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  1. Article: Data-driven selection of analysis decisions in single-cell RNA-seq trajectory inference.

    Dong, Xiaoru / Leary, Jack R / Yang, Chuanhao / Brusko, Maigan A / Brusko, Todd M / Bacher, Rhonda

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Single-cell RNA sequencing (scRNA-seq) experiments have become instrumental in developmental and differentiation studies, enabling the profiling of cells at a single or multiple time-points to uncover subtle variations in expression profiles reflecting ... ...

    Abstract Single-cell RNA sequencing (scRNA-seq) experiments have become instrumental in developmental and differentiation studies, enabling the profiling of cells at a single or multiple time-points to uncover subtle variations in expression profiles reflecting underlying biological processes. Benchmarking studies have compared many of the computational methods used to reconstruct cellular dynamics, however researchers still encounter challenges in their analysis due to uncertainties in selecting the most appropriate methods and parameters. Even among universal data processing steps used by trajectory inference methods such as feature selection and dimension reduction, trajectory methods' performances are highly dataset-specific. To address these challenges, we developed Escort, a framework for evaluating a dataset's suitability for trajectory inference and quantifying trajectory properties influenced by analysis decisions. Escort navigates single-cell trajectory analysis through data-driven assessments, reducing uncertainty and much of the decision burden associated with trajectory inference. Escort is implemented in an accessible R package and R/Shiny application, providing researchers with the necessary tools to make informed decisions during trajectory analysis and enabling new insights into dynamic biological processes at single-cell resolution.
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.18.572214
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Editorial: Footprints of Immune Cells in the Type 1 Diabetic Pancreas.

    Brusko, Todd M / Mallone, Roberto / Rodriguez-Calvo, Teresa

    Frontiers in endocrinology

    2021  Volume 12, Page(s) 767012

    MeSH term(s) Adaptive Immunity/immunology ; Diabetes Mellitus, Type 1/immunology ; Humans ; Immunity, Innate/immunology ; Pancreas/immunology
    Language English
    Publishing date 2021-10-14
    Publishing country Switzerland
    Document type Editorial ; Introductory Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2021.767012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The immunology of type 1 diabetes.

    Herold, Kevan C / Delong, Thomas / Perdigoto, Ana Luisa / Biru, Noah / Brusko, Todd M / Walker, Lucy S K

    Nature reviews. Immunology

    2024  

    Abstract: Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first ... ...

    Abstract Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.
    Language English
    Publishing date 2024-02-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062776-2
    ISSN 1474-1741 ; 1474-1733
    ISSN (online) 1474-1741
    ISSN 1474-1733
    DOI 10.1038/s41577-023-00985-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Strategies for durable β cell replacement in type 1 diabetes.

    Brusko, Todd M / Russ, Holger A / Stabler, Cherie L

    Science (New York, N.Y.)

    2021  Volume 373, Issue 6554, Page(s) 516–522

    Abstract: Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by ... ...

    Abstract Technological advancements in blood glucose monitoring and therapeutic insulin administration have improved the quality of life for people with type 1 diabetes. However, these efforts fall short of replicating the exquisite metabolic control provided by native islets. We examine the integrated advancements in islet cell replacement and immunomodulatory therapies that are coalescing to enable the restoration of endogenous glucose regulation. We highlight advances in stem cell biology and graft site design, which offer innovative sources of cellular material and improved engraftment. We also cover cutting-edge approaches for preventing allograft rejection and recurrent autoimmunity. These insights reflect a growing understanding of type 1 diabetes etiology, β cell biology, and biomaterial design, together highlighting therapeutic opportunities to durably replace the β cells destroyed in type 1 diabetes.
    MeSH term(s) Animals ; Autoimmunity ; Blood Glucose/metabolism ; Cell Differentiation ; Cell Engineering ; Cellular Microenvironment ; Diabetes Mellitus, Type 1/metabolism ; Diabetes Mellitus, Type 1/therapy ; Graft Rejection/prevention & control ; Graft Survival ; Humans ; Immune Tolerance ; Immunomodulation ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/physiology ; Insulin-Secreting Cells/transplantation ; Islets of Langerhans/physiology ; Islets of Langerhans Transplantation ; Pluripotent Stem Cells/transplantation ; Stem Cell Transplantation
    Chemical Substances Blood Glucose
    Language English
    Publishing date 2021-07-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abh1657
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Modeling cell-mediated immunity in human type 1 diabetes by engineering autoreactive CD8

    Peters, Leeana D / Yeh, Wen-I / Arnoletti, Juan M / Brown, Matthew E / Posgai, Amanda L / Mathews, Clayton E / Brusko, Todd M

    Frontiers in immunology

    2023  Volume 14, Page(s) 1142648

    Abstract: The autoimmune pathogenesis of type 1 diabetes (T1D) involves cellular infiltration from innate and adaptive immune subsets into the islets of Langerhans within the pancreas; however, the direct cytotoxic killing of insulin-producing β-cells is thought ... ...

