Cohenrobinson9006

62, p = 0.001). Anti-GRP78aa 246-260 concentrations were independent of CRP, IL-6, and TNF-α levels. GRP78 autoantigen expression was upregulated among human aortic endothelial cells (HAECs) stressed by incubation with tunicamycin (an unfolded protein response inducer) or exposure to culture media flow disturbances. Autoantibodies against GRP78aa 246-260, isolated from patient plasma by immunoprecipitation, induced HAEC production of proatherosclerotic mediators, including IL-8. In conclusion, anti-GRP78 autoantibodies are highly associated with carotid atherosclerosis in COPD patients and exert atherogenic effects on HAECs. These data implicate Ag-specific autoimmunity in the pathogenesis of atherosclerosis among COPD patients and raise possibilities that directed autoantibody reduction might ameliorate vascular disease in this high-risk population. Copyright © 2020 The Authors.TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 are normally part of the antiviral defense response, but they have also been implicated as drivers of autoimmune diseases such as lupus. The receptors have slightly different ligand-binding specificities and cellular expression patterns that suggest they have nonredundant specialized roles. How the roles of TLR7 and TLR8 differ may be determined by which cell types express each TLR and how the cells respond to activation of each receptor. To provide a better understanding of the effects of TLR7/8 activation, we have characterized changes induced by TLR-specific agonists in different human immune cell types and defined which responses are a direct consequence of TLR7 or TLR8 activation and which are secondary responses driven by type I IFN or cytokines produced subsequent to the primary response. Using cell sorting, gene expression analysis, and intracellular cytokine staining, we have found that the IFN regulatory factor (IRF) and NF-κB pathways are differentially activated downstream of the TLRs in various cell types. Studies with an anti-IFNAR Ab in human cells and lupus mice showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-κB-regulated genes induced directly by TLR7/8 activation at earlier timepoints. In summary, these results elucidate the different roles TLR7 and TLR8 play in immunity and inform strategies for potential treatment of autoimmune diseases driven by TLR7/8 activation. Copyright © 2020 The Authors.The IL-36 family cytokines have emerged as important mediators of dermal inflammation in psoriasis and have been reported to provide a proinflammatory stimulus to a variety of immune and stromal cell subsets in the inflamed skin. However, it remains to be determined which cell type, if any, in the skin plays a predominant role in mediating IL-36 cytokines instructive role in disease. Here, we demonstrate that targeted deletion of Il36r in keratinocytes results in similar levels of protection from psoriasiform inflammation observed in "global" Il36r-deficient mice. Mice with deficiency in IL-36 receptor expression on keratinocytes had significantly decreased expression, comparable with Il36r-deficient mice, of established mediators of psoriatic inflammation, including, IL-17a, IL-23, IL-22, and a loss of chemokine-induced neutrophil and IL-17A-expressing γδ T-cell subset infiltration to the inflamed skin. These data demonstrate that keratinocytes are the primary orchestrating cell in mediating the effects of IL-36-driven dermal inflammation in the imiquimod model of psoriasiform inflammation and shed new light on the cell-specific roles of IL-36 cytokines during psoriatic disease. © 2020 Hernández-Santana et al.Transcription is common at active mammalian enhancers sometimes giving rise to stable enhancer-associated long intergenic noncoding RNAs (elincRNAs). Expression of elincRNA is associated with changes in neighboring gene product abundance and local chromosomal topology, suggesting that transcription at these loci contributes to gene expression regulation in cis Despite the lack of evidence supporting sequence-dependent functions for most elincRNAs, splicing of these transcripts is unexpectedly common. Whether elincRNA splicing is a mere consequence of cognate enhancer activity or if it directly impacts enhancer function remains unresolved. Here, we investigate the association between elincRNA splicing and enhancer activity in mouse embryonic stem cells. We show that multi-exonic elincRNAs are enriched at conserved enhancers, and the efficient processing of elincRNAs is strongly associated with their cognate enhancer activity. This association is supported by their enrichment in enhancer-specific chromatin signatures; elevated binding of co-transcriptional regulators; increased local intra-chromosomal DNA contacts; and strengthened cis-regulation on target gene expression. Our results support the role of efficient RNA processing of enhancer-associated transcripts to cognate enhancer activity. © 2020 Tan et al.Glycolysis was downregulated in normal but not transformed cells upon transfer to softer substrates. ©2020 