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Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1232098


Comprehensive and accurate comparisons of transcriptomic distributions of cells from samples taken from two different biological states, such as healthy versus diseased individuals, are an emerging challenge in single-cell RNA sequencing (scRNA-seq) analysis. Current methods for detecting differentially abundant (DA) subpopulations between samples rely heavily on initial clustering of all cells in both samples. Often, this clustering step is inadequate since the DA subpopulations may not align with a clear cluster structure, and important differences between the two biological states can be missed. Here, we introduce DA-seq, a targeted approach for identifying DA subpopulations not restricted to clusters. DA-seq is a multiscale method that quantifies a local DA measure for each cell, which is computed from its k nearest neighboring cells across a range of k values. Based on this measure, DA-seq delineates contiguous significant DA subpopulations in the transcriptomic space. We apply DA-seq to several scRNA-seq datasets and highlight its improved ability to detect differences between distinct phenotypes in severe versus mildly ill COVID-19 patients, melanomas subjected to immune checkpoint therapy comparing responders to nonresponders, embryonic development at two time points, and young versus aging brain tissue. DA-seq enabled us to detect differences between these phenotypes. Importantly, we find that DA-seq not only recovers the DA cell types as discovered in the original studies but also reveals additional DA subpopulations that were not described before. Analysis of these subpopulations yields biological insights that would otherwise be undetected using conventional computational approaches.

Aging/genetics , COVID-19/genetics , Cell Lineage/genetics , Melanoma/genetics , RNA, Small Cytoplasmic/genetics , Skin Neoplasms/genetics , Aging/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/virology , Brain/cytology , Brain/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Lineage/immunology , Cytokines/genetics , Cytokines/immunology , Datasets as Topic , Dendritic Cells/immunology , Dendritic Cells/virology , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Melanoma/immunology , Melanoma/pathology , Monocytes/immunology , Monocytes/virology , Phenotype , RNA, Small Cytoplasmic/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Single-Cell Analysis/methods , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Transcriptome
Chem Commun (Camb) ; 57(4): 504-507, 2021 Jan 14.
Article in English | MEDLINE | ID: covidwho-983835


A novel STING agonist, CDGSF, ipsilaterally modified with phosphorothioate and fluorine, was synthesized. The phosphorothioate in CDGSF might be a site for covalent conjugation. Injection of CDGSF generated an immunogenic ("hot") tumor microenvironment to suppress melanoma, more efficiently than dithio CDG. In particular, immunization with SARS-CoV-2 spike protein using CDGSF as an adjuvant elicited an exceptionally high antibody titer and a robust T cell response, overcoming the drawbacks of aluminum hydroxide. These results highlighted the therapeutic potential of CDGSF for cancer immunotherapy and the adjuvant potential of the STING agonist in the SARS-CoV-2 vaccine for the first time.

Adjuvants, Immunologic/administration & dosage , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Melanoma, Experimental/drug therapy , Membrane Proteins/agonists , Nucleotides, Cyclic/administration & dosage , Skin Neoplasms/drug therapy , Adjuvants, Immunologic/chemical synthesis , Aluminum Hydroxide/administration & dosage , Aluminum Hydroxide/chemistry , Animals , Antibodies, Viral/biosynthesis , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , B-Lymphocytes/virology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/chemistry , Enzyme-Linked Immunospot Assay , Humans , Immunotherapy/methods , Interferon-gamma/biosynthesis , Melanoma, Experimental/immunology , Melanoma, Experimental/mortality , Melanoma, Experimental/pathology , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Nucleotides, Cyclic/chemical synthesis , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Skin Neoplasms/immunology , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Spike Glycoprotein, Coronavirus/administration & dosage , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Survival Analysis , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Tumor Burden/drug effects , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Vaccination/methods
J Am Acad Dermatol ; 83(2): 703-704, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-92098