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  1. Article ; Online: How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

    Yin, Rose / Melton, Samuel / Huseby, Eric S / Kardar, Mehran / Chakraborty, Arup K

    Proceedings of the National Academy of Sciences of the United States of America

    2024  Volume 121, Issue 11, Page(s) e2318599121

    Abstract: T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. ... ...

    Abstract T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.
    MeSH term(s) Animals ; Mice ; Persistent Infection ; Peripheral Tolerance ; T-Lymphocytes ; Autoantigens ; Peptides ; Autoimmune Diseases
    Chemical Substances Autoantigens ; Peptides
    Language English
    Publishing date 2024-03-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2318599121
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  2. Article ; Online: Discovering a sparse set of pairwise discriminating features in high-dimensional data.

    Melton, Samuel / Ramanathan, Sharad

    Bioinformatics (Oxford, England)

    2020  Volume 37, Issue 2, Page(s) 202–212

    Abstract: Motivation: Recent technological advances produce a wealth of high-dimensional descriptions of biological processes, yet extracting meaningful insight and mechanistic understanding from these data remains challenging. For example, in developmental ... ...

    Abstract Motivation: Recent technological advances produce a wealth of high-dimensional descriptions of biological processes, yet extracting meaningful insight and mechanistic understanding from these data remains challenging. For example, in developmental biology, the dynamics of differentiation can now be mapped quantitatively using single-cell RNA sequencing, yet it is difficult to infer molecular regulators of developmental transitions. Here, we show that discovering informative features in the data is crucial for statistical analysis as well as making experimental predictions.
    Results: We identify features based on their ability to discriminate between clusters of the data points. We define a class of problems in which linear separability of clusters is hidden in a low-dimensional space. We propose an unsupervised method to identify the subset of features that define a low-dimensional subspace in which clustering can be conducted. This is achieved by averaging over discriminators trained on an ensemble of proposed cluster configurations. We then apply our method to single-cell RNA-seq data from mouse gastrulation, and identify 27 key transcription factors (out of 409 total), 18 of which are known to define cell states through their expression levels. In this inferred subspace, we find clear signatures of known cell types that eluded classification prior to discovery of the correct low-dimensional subspace.
    Availability and implementation: https://github.com/smelton/SMD.
    Supplementary information: Supplementary data are available at Bioinformatics online.
    MeSH term(s) Algorithms ; Animals ; Cluster Analysis ; Mice ; RNA-Seq ; Sequence Analysis, RNA ; Single-Cell Analysis
    Language English
    Publishing date 2020-09-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btaa690
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  3. Article ; Online: Variation in the Yaa position of collagen peptides containing azaGlycine.

    Melton, Samuel D / Chenoweth, David M

    Chemical communications (Cambridge, England)

    2018  Volume 54, Issue 84, Page(s) 11937–11940

    Abstract: Herein, we report the systematic investigation of amino acid variation in the Yaa position of collagen peptides containing an adjacent azaGlycine residue. We demonstrate the reliability of azaGlycine as a glycine replacement and provide a sequence ... ...

    Abstract Herein, we report the systematic investigation of amino acid variation in the Yaa position of collagen peptides containing an adjacent azaGlycine residue. We demonstrate the reliability of azaGlycine as a glycine replacement and provide a sequence independent strategy for stabilizing the triple helical assembly of collagen peptides.
    Language English
    Publishing date 2018-10-05
    Publishing country England
    Document type Journal Article
    ZDB-ID 1472881-3
    ISSN 1364-548X ; 1359-7345 ; 0009-241X
    ISSN (online) 1364-548X
    ISSN 1359-7345 ; 0009-241X
    DOI 10.1039/c8cc06372a
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  4. Article ; Online: Correction to "Incorporation of Aza-Glycine into Collagen Peptides".

    Melton, Samuel D / Smith, Mason S / Chenoweth, David M

    The Journal of organic chemistry

    2020  Volume 85, Issue 6, Page(s) 4582

    Language English
    Publishing date 2020-03-09
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.0c00497
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4473: Show issues Location:
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  5. Article ; Online: Incorporation of Aza-Glycine into Collagen Peptides.

