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  1. Article ; Online: Parallel recovery of chromatin accessibility and gene expression dynamics from frozen human regulatory T cells.

    Wong, Ying Y / Harbison, Jessica E / Hope, Christopher M / Gundsambuu, Batjargal / Brown, Katherine A / Wong, Soon W / Brown, Cheryl Y / Couper, Jennifer J / Breen, Jimmy / Liu, Ning / Pederson, Stephen M / Köhne, Maren / Klee, Kathrin / Schultze, Joachim / Beyer, Marc / Sadlon, Timothy / Barry, Simon C

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 5506

    Abstract: Epigenetic features such as DNA accessibility dictate transcriptional regulation in a cell type- and cell state- specific manner, and mapping this in health vs. disease in clinically relevant material is opening the door to new mechanistic insights and ... ...

    Abstract Epigenetic features such as DNA accessibility dictate transcriptional regulation in a cell type- and cell state- specific manner, and mapping this in health vs. disease in clinically relevant material is opening the door to new mechanistic insights and new targets for therapy. Assay for Transposase Accessible Chromatin Sequencing (ATAC-seq) allows chromatin accessibility profiling from low cell input, making it tractable on rare cell populations, such as regulatory T (Treg) cells. However, little is known about the compatibility of the assay with cryopreserved rare cell populations. Here we demonstrate the robustness of an ATAC-seq protocol comparing primary Treg cells recovered from fresh or cryopreserved PBMC samples, in the steady state and in response to stimulation. We extend this method to explore the feasibility of conducting simultaneous quantitation of chromatin accessibility and transcriptome from a single aliquot of 50,000 cryopreserved Treg cells. Profiling of chromatin accessibility and gene expression in parallel within the same pool of cells controls for cellular heterogeneity and is particularly beneficial when constrained by limited input material. Overall, we observed a high correlation of accessibility patterns and transcription factor dynamics between fresh and cryopreserved samples. Furthermore, highly similar transcriptomic profiles were obtained from whole cells and from the supernatants recovered from ATAC-seq reactions. We highlight the feasibility of applying these techniques to profile the epigenomic landscape of cells recovered from cryopreservation biorepositories.
    MeSH term(s) Humans ; Chromatin/genetics ; T-Lymphocytes, Regulatory ; Leukocytes, Mononuclear ; High-Throughput Nucleotide Sequencing/methods ; Transcriptome
    Chemical Substances Chromatin
    Language English
    Publishing date 2023-04-04
    Publishing country England
    Document type Journal Article ; 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/s41598-023-32256-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cytotoxicity-Related Gene Expression and Chromatin Accessibility Define a Subset of CD4+ T Cells That Mark Progression to Type 1 Diabetes.

    Bediaga, Naiara G / Garnham, Alexandra L / Naselli, Gaetano / Bandala-Sanchez, Esther / Stone, Natalie L / Cobb, Joanna / Harbison, Jessica E / Wentworth, John M / Ziegler, Annette-G / Couper, Jennifer J / Smyth, Gordon K / Harrison, Leonard C

    Diabetes

    2022  Volume 71, Issue 3, Page(s) 566–577

    Abstract: Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has ... ...

    Abstract Type 1 diabetes in children is heralded by a preclinical phase defined by circulating autoantibodies to pancreatic islet antigens. How islet autoimmunity is initiated and then progresses to clinical diabetes remains poorly understood. Only one study has reported gene expression in specific immune cells of children at risk associated with progression to islet autoimmunity. We analyzed gene expression with RNA sequencing in CD4+ and CD8+ T cells, natural killer (NK) cells, and B cells, and chromatin accessibility by assay for transposase-accessible chromatin sequencing (ATAC-seq) in CD4+ T cells, in five genetically at risk children with islet autoantibodies who progressed to diabetes over a median of 3 years ("progressors") compared with five children matched for sex, age, and HLA-DR who had not progressed ("nonprogressors"). In progressors, differentially expressed genes (DEGs) were largely confined to CD4+ T cells and enriched for cytotoxicity-related genes/pathways. Several top-ranked DEGs were validated in a semi-independent cohort of 13 progressors and 11 nonprogressors. Flow cytometry confirmed that progression was associated with expansion of CD4+ cells with a cytotoxic phenotype. By ATAC-seq, progression was associated with reconfiguration of regulatory chromatin regions in CD4+ cells, some linked to differentially expressed cytotoxicity-related genes. Our findings suggest that cytotoxic CD4+ T cells play a role in promoting progression to type 1 diabetes.
    MeSH term(s) Adolescent ; Autoimmunity/genetics ; B-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/ultrastructure ; CD8-Positive T-Lymphocytes/metabolism ; Child ; Child, Preschool ; Chromatin/chemistry ; Cytotoxicity, Immunologic/genetics ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Disease Progression ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Humans ; Islets of Langerhans/immunology ; Killer Cells, Natural/metabolism ; Sequence Analysis, RNA
    Chemical Substances Chromatin
    Language English
    Publishing date 2022-03-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80085-5
    ISSN 1939-327X ; 0012-1797
    ISSN (online) 1939-327X
    ISSN 0012-1797
    DOI 10.2337/db21-0612
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Baricitinib and β-Cell Function in Patients with New-Onset Type 1 Diabetes.