American Association for Cancer Research.A lentiviral-barcoding approach using mouse embryonic cells allows driver-mutation identification. ©2020 American Association for Cancer Research.Having shown preclinical promise, the first clinical data are now in on natural killer cells equipped with a chimeric antigen receptor targeting CD19. Albeit in a small number of patients so far, the experimental immunotherapy has elicited a high response rate with little to no toxicity. ©2020 American Association for Cancer Research.Metastatic cells were remniscient of earlier developmental stages than primary tumor cells. ©2020 American Association for Cancer Research.Antibody-peptide epitope conjugates (APEC) can reprogram surface antigenicity of tumor cells. ©2020 American Association for Cancer Research.Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant. SIGNIFICANCE Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse. ©2020 American Association for Cancer Research.Many fungal pathogens have short generation times, large population sizes, and mixed reproductive systems providing high potential to adapt to heterogeneous environments of agroecosystems. Such adaptation complicates disease management and threatens food production. Better understanding of pathogen population biology in such environments is important to reveal key aspects of adaptive divergence processes to allow improved disease management. Here, we studied how evolutionary forces shape population structure of Botrytis cinerea, the causal agent of gray mold, in the Pacific Northwest agroecosystems. Populations of B. cinerea from adjacent fields of small fruit hosts were characterized by combining neutral markers (microsatellites) with markers that directly respond to human-induced selection pressures (fungicide resistance). Populations were diverse, without evidence for recombination and association of pathogen genotype with host. Populations were highly localized with limited migration even among adjacent fionary forces shape populations of one of the most important fungal plant pathogens, B. cinerea, in small fruit agroecosystems of the Pacific Northwest. We hypothesized that host, geographic, and anthropogenic factors of agroecosystems structure B. cinerea populations. By combining neutral markers with markers that directly respond to human-induced selection pressures, we show that pathogen populations are highly localized, and that selection pressure caused by fungicide use can have a greater effect on population structure than adaptation to host. Our results give a better understanding of population biology and evolution of this important plant pathogen in heterogeneous environments, but also provide a practical framework for the development of efficient management strategies by limiting pathogen adaptation to fungicides and other human-induced selection pressures present in agroecosystems of the Pacific Northwest and elsewhere. Copyright © 2020 American Society for Microbiology.Atmospheric cold plasma (ACP) treatment is an emerging food technology for product safety and quality retention, shelf-life extension and sustainable processing. The activated chemical species of ACP can act rapidly against microorganisms without leaving chemical residues on food surfaces. The main objective of this study was to investigate the efficiency and mechanisms of inactivation of fungal spores and biofilms by ACP and to understand the effects of gas-mediated versus liquid-mediated mode of application against important fungal contaminants. Aspergillus flavus was selected as the model microorganism. A. flavus spores were exposed to either gas plasma (GP) or plasma activated water (PAW), whereas gas plasma alone was used to treat A. flavus biofilms. This study demonstrated that both GP and PAW treatment independently resulted in a significant decrease of A. flavus metabolic activity and spore counts with maximal reductions of 2.2 and 0.6 log10 units for GP and PAW, respectively. The characterization of ociety for Microbiology.Ammonia monooxygenase (AMO) is a key nitrogen transforming enzyme belonging to the same copper-dependent membrane monooxygenase family (CuMMO) as the particulate methane monooxygenase (pMMO). The AMO from ammonia oxidising archaea (AOA) is very divergent from both the AMO of ammonia oxidising bacteria (AOB) and the pMMO from methanotrophs and little is known about the structure or substrate range of the archaeal AMO. This study compares inhibition by C2-C8 linear 1-alkynes of AMO from two phylogenetically distinct strains of AOA, "Candidatus Nitrosocosmicus franklandus" C13 and "Candidatus Nitrosotalea sinensis" Nd2, with AMO from Nitrosomonas europaea and pMMO from Methylococcus capsulatus (Bath). An increased sensitivity of the archaeal AMO to short-chain-length alkynes (≤C5) appeared to be conserved across AOA lineages. Similarities in C2-C8 alkyne inhibition profiles between AMO from AOA and pMMO from M. capsulatus suggested that the archaeal AMO has a narrower substrate range compared to that of N. europaea AMO.