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Article ; Online: Machine learning in EP research: New tools for old problems.

Figgett, William A / Hawson, Joshua / Lee, Geoffrey

Journal of cardiovascular electrophysiology

2023 Volume 34, Issue 5, Page(s) 1322–1323

MeSH term(s)	Humans ; Tachycardia, Ventricular/surgery ; Electrocardiography ; Machine Learning ; Catheter Ablation
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	1025989-2
ISSN	1540-8167 ; 1045-3873
ISSN (online)	1540-8167
ISSN	1045-3873
DOI	10.1111/jce.15851
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Article ; Online: CD8

Deliyanti, Devy / Figgett, William A / Gebhardt, Thomas / Trapani, Joseph A / Mackay, Fabienne / Wilkinson-Berka, Jennifer L

Arteriosclerosis, thrombosis, and vascular biology

2023 Volume 43, Issue 4, Page(s) 522–536

Abstract: Background: CD4: Methods: We describe how CD8: Results: In oxygen-induced retinopathy, flow cytometry revealed the numbers of CD4: Conclusions: We discovered that CXCR3 is central to the migration of ... ...

Abstract	Background: CD4 Methods: We describe how CD8 Results: In oxygen-induced retinopathy, flow cytometry revealed the numbers of CD4 Conclusions: We discovered that CXCR3 is central to the migration of CD8
MeSH term(s)	Animals ; Mice ; CD8-Positive T-Lymphocytes/metabolism ; Neovascularization, Pathologic ; Retina/metabolism ; Retinal Diseases/metabolism ; Interferon-gamma/metabolism ; Vascular Diseases/pathology ; Mice, Inbred C57BL
Chemical Substances	Interferon-gamma (82115-62-6)
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.122.318079
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Article ; Online: An unappreciated cell survival-independent role for BAFF initiating chronic lymphocytic leukemia.

Ullah, Md Ashik / Garcillán, Beatriz / Whitlock, Eden / Figgett, William A / Infantino, Simona / Eslami, Mahya / Yang, SiLing / Rahman, M Arifur / Sheng, Yong H / Weber, Nicholas / Schneider, Pascal / Tam, Constantine S / Mackay, Fabienne

Frontiers in immunology

2024 Volume 15, Page(s) 1345515

Abstract: Background: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19: Methods: We generated novel CLL models lacking BAFF or APRIL. : Results: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation ... ...

Abstract	Background: Chronic Lymphocytic Leukemia (CLL) is characterized by the expansion of CD19 Methods: We generated novel CLL models lacking BAFF or APRIL. Results: Our findings demonstrate a crucial role for BAFF, but not APRIL, in the initiation and dissemination of CLL cells. In the absence of BAFF or its receptor BAFF-R, the TCL1 transgene only increases CLL cell numbers in the peritoneal cavity, without dissemination into the periphery. While BAFF binding to BAFF-R is dispensable for peritoneal CLL cell survival, it is necessary to activate a tumor-promoting gene program, potentially linked to CLL initiation and progression. This direct role of BAFF in controlling the expression of tumor-promoting genes was confirmed in patient-derived primary CLL cells ex-vivo. Conclusions: Our study, involving both mouse and human CLL cells, suggests that BAFF might initiate CLL through mechanisms independent of cell survival. Combining current CLL therapies with BAFF inhibition could offer a dual benefit by reducing peripheral tumor burden and suppressing transformed CLL cell output.
MeSH term(s)	Animals ; Humans ; Mice ; B-Lymphocytes/metabolism ; Cell Survival/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology
Chemical Substances	TNFSF13B protein, human ; Tnfsf13b protein, mouse
Language	English
Publishing date	2024-02-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1345515
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Article ; Online: The effects of B-cell-activating factor on the population size, maturation and function of murine natural killer cells.

Quah, Pin Shie / Sutton, Vivien / Whitlock, Eden / Figgett, William A / Andrews, Daniel M / Fairfax, Kirsten A / Mackay, Fabienne

Immunology and cell biology

2022 Volume 100, Issue 10, Page(s) 761–776

Abstract: The role of B-cell-activating factor (BAFF) in B-lymphocyte biology has been comprehensively studied, but its contributions to innate immunity remain unclear. Natural killer (NK) cells form the first line of defense against viruses and tumors, and have ... ...