    Waibel, Michaela / Wentworth, John M / So, Michelle / Couper, Jennifer J / Cameron, Fergus J / MacIsaac, Richard J / Atlas, Gabby / Gorelik, Alexandra / Litwak, Sara / Sanz-Villanueva, Laura / Trivedi, Prerak / Ahmed, Simi / Martin, Francis J / Doyle, Madeleine E / Harbison, Jessica E / Hall, Candice / Krishnamurthy, Balasubramanian / Colman, Peter G / Harrison, Leonard C /
    Thomas, Helen E / Kay, Thomas W H

    The New England journal of medicine

    2023  Volume 389, Issue 23, Page(s) 2140–2150

    Abstract: Background: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves β-cell function in type 1 diabetes is unclear.: ... ...

    Abstract Background: Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves β-cell function in type 1 diabetes is unclear.
    Methods: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring.
    Results: A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval [CI], 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo.
    Conclusions: In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve β-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).
    MeSH term(s) Humans ; Australia ; Blood Glucose/analysis ; Blood Glucose Self-Monitoring ; C-Peptide/blood ; Diabetes Mellitus, Type 1/blood ; Diabetes Mellitus, Type 1/drug therapy ; Glycated Hemoglobin/analysis ; Insulin/therapeutic use ; Janus Kinase Inhibitors/adverse effects ; Janus Kinase Inhibitors/pharmacology ; Janus Kinase Inhibitors/therapeutic use ; Insulin-Secreting Cells/drug effects ; Double-Blind Method
    Chemical Substances baricitinib (ISP4442I3Y) ; Blood Glucose ; C-Peptide ; Glycated Hemoglobin ; Insulin ; Janus Kinase Inhibitors
    Language English
    Publishing date 2023-12-06
    Publishing country United States
    Document type Randomized Controlled Trial ; Clinical Trial, Phase II ; Journal Article
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa2306691
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.34: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: Associations between diet, the gut microbiome and short chain fatty acids in youth with islet autoimmunity and type 1 diabetes.

    Harbison, Jessica E / Thomson, Rebecca L / Wentworth, John M / Louise, Jennie / Roth-Schulze, Alexandra / Battersby, Rachel J / Ngui, Katrina M / Penno, Megan A S / Colman, Peter G / Craig, Maria E / Barry, Simon C / Tran, Cuong D / Makrides, Maria / Harrison, Leonard C / Couper, Jennifer J

    Pediatric diabetes

    2021  Volume 22, Issue 3, Page(s) 425–433

    Abstract: Aim: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls.: Research design and methods: Eighty ... ...

    Abstract Aim: We aimed to characterize associations between diet and the gut microbiome and short chain fatty acid (SCFA) products in youth with islet autoimmunity or type 1 diabetes (IA/T1D) in comparison with controls.
    Research design and methods: Eighty participants (25 diagnosed with T1D, 17 with confirmed IA, 38 sibling or unrelated controls) from the Australian T1D Gut Study cohort were studied (median [IQR] age 11.7 [8.9, 14.0] years, 43% female). A Food Frequency Questionnaire characterized daily macronutrient intake over the preceding 6 months. Plasma and fecal SCFA were measured by gas chromatography; gut microbiome composition and diversity by 16S rRNA gene sequencing.
    Results: A 10 g increase in daily carbohydrate intake associated with higher plasma acetate in IA/T1D (adjusted estimate +5.2 (95% CI 1.1, 9.2) μmol/L p = 0.01) and controls (adjusted estimate +4.1 [95% CI 1.7, 8.5] μmol/L p = 0.04). A 5 g increase in total fat intake associated with lower plasma acetate in IA/T1D and controls. A 5% increase in noncore (junk) food intake associated with reduced richness (adjusted estimate -4.09 [95%CI -7.83, -0.35] p = .03) and evenness (-1.25 [95% CI -2.00, -0.49] p < 0.01) of the gut microbiome in IA/T1D. Fiber intake associated with community structure of the microbiome in IA/T1D.
    Conclusions: Modest increments in carbohydrate and fat intake associated with plasma acetate in all youth. Increased junk food intake associated with reduced diversity of the gut microbiome in IA/T1D alone. These associations with the gut microbiome in IA/T1D support future efforts to promote SCFA by using dietary interventions.
    MeSH term(s) Adolescent ; Autoimmunity/physiology ; Case-Control Studies ; Child ; Cross-Sectional Studies ; Diabetes Mellitus, Type 1/complications ; Diabetes Mellitus, Type 1/metabolism ; Diet ; Fatty Acids, Volatile/metabolism ; Female ; Gastrointestinal Microbiome ; Humans ; Islets of Langerhans/immunology ; Male ; Surveys and Questionnaires
    Chemical Substances Fatty Acids, Volatile
    Language English
    Publishing date 2021-02-01
    Publishing country Denmark
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1502504-4
    ISSN 1399-5448 ; 1745-1426 ; 1399-543X
    ISSN (online) 1399-5448
    ISSN 1745-1426 ; 1399-543X
    DOI 10.1111/pedi.13178
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5422: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Gut microbiome dysbiosis and increased intestinal permeability in children with islet autoimmunity and type 1 diabetes: A prospective cohort study.

    Harbison, Jessica E / Roth-Schulze, Alexandra J / Giles, Lynne C / Tran, Cuong D / Ngui, Katrina M / Penno, Megan A / Thomson, Rebecca L / Wentworth, John M / Colman, Peter G / Craig, Maria E / Morahan, Grant / Papenfuss, Anthony T / Barry, Simon C / Harrison, Leonard C / Couper, Jennifer J

    Pediatric diabetes

    2019  Volume 20, Issue 5, Page(s) 574–583

    Abstract: Aims/hypothesis: To investigate the longitudinal relationship between the gut microbiome, circulating short chain fatty acids (SCFAs) and intestinal permeability in children with islet autoimmunity or type 1 diabetes and controls.: Methods: We ... ...

    Abstract Aims/hypothesis: To investigate the longitudinal relationship between the gut microbiome, circulating short chain fatty acids (SCFAs) and intestinal permeability in children with islet autoimmunity or type 1 diabetes and controls.
    Methods: We analyzed the gut bacterial microbiome, plasma SCFAs, small intestinal permeability and dietary intake in 47 children with islet autoimmunity or recent-onset type 1 diabetes and in 41 unrelated or sibling controls over a median (range) of 13 (2-34) months follow-up.
    Results: Children with multiple islet autoantibodies (≥2 IA) or type 1 diabetes had gut microbiome dysbiosis. Anti-inflammatory Prevotella and Butyricimonas genera were less abundant and these changes were not explained by differences in diet. Small intestinal permeability measured by blood lactulose:rhamnose ratio was higher in type 1 diabetes. Children with ≥2 IA who progressed to type 1 diabetes (progressors), compared to those who did not progress, had higher intestinal permeability (mean [SE] difference +5.14 [2.0], 95% confidence interval [CI] 1.21, 9.07, P = .006), lower within-sample (alpha) microbial diversity (31.3 [11.2], 95% CI 9.3, 53.3, P = .005), and lower abundance of SCFA-producing bacteria. Alpha diversity (observed richness) correlated with plasma acetate levels in all groups combined (regression coefficient [SE] 0.57 [0.21], 95% CI 0.15, 0.99 P = .008).
    Conclusions/interpretation: Children with ≥2 IA who progress to diabetes, like those with recent-onset diabetes, have gut microbiome dysbiosis associated with increased intestinal permeability. Interventions that expand gut microbial diversity, in particular SCFA-producing bacteria, may have a role to decrease progression to diabetes in children at-risk.
    MeSH term(s) Adolescent ; Autoimmunity ; Child ; Child, Preschool ; Diabetes Mellitus, Type 1/blood ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/microbiology ; Dysbiosis/immunology ; Fatty Acids, Volatile/blood ; Female ; Gastrointestinal Microbiome ; Humans ; Intestinal Mucosa/metabolism ; Islets of Langerhans/immunology ; Male ; Permeability ; Prospective Studies
    Chemical Substances Fatty Acids, Volatile
    Language English
    Publishing date 2019-05-20
    Publishing country Denmark
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1502504-4
    ISSN 1399-5448 ; 1745-1426 ; 1399-543X
    ISSN (online) 1399-5448
    ISSN 1745-1426 ; 1399-543X
    DOI 10.1111/pedi.12865
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5422: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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