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"Stevens, Jonathan"
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Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes
An analysis of the HLA class I loci in 7,930 tumor samples detects recurrent mutation 'hotspots' in these genes.
Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I
HLA-A, B
and
C
genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these 'hotspot' sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer.
Journal Article
Density functional theory investigation of mechanisms of degradation reactions of sulfonated PEEK membranes with OH radicals in fuel cells: addition–elimination reactions and acid catalyzed water elimination
Sulfonated polyether (ether) ketone or sulfonated PEEK (sPEEK) membranes are one possible candidate for proton-transfer membranes in hydrogen fuel cells. Reaction with hydroxy radicals is expected to be a significant source of degradation of these membranes during fuel cell operation. In this work, the reactivity of the sPEEK polymer molecule with OH radicals is studied by M062X hybrid density functional calculations of the energetics of several reaction paths in a water environment as modeled by polarized continuum model calculations. Reactants, products, encounter minima and transition states are optimized for a reaction pathway in which OH addition is followed by acid-catalyzed water elimination which cationizes the polymer, degradation is expected to follow this reaction as the unstable cation then undergoes bond-breaking or other reactions. Two pathways for this acid-catalyzed cationization, one in which a water molecule plays the role of an additional co-catalyst, are reported. Further calculations explore reaction pathways in which addition of OH to the polymer is followed by bond breaking reactions which would break the polymer chain or the bond between the polymer and sulfonyl groups. Examination of the free energy barriers to all these reactions, relative to reactants, suggests that these direct bond-breaking reactions may compete somewhat with acid-catalyzed water elimination following OH addition.
Journal Article
Integrated Immunopeptidomic and Proteomic Analysis of COVID-19 lung biopsies
Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2.
To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants.
We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades.
Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients.
Journal Article
Density functional theory investigation of mechanisms of degradation reactions of sulfonated PEEK membranes with H radicals in fuel cells: addition–elimination bond-breaking reactions in a model molecule
Polymer electrolyte membrane fuel cells are expected to continue to play a role in the development of alternative energy sources. Sulfonated polyether (ether) ketone, or sulfonated PEEK (sPEEK), membranes are one possible candidate for fuel cell membranes. In this work, the reactivity of the sPEEK polymer molecule with H radicals is studied by M062X hybrid density functional calculations. The energetics of relevant reaction paths were computed in both gas phase and a water environment as modeled by polarized continuum model calculations. Results suggest a simple degradation process in which the addition of H radicals to aromatic rings within the polymer is followed by bond-breaking processes within the polymer chain.
Journal Article
Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
Journal Article
Reversal of viral and epigenetic HLA class I repression in Merkel cell carcinoma
Cancers avoid immune surveillance through an array of mechanisms, including perturbation of HLA class I antigen presentation. Merkel cell carcinoma (MCC) is an aggressive, HLA-I-low, neuroendocrine carcinoma of the skin often caused by the Merkel cell polyomavirus (MCPyV). Through the characterization of 11 newly generated MCC patient-derived cell lines, we identified transcriptional suppression of several class I antigen presentation genes. To systematically identify regulators of HLA-I loss in MCC, we performed parallel, genome-scale, gain- and loss-of-function screens in a patient-derived MCPyV-positive cell line and identified MYCL and the non-canonical Polycomb repressive complex 1.1 (PRC1.1) as HLA-I repressors. We observed physical interaction of MYCL with the MCPyV small T viral antigen, supporting a mechanism of virally mediated HLA-I suppression. We further identify the PRC1.1 component USP7 as a pharmacologic target to restore HLA-I expression in MCC.
Journal Article
Facing Overweight and Obesity: A Guide for Mental Health Professionals
The number of people who are overweight and obese has reached epidemic proportions in the United States. Estimates show that 78% of the adult population is either overweight, obese, or extremely obese. This represents a substantial increase from recent decades. Overwhelming scientific evidence links an increasing body mass index to increasing morbidity and mortality. Although numerous treatments for obesity are available, the cornerstone of treatment is behavioral modification, focusing on diet changes and exercise regimens. Additional therapies include a growing array of medications and surgeries. To improve care for patients who are overweight or obese, mental health providers should have a thorough understanding of overweight and obesity and its treatment to effectively address this topic with their patients. In addition, they must recognize that recidivism and failure to maintain weight loss is quite high, and that successful treatment requires a concerted and sustained effort. [ Psychiatr Ann . 2019;49(2):65–77.]
Journal Article
Idiosyncratic Adverse Reactions to Psychotropic Medications
Idiosyncratic adverse events related to psychotropic medications are prevalent and problematic, and they are the most frequent cause of postmarketing (or black-box) warnings and withdrawals of drugs from the market. This review examines the clinical nature of idiosyncratic adverse events, predictors of their onset, and the role of clinician awareness in avoiding irreversible and serious injury from medications prescribed for psychiatric conditions. Idiosyncratic reactions can be minimized or avoided by knowledge of risk factors, cautious use (or avoidance) of specific agents in subpopulations at risk, informed dose titration, and careful monitoring of clinical response. [ Psychiatr Ann . 2016;46(8):456–465.]
Journal Article
An Analysis of Increased Vertical Scaling in Three-Dimensional Virtual World Simulation
In this paper, we describe the analysis of the effect of vertical computational scaling on the performance of a simulation based training prototype currently under development by the U.S. Army Research Laboratory. The United States military is interested in facilitating Warfighter training by investigating large-scale realistic virtual operational environments. In order to support expanded training at higher echelons, virtual world simulators need to scale to support more simultaneous client connections, more intelligent agents, and more physics interactions. This work provides an in-depth analysis of a virtual world simulator under different hardware profiles to determine the effect of increased vertical computational scaling.
Journal Article