    Melton, Samuel D / Smith, Mason S / Chenoweth, David M

    The Journal of organic chemistry

    2019  Volume 85, Issue 3, Page(s) 1706–1711

    Abstract: Substitution of natural amino acids with their aza-amino acid counterparts in peptides has been a historically challenging prospect due to the diminished reactivity of the involved reagents. Current methods require lengthy reaction times or difficult ... ...

    Abstract Substitution of natural amino acids with their aza-amino acid counterparts in peptides has been a historically challenging prospect due to the diminished reactivity of the involved reagents. Current methods require lengthy reaction times or difficult synthetic strategies. Aza-glycine has proven to be a valuable tool in the design of triple-helix-forming collagen peptides. Herein, we describe a method for incorporation of aza-glycine in collagen peptides, and we apply the method to the synthesis of collagen peptides containing multiple aza-glycine residues.
    MeSH term(s) Amino Acids ; Collagen ; Glycine ; Peptides
    Chemical Substances Amino Acids ; Peptides ; Collagen (9007-34-5) ; Glycine (TE7660XO1C)
    Language English
    Publishing date 2019-12-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.9b02539
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4473: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  6. Book ; Online: Discovering a sparse set of pairwise discriminating features in high dimensional data

    Melton, Samuel / Ramanathan, Sharad

    2019  

    Abstract: Extracting an understanding of the underlying system from high dimensional data is a growing problem in science. Discovering informative and meaningful features is crucial for clustering, classification, and low dimensional data embedding. Here we ... ...

    Abstract Extracting an understanding of the underlying system from high dimensional data is a growing problem in science. Discovering informative and meaningful features is crucial for clustering, classification, and low dimensional data embedding. Here we propose to construct features based on their ability to discriminate between clusters of the data points. We define a class of problems in which linear separability of clusters is hidden in a low dimensional space. We propose an unsupervised method to identify the subset of features that define a low dimensional subspace in which clustering can be conducted. This is achieved by averaging over discriminators trained on an ensemble of proposed cluster configurations. We then apply our method to single cell RNA-seq data from mouse gastrulation, and identify 27 key transcription factors (out of 409 total), 18 of which are known to define cell states through their expression levels. In this inferred subspace, we find clear signatures of known cell types that eluded classification prior to discovery of the correct low dimensional subspace.
    Keywords Statistics - Machine Learning ; Computer Science - Machine Learning ; Quantitative Biology - Genomics ; Quantitative Biology - Quantitative Methods ; Statistics - Applications
    Subject code 006
    Publishing date 2019-10-13
    Publishing country us
    Document type Book ; Online
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  7. Article: Variation in the Yaa position of collagen peptides containing azaGlycine

    Melton, Samuel D / David M. Chenoweth

    Chemical communications. 2018 Oct. 18, v. 54, no. 84

    2018  

    Abstract: Herein, we report the systematic investigation of amino acid variation in the Yaa position of collagen peptides containing an adjacent azaGlycine residue. We demonstrate the reliability of azaGlycine as a glycine replacement and provide a sequence ... ...

    Abstract Herein, we report the systematic investigation of amino acid variation in the Yaa position of collagen peptides containing an adjacent azaGlycine residue. We demonstrate the reliability of azaGlycine as a glycine replacement and provide a sequence independent strategy for stabilizing the triple helical assembly of collagen peptides.
    Keywords amino acids ; chemical compounds ; chemical reactions ; collagen ; peptides
    Language English
    Dates of publication 2018-1018
    Size p. 11937-11940.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 1472881-3
    ISSN 1364-548X ; 1359-7345 ; 0009-241X
    ISSN (online) 1364-548X
    ISSN 1359-7345 ; 0009-241X
    DOI 10.1039/c8cc06372a
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  8. Article: Rules for the design of aza-glycine stabilized triple-helical collagen peptides.

    Melton, Samuel D / Brackhahn, Emily A E / Orlin, Samuel J / Jin, Pengfei / Chenoweth, David M

    Chemical science

    2020  Volume 11, Issue 39, Page(s) 10638–10646

    Abstract: The stability of the triple-helical structure of collagen is modulated by a delicate balance of effects including polypeptide backbone geometry, a buried hydrogen bond network, dispersive interfacial interactions, and subtle stereoelectronic effects. ... ...