    Abstract The autoimmune pathogenesis of type 1 diabetes (T1D) involves cellular infiltration from innate and adaptive immune subsets into the islets of Langerhans within the pancreas; however, the direct cytotoxic killing of insulin-producing β-cells is thought to be mediated primarily by antigen-specific CD8
    MeSH term(s) Humans ; CD8-Positive T-Lymphocytes ; Diabetes Mellitus, Type 1 ; Insulin-Secreting Cells ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Immunity, Cellular
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-05-30
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1142648
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Immune engineered extracellular vesicles to modulate T cell activation in the context of type 1 diabetes.

    Becker, Matthew W / Peters, Leeana D / Myint, Thinzar / Smurlick, Dylan / Powell, Andrece / Brusko, Todd M / Phelps, Edward A

    Science advances

    2023  Volume 9, Issue 22, Page(s) eadg1082

    Abstract: Extracellular vesicles (EVs) can affect immune responses through antigen presentation and costimulation or coinhibition. We generated designer EVs to modulate T cells in the context of type 1 diabetes, a T cell-mediated autoimmune disease, by engineering ...

    Abstract Extracellular vesicles (EVs) can affect immune responses through antigen presentation and costimulation or coinhibition. We generated designer EVs to modulate T cells in the context of type 1 diabetes, a T cell-mediated autoimmune disease, by engineering a lymphoblast cell line, K562, to express HLA-A*02 (HLA-A2) alongside costimulatory CD80 and/or coinhibitory programmed death ligand 1 (PD-L1). EVs presenting HLA-A2 and CD80 activated CD8
    MeSH term(s) Humans ; B7-H1 Antigen/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; HLA-A2 Antigen/metabolism ; Diabetes Mellitus, Type 1/therapy ; Diabetes Mellitus, Type 1/metabolism ; Extracellular Vesicles/metabolism
    Chemical Substances B7-H1 Antigen ; HLA-A2 Antigen
    Language English
    Publishing date 2023-06-02
    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.adg1082
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Low-Dose Antithymocyte Globulin: A Pragmatic Approach to Treating Stage 2 Type 1 Diabetes.

    Foster, Timothy P / Jacobsen, Laura M / Bruggeman, Brittany / Salmon, Chelsea / Hosford, Jennifer / Chen, Angela / Cintron, Miriam / Mathews, Clayton E / Wasserfall, Clive / Brusko, Maigan A / Brusko, Todd M / Atkinson, Mark A / Schatz, Desmond A / Haller, Michael J

    Diabetes care

    2023  Volume 47, Issue 2, Page(s) 285–289

    Abstract: Objective: Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated.: Research design and methods!# ...

    Abstract Objective: Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated.
    Research design and methods: Children (n = 6) aged 5-14 years with stage 2 type 1 diabetes received off-label, low-dose ATG. HbA1c, C-peptide, continuous glucose monitoring, insulin requirements, and side effects were followed for 18-48 months.
    Results: Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1-2 months after therapy. Eighteen months posttreatment, even disease progressors demonstrated near-normal HbA1c (5.1% [32 mmol/mol], 5.6% [38 mmol/mol], and 5.3% [34 mmol/mol]), time in range (93%, 88%, and 98%), low insulin requirements (0.17, 0.18, and 0.34 units/kg/day), and robust C-peptide 90 min after mixed meal (1.3 ng/dL, 2.3 ng/dL, and 1.4 ng/dL).
    Conclusions: These observations support additional prospective studies evaluating ATG in stage 2 type 1 diabetes.
    MeSH term(s) Child ; Humans ; Antilymphocyte Serum/therapeutic use ; Blood Glucose ; Blood Glucose Self-Monitoring ; C-Peptide ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/chemically induced ; Glycated Hemoglobin ; Hypoglycemic Agents ; Insulin ; Prospective Studies
    Chemical Substances Antilymphocyte Serum ; Blood Glucose ; C-Peptide ; Glycated Hemoglobin ; Hypoglycemic Agents ; Insulin
    Language English
    Publishing date 2023-12-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 441231-x
    ISSN 1935-5548 ; 0149-5992
    ISSN (online) 1935-5548
    ISSN 0149-5992
    DOI 10.2337/dc23-1750
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells.

