Relationship of the morality of Henry Fielding's novels to their art

Recent studies of Fielding*s work have concentrated on the elucidation of his morality in an attempt to demonstrate that Fielding was not only a comic novelist but also possessed depth and moral earnestness. Prior to this "moralistic" phase of "Fielding" studies, oritics had devoted their attention to the oomic aspects of his art. But each of these approaches is inadequate and limited. The weakness of the first is that Fielding* s novels are made to read like heavily didactic, overtly moralistic sermons rather than complex works of art. Biis is clearly exemplified in Martin Battestin'a book, Ihe Moral Basis of Fielding's Art and, to a oertain extent, in George Sherburn's essay, "Fielding's Amelia; an Interpretation". The second approach has the disadvantage of leaving the impression that Fielding's works are hilarious (perhaps even bawdy) but are completely lacking in depth and serious meaning. Behind these two approaches lies the assumption that there is tension between the "oomio" and the "moralistic" and that the two oannot be blended. A modern critic, Professor Andrew Wrigit, goes so far as to suggest that Fielding had no moral intention and that the atmosphere in his work is festive rather than lenten. Another, Professor Ian Watt, believes that the comedy in some of the scenes alleviates the brutality and forestalls moral condemnation. But the truth must be that the comic and moralistic are interdependent and that Fielding's comedy is part of the technique he evolved for promoting moral judgement

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer