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  1. Article ; Online: Human immune phenotyping reveals accelerated aging in type 1 diabetes

    Melanie R. Shapiro / Xiaoru Dong / Daniel J. Perry / James M. McNichols / Puchong Thirawatananond / Amanda L. Posgai / Leeana D. Peters / Keshav Motwani / Richard S. Musca / Andrew Muir / Patrick Concannon / Laura M. Jacobsen / Clayton E. Mathews / Clive H. Wasserfall / Michael J. Haller / Desmond A. Schatz / Mark A. Atkinson / Maigan A. Brusko / Rhonda Bacher /
    Todd M. Brusko

    JCI Insight, Vol 8, Iss

    2023  Volume 17

    Abstract: The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We ... ...

    Abstract The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals (stage 3 T1D, their first-degree relatives, those with ≥2 islet autoantibodies, and autoantibody-negative unaffected controls). We constructed an immune age predictive model in unaffected participants and observed accelerated immune aging in T1D. We used generalized additive models for location, shape, and scale to obtain age-corrected data for flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and programmed cell death 1–positive (PD-1+) frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels on memory T cells. Phenotypes associated with T1D after age correction were predictive of T1D status. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.
    Keywords Autoimmunity ; Immunology ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2023-09-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Machine learning on genome-wide association studies to predict the risk of radiation-associated contralateral breast cancer in the WECARE Study.

    Sangkyu Lee / Xiaolin Liang / Meghan Woods / Anne S Reiner / Patrick Concannon / Leslie Bernstein / Charles F Lynch / John D Boice / Joseph O Deasy / Jonine L Bernstein / Jung Hun Oh

    PLoS ONE, Vol 15, Iss 2, p e

    2020  Volume 0226157

    Abstract: The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women ...

    Abstract The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve (AUC) of 0.62 (p = 0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A genomic data archive from the Network for Pancreatic Organ donors with Diabetes

    Daniel J. Perry / Melanie R. Shapiro / Sonya W. Chamberlain / Irina Kusmartseva / Srikar Chamala / Leandro Balzano-Nogueira / Mingder Yang / Jason O. Brant / Maigan Brusko / MacKenzie D. Williams / Kieran M. McGrail / James McNichols / Leeana D. Peters / Amanda L. Posgai / John S. Kaddis / Clayton E. Mathews / Clive H. Wasserfall / Bobbie-Jo M. Webb-Robertson / Martha Campbell-Thompson /
    Desmond Schatz / Carmella Evans-Molina / Alberto Pugliese / Patrick Concannon / Mark S. Anderson / Michael S. German / Chester E. Chamberlain / Mark A. Atkinson / Todd M. Brusko

    Scientific Data, Vol 10, Iss 1, Pp 1-

    2023  Volume 16

    Abstract: Abstract The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis- ... ...

    Abstract Abstract The Network for Pancreatic Organ donors with Diabetes (nPOD) is the largest biorepository of human pancreata and associated immune organs from donors with type 1 diabetes (T1D), maturity-onset diabetes of the young (MODY), cystic fibrosis-related diabetes (CFRD), type 2 diabetes (T2D), gestational diabetes, islet autoantibody positivity (AAb+), and without diabetes. nPOD recovers, processes, analyzes, and distributes high-quality biospecimens, collected using optimized standard operating procedures, and associated de-identified data/metadata to researchers around the world. Herein describes the release of high-parameter genotyping data from this collection. 372 donors were genotyped using a custom precision medicine single nucleotide polymorphism (SNP) microarray. Data were technically validated using published algorithms to evaluate donor relatedness, ancestry, imputed HLA, and T1D genetic risk score. Additionally, 207 donors were assessed for rare known and novel coding region variants via whole exome sequencing (WES). These data are publicly-available to enable genotype-specific sample requests and the study of novel genotype:phenotype associations, aiding in the mission of nPOD to enhance understanding of diabetes pathogenesis to promote the development of novel therapies.
    Keywords Science ; Q
    Subject code 571
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Genetic and epigenetic variation in the lineage specification of regulatory T cells

    Aaron Arvey / Joris van der Veeken / George Plitas / Stephen S Rich / Patrick Concannon / Alexander Y Rudensky

    eLife, Vol

    2015  Volume 4

    Abstract: Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the ... ...

    Abstract Regulatory T (Treg) cells, which suppress autoimmunity and other inflammatory states, are characterized by a distinct set of genetic elements controlling their gene expression. However, the extent of genetic and associated epigenetic variation in the Treg cell lineage and its possible relation to disease states in humans remain unknown. We explored evolutionary conservation of regulatory elements and natural human inter-individual epigenetic variation in Treg cells to identify the core transcriptional control program of lineage specification. Analysis of single nucleotide polymorphisms in core lineage-specific enhancers revealed disease associations, which were further corroborated by high-resolution genotyping to fine map causal polymorphisms in lineage-specific enhancers. Our findings suggest that a small set of regulatory elements specify the Treg lineage and that genetic variation in Treg cell-specific enhancers may alter Treg cell function contributing to polygenic disease.
    Keywords immunogenetics ; regulatory T cell ; immune regulation ; epigenome ; human ; mouse ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2015-10-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor

    Smith, Michelle I / Andrew L. Kau / Dan Knights / Elaine Holmes / Eric Houpt / Indi Trehan / Jeffrey I. Gordon / Jeremy Nicholson / Jia V. Li / Jie Liu / Jiye Cheng / Josyf C. Mychaleckyj / Luke K. Ursell / Mark J. Manary / Patrick Concannon / Rajhab Mkakosya / Rob Knight / Stephen S. Rich / Tanya Yatsunenko

    Science. 2013 Feb. 1, v. 339, no. 6119

    2013  

    Abstract: Not Just Wasting Malnutrition is well known in Malawi, including a severe form—kwashiorkor—in which children do not simply waste away, they also suffer edema, liver damage, skin ulceration, and anorexia. Smith et al. (p. 548; see the Perspective by ... ...

    Abstract Not Just Wasting Malnutrition is well known in Malawi, including a severe form—kwashiorkor—in which children do not simply waste away, they also suffer edema, liver damage, skin ulceration, and anorexia. Smith et al. (p. 548; see the Perspective by Relman) investigated the microbiota of pairs of twins in Malawian villages and found notable differences in the composition of the gut microbiota in children with kwashiorkor. In these children, a bacterial species related to Desulfovibrio , which has been associated with bowel disease and inflammation, was noticeable. When the fecal flora from either the healthy or the sick twin was transplanted into groups of germ-free mice, the mice that received the kwashiorkor sample started to lose weight, like their human counterpart.
    Keywords anorexia ; children ; Desulfovibrio ; edema ; germ-free animals ; humans ; inflammation ; intestinal microorganisms ; kwashiorkor ; liver ; mice ; microbiome ; twins ; villages ; Malawi
    Language English
    Dates of publication 2013-0201
    Size p. 548-554.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1229000
    Database NAL-Catalogue (AGRICOLA)

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