas

    Mobile DNA

    2023  Volume 14, Issue 1, Page(s) 5

    Abstract: Background: Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, ( ... ...

    Abstract Background: Patients with systemic lupus erythematosus (SLE) have autoantibodies against the L1-encoded open-reading frame 1 protein (ORF1p). Here, we report (i) which immune cells ORF1p emanates from, (ii) which L1 loci are transcriptionally active, (iii) whether the cells express L1-dependent interferon and interferon-stimulated genes, and (iv) the effect of inhibition of L1 ORF2p by reverse transcriptase inhibitors.
    Results: L1 ORF1p was detected by flow cytometry primarily in SLE CD66b
    Conclusions: We identified L1Hs loci that are transcriptionally active in SLE neutrophils, and a reduction in the epigenetic silencing mechanisms that normally counteract L1 transcription. SLE neutrophils contained L1-encoded ORF1p protein, as well as activation of the type I interferon system, which was inhibited by treatment with reverse transcriptase inhibitors. Our findings will enable a deeper analysis of L1 dysregulation and its potential role in SLE pathogenesis.
    Language English
    Publishing date 2023-05-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2536054-1
    ISSN 1759-8753
    ISSN 1759-8753
    DOI 10.1186/s13100-023-00293-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Allergic Aspects of IgG4-Related Disease: Implications for Pathogenesis and Therapy.

    Michailidou, Despina / Schwartz, Daniella Muallem / Mustelin, Tomas / Hughes, Grant C

    Frontiers in immunology

    2021  Volume 12, Page(s) 693192

    Abstract: IgG4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease frequently associated with allergy. The pathogenesis of IgG4-RD is poorly understood, and effective therapies are limited. However, IgG4-RD appears to involve some of the same ... ...

    Abstract IgG4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease frequently associated with allergy. The pathogenesis of IgG4-RD is poorly understood, and effective therapies are limited. However, IgG4-RD appears to involve some of the same pathogenic mechanisms observed in allergic disease, such as T helper 2 (Th2) and regulatory T cell (Treg) activation, IgG4 and IgE hypersecretion, and blood/tissue eosinophilia. In addition, IgG4-RD tissue fibrosis appears to involve activation of basophils and mast cells and their release of alarmins and cytokines. In this article, we review allergy-like features of IgG4-RD and highlight targeted therapies for allergy that have potential in treating patients with IgG4-RD.
    MeSH term(s) Alarmins/metabolism ; Animals ; Cytokines/metabolism ; Fibrosis ; Humans ; Hypersensitivity/immunology ; Hypersensitivity/metabolism ; Hypersensitivity/physiopathology ; Immune System/immunology ; Immune System/metabolism ; Immune System/physiopathology ; Immunoglobulin E/metabolism ; Immunoglobulin G/immunology ; Immunoglobulin G/metabolism ; Immunoglobulin G4-Related Disease/immunology ; Immunoglobulin G4-Related Disease/metabolism ; Immunoglobulin G4-Related Disease/physiopathology ; Signal Transduction
    Chemical Substances Alarmins ; Cytokines ; Immunoglobulin G ; Immunoglobulin E (37341-29-0)
    Language English
    Publishing date 2021-07-07
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.693192
    Database MEDical Literature Analysis and Retrieval System OnLINE

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