6 results on '"Jack P. Dodson"'
Search Results
2. Data from Single-Cell Analysis in Lung Adenocarcinoma Implicates RNA Editing in Cancer Innate Immunity and Patient Prognosis
- Author
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Xinshu Xiao, Paul C. Boutros, Jaron Arbet, Jack P. Dodson, and Tracey W. Chan
- Abstract
RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis.Significance:RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival.See related commentary by Luo and Liang, p. 351
- Published
- 2023
3. Single-cell analysis in lung adenocarcinoma implicates RNA editing in cancer innate immunity and patient prognosis
- Author
-
Tracey W. Chan, Jack P. Dodson, Jaron Arbet, Paul C. Boutros, and Xinshu Xiao
- Subjects
Cancer Research ,Oncology - Abstract
RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis. Significance: RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival. See related commentary by Luo and Liang, p. 351
- Published
- 2022
4. The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition
- Author
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Joshua M. Lensmire, Elliot Ensink, Michael R. Wischer, Martha H. Mulks, Lo M. Sosinski, Neal D. Hammer, Jack P. Dodson, Sophia Y. Lunt, Daniel H. Havlichek, John C. Shook, Christopher C Cooper, Janani Ravi, and Phillip C. Delekta
- Subjects
chemistry.chemical_classification ,biology ,Operon ,chemistry.chemical_element ,Human pathogen ,Transporter ,Glutathione ,medicine.disease_cause ,biology.organism_classification ,Sulfur ,chemistry.chemical_compound ,Enzyme ,chemistry ,Biochemistry ,Staphylococcus aureus ,Staphylococcus epidermidis ,medicine - Abstract
Sulfur is an indispensable element for proliferation of bacterial pathogens. Prior studies indicated that the human pathogen, Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a previously uncharacterized five-gene locus comprising a putative ABC-transporter and γ–glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter the Glutathione import system (GisABCD). We confirm that Ggt is capable of cleaving GSH and GSSG γ–bonds and that this process is required for their use as nutrient sulfur sources. Additionally, we find that the enzyme is cell associated. Bioinformatic analyses reveal that only Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologues. Homologues are not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSH and promotes competition against other staphylococci commonly associated with the human microbiota.
- Published
- 2021
5. Benchmarking of a Bayesian single cell RNAseq differential gene expression test for dose-response study designs
- Author
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Timothy R. Zacharewski, Sudin Bhattacharya, Satabdi Saha, Tapabrata Maiti, Rance Nault, Jack P. Dodson, and Samiran Sinha
- Subjects
Computer science ,business.industry ,Clinical study design ,Bayesian probability ,Gene Expression ,Experimental data ,Bayes Theorem ,Benchmarking ,Test method ,Machine learning ,computer.software_genre ,Test (assessment) ,Research Design ,Frequentist inference ,Genetics ,Benchmark (computing) ,Artificial intelligence ,business ,computer - Abstract
The application of single-cell RNA sequencing (scRNAseq) for the evaluation of chemicals, drugs, and food contaminants presents the opportunity to consider cellular heterogeneity in pharmacological and toxicological responses. Current differential gene expression analysis (DGEA) methods focus primarily on two group comparisons, not multi-group dose–response study designs used in safety assessments. To benchmark DGEA methods for dose–response scRNAseq experiments, we proposed a multiplicity corrected Bayesian testing approach and compare it against 8 other methods including two frequentist fit-for-purpose tests using simulated and experimental data. Our Bayesian test method outperformed all other tests for a broad range of accuracy metrics including control of false positive error rates. Most notable, the fit-for-purpose and standard multiple group DGEA methods were superior to the two group scRNAseq methods for dose–response study designs. Collectively, our benchmarking of DGEA methods demonstrates the importance in considering study design when determining the most appropriate test methods.
- Published
- 2021
6. The Staphylococcus aureus Cystine Transporters TcyABC and TcyP Facilitate Nutrient Sulfur Acquisition during Infection
- Author
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Michael R. Wischer, Phillip C. Delekta, Neal D. Hammer, Joshua M. Lensmire, Janani Ravi, Brian Hsueh, Paige J. Kies, Jack P. Dodson, John C. Shook, and Elizabeth N. Ottosen
- Subjects
Staphylococcus aureus ,Immunology ,Cystine ,chemistry.chemical_element ,Bacillus subtilis ,medicine.disease_cause ,Microbiology ,chemistry.chemical_compound ,Mice ,Extracellular ,medicine ,Animals ,biology ,Membrane Transport Proteins ,Glutathione ,Staphylococcal Infections ,biology.organism_classification ,Sulfur ,Molecular Pathogenesis ,Chemically defined medium ,Infectious Diseases ,chemistry ,Parasitology ,Cysteine - Abstract
Staphylococcus aureus is a significant human pathogen due to its capacity to cause a multitude of diseases. As such, S. aureus efficiently pillages vital nutrients from the host; however, the molecular mechanisms that support sulfur acquisition during infection have not been established. One of the most abundant extracellular sulfur-containing metabolites within the host is cysteine, which acts as the major redox buffer in the blood by transitioning between reduced and oxidized (cystine) forms. We therefore hypothesized that S. aureus acquires host-derived cysteine and cystine as sources of nutrient sulfur during systemic infection. To test this hypothesis, we used the toxic cystine analogue selenocystine to initially characterize S. aureus homologues of the Bacillus subtilis cystine transporters TcyABC and TcyP. We found that genetic inactivation of both TcyA and TcyP induced selenocystine resistance. The double mutant also failed to proliferate in medium supplemented with cystine, cysteine, or N-acetyl cysteine as the sole sulfur source. However, only TcyABC was necessary for proliferation in defined medium containing homocystine as the sulfur source. Using a murine model of systemic infection, we observed tcyP-dependent competitive defects in the liver and heart, indicating that this sulfur acquisition strategy supports proliferation of S. aureus in these organs. Phylogenetic analyses identified TcyP homologues in many pathogenic species, implying that this sulfur procurement strategy is conserved. In total, this study is the first to experimentally validate sulfur acquisition systems in S. aureus and establish their importance during pathogenesis.
- Published
- 2020
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