    Shapiro, Melanie R / Peters, Leeana D / Brown, Matthew E / Cabello-Kindelan, Cecilia / Posgai, Amanda L / Bayer, Allison L / Brusko, Todd M

    Journal of immunology (Baltimore, Md. : 1950)

    2023  Volume 211, Issue 7, Page(s) 1108–1122

    Abstract: IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of ... ...

    Abstract IL-2 has been proposed to restore tolerance via regulatory T cell (Treg) expansion in autoimmunity, yet off-target effects necessitate identification of a combinatorial approach allowing for lower IL-2 dosing. We recently reported reduced levels of immunoregulatory insulin-like growth factor-1 (IGF1) during type 1 diabetes progression. Thus, we hypothesized that IGF1 would synergize with IL-2 to expand Tregs. We observed IGF1 receptor was elevated on murine memory and human naive Treg subsets. IL-2 and IGF1 promoted PI3K/Akt signaling in Tregs, inducing thymically-derived Treg expansion beyond either agent alone in NOD mice. Increased populations of murine Tregs of naive or memory, as well as CD5lo polyclonal or CD5hi likely self-reactive, status were also observed. Expansion was attributed to increased IL-2Rγ subunit expression on murine Tregs exposed to IL-2 and IGF1 as compared with IL-2 or IGF1 alone. Assessing translational capacity, incubation of naive human CD4+ T cells with IL-2 and IGF1 enhanced thymically-derived Treg proliferation in vitro, without the need for TCR ligation. We then demonstrated that IGF1 and IL-2 or IL-7, which is also IL-2Rγ-chain dependent, can be used to induce proliferation of genetically engineered naive human Tregs or T conventional cells, respectively. These data support the potential use of IGF1 in combination with common γ-chain cytokines to drive homeostatic T cell expansion, both in vitro and in vivo, for cellular therapeutics and ex vivo gene editing.
    MeSH term(s) Humans ; Animals ; Mice ; Mice, Inbred NOD ; Insulin-Like Growth Factor I ; T-Lymphocytes, Regulatory ; Interleukin-2 ; Phosphatidylinositol 3-Kinases ; Cell Proliferation
    Chemical Substances Insulin-Like Growth Factor I (67763-96-6) ; Interleukin-2 ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
    Language English
    Publishing date 2023-08-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2200651
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Infant T cells are developmentally adapted for robust lung immune responses through enhanced T cell receptor signaling.

    Thapa, Puspa / Guyer, Rebecca S / Yang, Alexander Y / Parks, Christopher A / Brusko, Todd M / Brusko, Maigan / Connors, Thomas J / Farber, Donna L

    Science immunology

    2021  Volume 6, Issue 66, Page(s) eabj0789

    Abstract: Infants require coordinated immune responses to prevent succumbing to multiple infectious challenges during early life, particularly in the respiratory tract. The mechanisms by which infant T cells are functionally adapted for these responses are not ... ...

    Abstract Infants require coordinated immune responses to prevent succumbing to multiple infectious challenges during early life, particularly in the respiratory tract. The mechanisms by which infant T cells are functionally adapted for these responses are not well understood. Here, we demonstrated using an in vivo mouse cotransfer model that infant T cells generated greater numbers of lung-homing effector cells in response to influenza infection compared with adult T cells in the same host, due to augmented T cell receptor (TCR)–mediated signaling. Mouse infant T cells showed increased sensitivity to low antigen doses, originating at the interface between T cells and antigen-bearing accessory cells—through actin-mediated mobilization of signaling molecules to the immune synapse. This enhanced signaling was also observed in human infant versus adult T cells. Our findings provide a mechanism for how infants control pathogen load and dissemination, which is important for designing developmentally targeted strategies for promoting immune responses at this vulnerable life stage.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/immunology ; Female ; Lung/immunology ; Male ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; Mice, Transgenic ; Receptors, Antigen, T-Cell/immunology ; Signal Transduction/immunology
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2021-12-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2470-9468
    ISSN (online) 2470-9468
    DOI 10.1126/sciimmunol.abj0789
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Improving the Prediction of Type 1 Diabetes Across Ancestries.

    Kaddis, John S / Perry, Daniel J / Vu, Anh Nguyet / Rich, Stephen S / Atkinson, Mark A / Schatz, Desmond A / Roep, Bart O / Brusko, Todd M

    Diabetes care

    2022  Volume 45, Issue 3, Page(s) e48–e50

    MeSH term(s) Diabetes Mellitus, Type 1/diagnosis ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans
    Language English
    Publishing date 2022-01-18
    Publishing country United States
    Document type Letter ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 441231-x
    ISSN 1935-5548 ; 0149-5992
    ISSN (online) 1935-5548
    ISSN 0149-5992
    DOI 10.2337/dc21-1254
    Database MEDical Literature Analysis and Retrieval System OnLINE

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