Abstract	The role of B-cell-activating factor (BAFF) in B-lymphocyte biology has been comprehensively studied, but its contributions to innate immunity remain unclear. Natural killer (NK) cells form the first line of defense against viruses and tumors, and have been shown to be defective in patients with systemic lupus erythematosus (SLE). The link between BAFF and NK cells in the development and progression of SLE remains unstudied. By assessing NK cell numbers in wild-type (WT), BAFF<sup>-/-</sup> (BAFF deficient), BAFF-R<sup>-/-</sup> (BAFF receptor deficient), TACI<sup>-/-</sup> (transmembrane activator and calcium modulator and cyclophilin ligand interactor deficient), BCMA<sup>-/-</sup> (B-cell maturation antigen deficient) and BAFF transgenic (Tg) mice, we observed that BAFF signaling through BAFF-R was essential for sustaining NK cell numbers in the spleen. However, according to the cell surface expression of CD27 and CD11b on NK cells, we found that BAFF was dispensable for NK cell maturation. Ex vivo and in vivo models showed that NK cells from BAFF<sup>-/-</sup> and BAFF Tg mice produced interferon-γ and killed tumor cells at a level similar to that in WT mice. Finally, we established that NK cells do not express receptors that interact with BAFF in the steady state or in the BAFF Tg mouse model of SLE. Our findings demonstrate that BAFF has an indirect effect on NK cell homeostasis and no effect on NK cell function.
MeSH term(s)	Mice ; Animals ; Transmembrane Activator and CAML Interactor Protein/genetics ; Population Density ; Lupus Erythematosus, Systemic ; Interleukin-4 ; Mice, Transgenic ; Killer Cells, Natural/metabolism
Chemical Substances	Transmembrane Activator and CAML Interactor Protein ; Interleukin-4 (207137-56-2)
Language	English
Publishing date	2022-10-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12585
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Article ; Online: Molecular control of B-cell homeostasis in health and malignancy.

Garcillán, Beatriz / Figgett, William A / Infantino, Simona / Lim, Ee Xin / Mackay, Fabienne

Immunology and cell biology

2018 Volume 96, Issue 5, Page(s) 453–462

Abstract: Altered B-cell homeostasis underlies a wide range of pathologies, from cancers to autoimmunity and immunodeficiency. The molecular safeguards against those disorders, which also allow effective immune responses, are therefore particularly critical. Here, ...

Abstract	Altered B-cell homeostasis underlies a wide range of pathologies, from cancers to autoimmunity and immunodeficiency. The molecular safeguards against those disorders, which also allow effective immune responses, are therefore particularly critical. Here, we review recent findings detailing the fine control of B-cell homeostasis, during B-cell development, maturation in the periphery and during activation and differentiation into antibody-producing cells.
MeSH term(s)	Animals ; Antibody-Producing Cells/immunology ; B-Lymphocytes/immunology ; Cell Differentiation ; Homeostasis ; Humans ; Immune System Diseases/immunology ; Immune Tolerance ; Immunity, Humoral ; Lymphocyte Activation
Language	English
Publishing date	2018-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	284057-1
ISSN	1440-1711 ; 0818-9641
ISSN (online)	1440-1711
ISSN	0818-9641
DOI	10.1111/imcb.12030
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Article: Machine learning applied to whole-blood RNA-sequencing data uncovers distinct subsets of patients with systemic lupus erythematosus.

Figgett, William A / Monaghan, Katherine / Ng, Milica / Alhamdoosh, Monther / Maraskovsky, Eugene / Wilson, Nicholas J / Hoi, Alberta Y / Morand, Eric F / Mackay, Fabienne

Clinical & translational immunology

2019 Volume 8, Issue 12, Page(s) e01093

Abstract: Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus, responses to available treatments are unpredictable. Here, we ... ...

