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  1. Article ; Online: sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data.

    Ng, Joseph C F / Montamat Garcia, Guillem / Stewart, Alexander T / Blair, Paul / Mauri, Claudia / Dunn-Walters, Deborah K / Fraternali, Franca

    Nature methods

    2023  

    Abstract: Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline that analyzes CSR events and dynamics of B cells from ... ...

    Abstract Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline that analyzes CSR events and dynamics of B cells from single-cell RNA sequencing (scRNA-seq) experiments. Validated on both simulated and real data, sciCSR re-analyzes scRNA-seq alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline 'sterile' transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built to infer the dynamics and direction of CSR. Applying sciCSR on severe acute respiratory syndrome coronavirus 2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier time point in the collected time-course, the isotype distribution of B cell receptor repertoires of subsequent time points with high accuracy (cosine similarity ~0.9). Using processes specific to B cells, sciCSR identifies transitions that are often missed by conventional RNA velocity analyses and can reveal insights into the dynamics of B cell CSR during immune response.
    Language English
    Publishing date 2023-11-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2169522-2
    ISSN 1548-7105 ; 1548-7091
    ISSN (online) 1548-7105
    ISSN 1548-7091
    DOI 10.1038/s41592-023-02060-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks.

    Chung, Sun Sook / Ng, Joseph C F / Laddach, Anna / Thomas, N Shaun B / Fraternali, Franca

    NAR genomics and bioinformatics

    2021  Volume 3, Issue 1, Page(s) lqab010

    Abstract: Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein-protein interactions (PPIs). Here, we establish ... ...

    Abstract Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein-protein interactions (PPIs). Here, we establish an
    Language English
    Publishing date 2021-03-01
    Publishing country England
    Document type Journal Article
    ISSN 2631-9268
    ISSN (online) 2631-9268
    DOI 10.1093/nargab/lqab010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In Silico and In Vitro Analysis of IL36RN Alterations Reveals Critical Residues for the Function of the Interleukin-36 Receptor Complex.

    Hassi, Niina K / Weston, Timir / Rinaldi, Giulia / Ng, Joseph C / Smahi, Asma / Twelves, Sophie / Davan-Wetton, Camilla / Fakhreddine, Dana / Fraternali, Franca / Capon, Francesca

    The Journal of investigative dermatology

    2023  Volume 143, Issue 12, Page(s) 2468–2475.e6

    Abstract: Generalized pustular psoriasis is a potentially life-threatening skin disease, associated with IL36RN disease alleles. IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their ... ...

    Abstract Generalized pustular psoriasis is a potentially life-threatening skin disease, associated with IL36RN disease alleles. IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). Although generalized pustular psoriasis can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. In this study, we sought to address this question by systematically investigating the effects of IL36RN sequence changes. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machinelearning tool (Rhapsody) to analyze the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential for IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signaling. Combining invitro assays and machine learning with a second program (mCSM), we identified 13 amino acids that are critical for IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings.
    MeSH term(s) Humans ; Amino Acid Substitution ; Amino Acids ; Exanthema ; Interleukins/metabolism ; Psoriasis/genetics ; Reproducibility of Results ; Skin Diseases, Vesiculobullous
    Chemical Substances Amino Acids ; IL36RN protein, human ; Interleukins ; interleukin-36 receptor, human
    Language English
    Publishing date 2023-07-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2023.06.191
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pan-cancer transcriptomic analysis dissects immune and proliferative functions of APOBEC3 cytidine deaminases.

    Ng, Joseph C F / Quist, Jelmar / Grigoriadis, Anita / Malim, Michael H / Fraternali, Franca

    Nucleic acids research

    2019  Volume 47, Issue 3, Page(s) 1178–1194

    Abstract: APOBEC3 cytidine deaminases are largely known for their innate immune protection from viral infections. Recently, members of the family have been associated with a distinct mutational activity in some cancer types. We report a pan-tissue, pan-cancer ... ...

    Abstract APOBEC3 cytidine deaminases are largely known for their innate immune protection from viral infections. Recently, members of the family have been associated with a distinct mutational activity in some cancer types. We report a pan-tissue, pan-cancer analysis of RNA-seq data specific to the APOBEC3 genes in 8,951 tumours, 786 cancer cell lines and 6,119 normal tissues. By deconvolution of levels of different cell types in tumour admixtures, we demonstrate that APOBEC3B (A3B), the primary candidate as a cancer mutagen, shows little association with immune cell types compared to its paralogues. We present a pipeline called RESPECTEx (REconstituting SPecific Cell-Type Expression) and use it to deconvolute cell-type specific expression levels in a given cohort of tumour samples. We functionally annotate APOBEC3 co-expressing genes, and create an interactive visualization tool which 'barcodes' the functional enrichment (http://fraternalilab.kcl.ac.uk/apobec-barcodes/). These analyses reveal that A3B expression correlates with cell cycle and DNA repair genes, whereas the other APOBEC3 members display specificity for immune processes and immune cell populations. We offer molecular insights into the functions of individual APOBEC3 proteins in antiviral and proliferative contexts, and demonstrate the diversification this family of enzymes displays at the transcriptomic level, despite their high similarity in protein sequences and structures.
    MeSH term(s) APOBEC Deaminases ; Cell Line, Tumor ; Cell Proliferation ; Cytidine Deaminase/genetics ; Cytidine Deaminase/metabolism ; Cytosine Deaminase/genetics ; Cytosine Deaminase/metabolism ; Gene Expression Profiling ; Humans ; Immune System/metabolism ; Minor Histocompatibility Antigens/genetics ; Minor Histocompatibility Antigens/metabolism ; Mutation ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/metabolism ; Software ; Transcriptome
    Chemical Substances Minor Histocompatibility Antigens ; Cytosine Deaminase (EC 3.5.4.1) ; APOBEC Deaminases (EC 3.5.4.5) ; APOBEC3 proteins, human (EC 3.5.4.5) ; APOBEC3B protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5)
    Language English
    Publishing date 2019-01-17
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gky1316
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1067: Show issues Location:
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  5. Article ; Online: Tumor-Infiltrating B Lymphocyte Profiling Identifies IgG-Biased, Clonally Expanded Prognostic Phenotypes in Triple-Negative Breast Cancer.