    Abstract The stability of the triple-helical structure of collagen is modulated by a delicate balance of effects including polypeptide backbone geometry, a buried hydrogen bond network, dispersive interfacial interactions, and subtle stereoelectronic effects. Although the different amino acid propensities for the Xaa and Yaa positions of collagen's repeating (Glycine-Xaa-Yaa) primary structure have been described, our understanding of the impact of incorporating aza-glycine (azGly) residues adjacent to varied Xaa and Yaa position residues has been limited to specific sequences. Here, we detail the impact of variation in the Xaa position adjacent to an azGly residue and compare these results to our study on the impact of the Yaa position. For the first time, we present a set of design rules for azGly-stabilized triple-helical collagen peptides, accounting for all canonical amino acids in the Xaa and Yaa positions adjacent to an azGly residue, and extend these rules using multiple azGly residues. To gain atomic level insight into these new rules we present two high-resolution crystal structures of collagen triple helices, with the first peptoid-containing collagen peptide structure. In conjunction with biophysical and computational data, we highlight the critical importance of preserving the triple helix geometry and protecting the hydrogen bonding network proximal to the azGly residue from solvent. Our results provide a set of design guidelines for azGly-stabilized triple-helical collagen peptides and fundamental insight into collagen structure and stability.
    Language English
    Publishing date 2020-07-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2559110-1
    ISSN 2041-6539 ; 2041-6520
    ISSN (online) 2041-6539
    ISSN 2041-6520
    DOI 10.1039/d0sc03003a
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  9. Article: Incorporation of Aza-Glycine into Collagen Peptides

    Melton, Samuel D / Smith, Mason S / Chenoweth, David M

    Journal of organic chemistry. 2019 Nov. 14, v. 85, no. 3

    2019  

    Abstract: Substitution of natural amino acids with their aza-amino acid counterparts in peptides has been a historically challenging prospect due to the diminished reactivity of the involved reagents. Current methods require lengthy reaction times or difficult ... ...

    Abstract Substitution of natural amino acids with their aza-amino acid counterparts in peptides has been a historically challenging prospect due to the diminished reactivity of the involved reagents. Current methods require lengthy reaction times or difficult synthetic strategies. Aza-glycine has proven to be a valuable tool in the design of triple-helix-forming collagen peptides. Herein, we describe a method for incorporation of aza-glycine in collagen peptides, and we apply the method to the synthesis of collagen peptides containing multiple aza-glycine residues.
    Keywords amino acids ; chemical reactions ; chemical structure ; collagen ; organic chemistry ; organic compounds ; peptides
    Language English
    Dates of publication 2019-1114
    Size p. 1706-1711.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.9b02539
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  10. Article ; Online: Discovering sparse transcription factor codes for cell states and state transitions during development.

    Furchtgott, Leon A / Melton, Samuel / Menon, Vilas / Ramanathan, Sharad

    eLife

    2017  Volume 6

    Abstract: Computational analysis of gene expression to determine both the sequence of lineage choices made by multipotent cells and to identify the genes influencing these decisions is challenging. Here we discover a pattern in the expression levels of a sparse ... ...

    Abstract Computational analysis of gene expression to determine both the sequence of lineage choices made by multipotent cells and to identify the genes influencing these decisions is challenging. Here we discover a pattern in the expression levels of a sparse subset of genes among cell types in B- and T-cell developmental lineages that correlates with developmental topologies. We develop a statistical framework using this pattern to simultaneously infer lineage transitions and the genes that determine these relationships. We use this technique to reconstruct the early hematopoietic and intestinal developmental trees. We extend this framework to analyze single-cell RNA-seq data from early human cortical development, inferring a neocortical-hindbrain split in early progenitor cells and the key genes that could control this lineage decision. Our work allows us to simultaneously infer both the identity and lineage of cell types as well as a small set of key genes whose expression patterns reflect these relationships.
    MeSH term(s) Cell Differentiation ; Cell Lineage ; Computational Biology/methods ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Humans ; Transcription, Genetic
    Language English
    Publishing date 2017-03-15
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.20488
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