Abstract	Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease that is difficult to treat. There is currently no optimal stratification of patients with SLE, and thus, responses to available treatments are unpredictable. Here, we developed a new stratification scheme for patients with SLE, based on the computational analysis of patients' whole-blood transcriptomes. Methods: We applied machine learning approaches to RNA-sequencing (RNA-seq) data sets to stratify patients with SLE into four distinct clusters based on their gene expression profiles. A meta-analysis on three recently published whole-blood RNA-seq data sets was carried out, and an additional similar data set of 30 patients with SLE and 29 healthy donors was incorporated in this study; a total of 161 patients with SLE and 57 healthy donors were analysed. Results: Examination of SLE clusters, as opposed to unstratified SLE patients, revealed underappreciated differences in the pattern of expression of disease-related genes relative to clinical presentation. Moreover, gene signatures correlated with flare activity were successfully identified. Conclusion: Given that SLE disease heterogeneity is a key challenge hindering the design of optimal clinical trials and the adequate management of patients, our approach opens a new possible avenue addressing this limitation via a greater understanding of SLE heterogeneity in humans. Stratification of patients based on gene expression signatures may be a valuable strategy allowing the identification of separate molecular mechanisms underpinning disease in SLE. Further, this approach may have a use in understanding the variability in responsiveness to therapeutics, thereby improving the design of clinical trials and advancing personalised therapy.
Language	English
Publishing date	2019-12-12
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2694482-0
ISSN	2050-0068
ISSN	2050-0068
DOI	10.1002/cti2.1093
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Article ; Online: Molecular Analysis of pSK1 par: A Novel Plasmid Partitioning System Encoded by Staphylococcal Multiresistance Plasmids.

Chan, Helena Y / Jensen, Slade O / LeBard, Rebecca J / Figgett, William A / Lai, Evelyn / Simpson, Alice E / Brzoska, Anthony J / Davies, Danielle S / Connolly, Angela M / Cordwell, Stuart J / Travis, Brady A / Salinas, Raul / Skurray, Ronald A / Firth, Neville / Schumacher, Maria A

Journal of molecular biology

2022 Volume 434, Issue 19, Page(s) 167770

Abstract: The segregation of prokaryotic plasmids typically requires a centromere-like site and two proteins, a centromere-binding protein (CBP) and an NTPase. By contrast, a single 245 residue Par protein mediates partition of the prototypical staphylococcal ... ...

Abstract	The segregation of prokaryotic plasmids typically requires a centromere-like site and two proteins, a centromere-binding protein (CBP) and an NTPase. By contrast, a single 245 residue Par protein mediates partition of the prototypical staphylococcal multiresistance plasmid pSK1 in the absence of an identifiable NTPase component. To gain insight into centromere binding by pSK1 Par and its segregation function we performed structural, biochemical and in vivo studies. Here we show that pSK1 Par binds a centromere consisting of seven repeat elements. We demonstrate this Par-centromere interaction also mediates Par autoregulation. To elucidate the Par centromere binding mechanism, we obtained a structure of the Par N-terminal DNA-binding domain bound to centromere DNA to 2.25 Å. The pSK1 Par structure, which harbors a winged-helix-turn-helix (wHTH), is distinct from other plasmid CBP structures but shows homology to the B. subtilis chromosome segregation protein, RacA. Biochemical studies suggest the region C-terminal to the Par wHTH forms coiled coils and mediates oligomerization. Fluorescence microscopy analyses show that pSK1 Par enhances the separation of plasmids from clusters, driving effective segregation upon cell division. Combined the data provide insight into the molecular properties of a single protein partition system.
MeSH term(s)	Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Centromere/genetics ; Centromere/metabolism ; Chromosome Segregation ; DNA/chemistry ; Nucleoside-Triphosphatase/metabolism ; Plasmids/genetics ; Staphylococcus/genetics
Chemical Substances	Bacterial Proteins ; chromosome partition proteins, bacterial ; DNA (9007-49-2) ; Nucleoside-Triphosphatase (EC 3.6.1.15)
Language	English
Publishing date	2022-07-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167770
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Article ; Online: Molecular Analysis of pSK1 par: A Novel Plasmid Partitioning System Encoded by Staphylococcal Multiresistance Plasmids

Chan, Helena Y. / Jensen, Slade O. / LeBard, Rebecca J. / Figgett, William A. / Lai, Evelyn / Simpson, Alice E. / Brzoska, Anthony J. / Davies, Danielle S. / Connolly, Angela M. / Cordwell, Stuart J. / Travis, Brady A. / Salinas, Raúl / Skurray, Ronald A. / Firth, Neville / Schumacher, Maria A.