    Harris, Robert J / Cheung, Anthony / Ng, Joseph C F / Laddach, Roman / Chenoweth, Alicia M / Crescioli, Silvia / Fittall, Matthew / Dominguez-Rodriguez, Diana / Roberts, James / Levi, Dina / Liu, Fangfang / Alberts, Elena / Quist, Jelmar / Santaolalla, Aida / Pinder, Sarah E / Gillett, Cheryl / Hammar, Niklas / Irshad, Sheeba / Van Hemelrijck, Mieke /
    Dunn-Walters, Deborah K / Fraternali, Franca / Spicer, James F / Lacy, Katie E / Tsoka, Sophia / Grigoriadis, Anita / Tutt, Andrew N J / Karagiannis, Sophia N

    Cancer research

    2021  Volume 81, Issue 16, Page(s) 4290–4304

    Abstract: In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive ... ...

    Abstract In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20
    MeSH term(s) Antigens, CD/biosynthesis ; Antigens, CD20/biosynthesis ; Antigens, Differentiation, T-Lymphocyte/biosynthesis ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; Base Sequence ; Cell Line, Tumor ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Immunoglobulin D/biosynthesis ; Immunoglobulin G/immunology ; Immunohistochemistry ; Lectins, C-Type/biosynthesis ; Lymphocytes/cytology ; Models, Statistical ; Phenotype ; Prognosis ; RNA-Seq ; Receptors, Antigen, B-Cell/metabolism ; Single-Cell Analysis ; Transcriptome ; Triple Negative Breast Neoplasms/immunology ; Triple Negative Breast Neoplasms/metabolism ; Tumor Necrosis Factor Receptor Superfamily, Member 7/biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; User-Computer Interface
    Chemical Substances Antigens, CD ; Antigens, CD20 ; Antigens, Differentiation, T-Lymphocyte ; CD69 antigen ; Immunoglobulin D ; Immunoglobulin G ; Lectins, C-Type ; Receptors, Antigen, B-Cell ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2021-06-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-3773
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: High titer and avidity of nonneutralizing antibodies against influenza vaccine antigen are associated with severe influenza.

    To, Kelvin K W / Zhang, Anna J X / Hung, Ivan F N / Xu, Ting / Ip, Whitney C T / Wong, Rebecca T Y / Ng, Joseph C K / Chan, Jasper F W / Chan, Kwok-Hung / Yuen, Kwok-Yung

    Clinical and vaccine immunology : CVI

    2012  Volume 19, Issue 7, Page(s) 1012–1018

    Abstract: The importance of neutralizing antibody in protection against influenza virus is well established, but the role of the early antibody response during the initial stage of infection in affecting the severity of disease is unknown. The 2009 influenza ... ...

    Abstract The importance of neutralizing antibody in protection against influenza virus is well established, but the role of the early antibody response during the initial stage of infection in affecting the severity of disease is unknown. The 2009 influenza pandemic provided a unique opportunity for study because most patients lacked preexisting neutralizing antibody. In this study, we compared the antibody responses of 52 patients with severe or mild disease, using sera collected at admission. A microneutralization (MN) assay was used to detect neutralizing antibody. We also developed an enzyme-linked immunosorbent assay (ELISA) which detects both neutralizing and nonneutralizing antibodies against viral antigens from a split-virion inactivated monovalent influenza virus vaccine. While the MN titers were not significantly different between the two groups (P = 0.764), the ELISA titer and ELISA/MN titer ratio were significantly higher for patients with severe disease than for those with mild disease (P = 0.004 and P = 0.011, respectively). This finding suggested that in patients with severe disease, a larger proportion of serum antibodies were antibodies with no detectable neutralizing activity. The antibody avidity was also significantly higher in patients with severe disease than in those with mild disease (P < 0.05). Among patients with severe disease, those who required positive pressure ventilation (PPV) had significantly higher ELISA titers than those who did not require PPV (P < 0.05). Multivariate analysis showed that the ELISA titer and antibody avidity were independently associated with severe disease. Higher titers of nonneutralizing antibody with higher avidity at the early stage of influenza virus infection may be associated with worse clinical severity and poorer outcomes.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antibodies, Neutralizing/blood ; Antibodies, Viral/blood ; Antibody Affinity ; Antigens, Viral/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Humans ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza, Human/immunology ; Influenza, Human/pathology ; Influenza, Human/virology ; Male ; Middle Aged ; Neutralization Tests ; Orthomyxoviridae/immunology ; Severity of Illness Index
    Chemical Substances Antibodies, Neutralizing ; Antibodies, Viral ; Antigens, Viral
    Keywords covid19
    Language English
    Publishing date 2012-05-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2221082-9
    ISSN 1556-679X ; 1556-6811
    ISSN (online) 1556-679X
    ISSN 1556-6811
    DOI 10.1128/CVI.00081-12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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