Journal of Molecular Biology. 2022 Oct., v. 434, no. 19 p.167770-

2022

Abstract	The segregation of prokaryotic plasmids typically requires a centromere-like site and two proteins, a centromere-binding protein (CBP) and an NTPase. By contrast, a single 245 residue Par protein mediates partition of the prototypical staphylococcal multiresistance plasmid pSK1 in the absence of an identifiable NTPase component. To gain insight into centromere binding by pSK1 Par and its segregation function we performed structural, biochemical and in vivo studies. Here we show that pSK1 Par binds a centromere consisting of seven repeat elements. We demonstrate this Par-centromere interaction also mediates Par autoregulation. To elucidate the Par centromere binding mechanism, we obtained a structure of the Par N-terminal DNA-binding domain bound to centromere DNA to 2.25 Å. The pSK1 Par structure, which harbors a winged-helix-turn-helix (wHTH), is distinct from other plasmid CBP structures but shows homology to the B. subtilis chromosome segregation protein, RacA. Biochemical studies suggest the region C-terminal to the Par wHTH forms coiled coils and mediates oligomerization. Fluorescence microscopy analyses show that pSK1 Par enhances the separation of plasmids from clusters, driving effective segregation upon cell division. Combined the data provide insight into the molecular properties of a single protein partition system.
Keywords	DNA-binding domains ; autoregulation ; centromeres ; chromosome segregation ; fluorescence microscopy ; molecular biology ; nucleoside-triphosphate phosphatase ; oligomerization ; plasmids ; pSK1 plasmid ; DNA segregation ; par protein ; X-ray crystallography ; S. aureus
Language	English
Dates of publication	2022-10
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Use and reproduction
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2022.167770
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Article ; Online: Roles of ligands from the TNF superfamily in B cell development, function, and regulation.

Figgett, William A / Vincent, Fabien B / Saulep-Easton, Damien / Mackay, Fabienne

Seminars in immunology

2014 Volume 26, Issue 3, Page(s) 191–202

Abstract: Most ligands from the tumour necrosis factor (TNF) superfamily play very important roles in the immune system, and particularly so in B lymphocyte biology. TNF ligands are essential to many aspects of normal B cell biology from development in the bone ... ...

Abstract	Most ligands from the tumour necrosis factor (TNF) superfamily play very important roles in the immune system, and particularly so in B lymphocyte biology. TNF ligands are essential to many aspects of normal B cell biology from development in the bone marrow to maturation in the periphery as well as for activation and differentiation into germinal centre, memory or plasma cells. TNF ligands also influence other aspects of B cell biology such as their ability to present antigens or regulate immune responses. Importantly, inadequate regulation of many TNF ligands is associated with B cell disorders including autoimmunity and cancers. As a result, inhibitors of a number of TNF ligands have been tested in the clinic, with some becoming very successful approved treatments alleviating B cell-mediated pathologies.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Survival ; Humans ; T-Lymphocytes/immunology ; Tumor Necrosis Factors/classification ; Tumor Necrosis Factors/metabolism
Chemical Substances	Tumor Necrosis Factors
Language	English
Publishing date	2014-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2014.06.001
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Article ; Online: B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF.

Bakhuraysah, Maha M / Theotokis, Paschalis / Lee, Jae Young / Alrehaili, Amani A / Aui, Pei-Mun / Figgett, William A / Azari, Michael F / Abou-Afech, John-Paul / Mackay, Fabienne / Siatskas, Christopher / Alderuccio, Frank / Strittmatter, Stephen M / Grigoriadis, Nikolaos / Petratos, Steven

Scientific reports

2021 Volume 11, Issue 1, Page(s) 2890

Abstract: We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may ...

Abstract	We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1
MeSH term(s)	Animals ; B-Cell Activating Factor/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Female ; Humans ; Meninges/immunology ; Meninges/pathology ; Mice ; Mice, Knockout ; Multiple Sclerosis/immunology ; Multiple Sclerosis/pathology ; Nogo Proteins/metabolism ; Nogo Receptor 1/genetics ; Nogo Receptor 1/metabolism ; Nogo Receptors/metabolism
Chemical Substances	B-Cell Activating Factor ; Nogo Proteins ; Nogo Receptor 1 ; Nogo Receptors ; Rtn4r protein, mouse ; Rtn4rl1 protein, mouse ; Tnfsf13b protein, mouse
Language	English
Publishing date	2021-02-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-82346-6
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