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INTRODUCTION: The human orthopneumovirus, Respiratory Syncytial Virus (RSV), is the causative agent of severe lower respiratory tract infections (LRTI) and exacerbations of chronic lung diseases. In immune competent hosts, RSV productively infects highly differentiated epithelial cells, where it elicits robust anti-viral, cytokine and remodeling programs. By contrast, basal cells are relatively resistant to RSV infection, in part, because of constitutive expression of an intrinsic innate immune response (IIR) consisting of a subgroup of interferon (IFN) responsive genes...

The Clinical and Translational Science Awards (CTSA) Program supports a national network of medical research institutions working to improve the translational process. High-performing translational teams (TTs) are critical for advancing evidence-based approaches that improve human health. When focused on content-appropriate knowledge, skills, and attitudes, targeted training results in the substantial internalization of training content, producing new skills that can be applied to improve team outputs, outcomes, and benefits...

Despite understanding its impact on organizational effectiveness, practical guidance on how to train translational team (TT) leaders is lacking. Previously, we developed an evolutionary learning model of TT maturation consisting of three goal-directed phases: (1). team assembly ( Formation ); (2). conducting research ( Knowledge Generation ); and (3). dissemination and implementation ( Translation ). At each phase, the team acquires group-level knowledge, skills, and attitudes (KSAs) that enhance its performance...

Recent advances have uncovered the non-random distribution of 7, 8-dihydro-8-oxoguanine (8-oxoGua) induced by reactive oxygen species, which is believed to have epigenetic effects. Its cognate repair protein, 8-oxoguanine DNA glycosylase 1 (OGG1), reads oxidative substrates and participates in transcriptional initiation. When redox signaling is activated in small airway epithelial cells, the DNA repair function of OGG1 is repurposed to transmit acute inflammatory signals accompanied by cell state transitions and modification of the extracellular matrix...

Interferons (IFNs) are secreted cytokines with the ability to activate expression of IFN stimulated genes that increase resistance of cells to virus infections. Activated transcription factors in conjunction with chromatin remodelers induce epigenetic changes that reprogram IFN responses. Unexpectedly, 8-oxoguanine DNA glycosylase1 (Ogg1) knockout mice show enhanced stimuli-driven IFN expression that confers increased resistance to viral and bacterial infections and allergen challenges. Here, we tested the hypothesis that the DNA repair protein OGG1 recognizes 8-oxoguanine (8-oxoGua) in promoters modulating IFN expression...

INTRODUCTION: The unfolded protein response (UPR) has emerged as an important signaling pathway mediating anti-viral defenses to Respiratory Syncytial Virus (RSV) infection. Earlier we found that RSV replication predominantly activates the evolutionarily conserved Inositol Requiring Enzyme 1α (IRE1α)-X-Box Binding Protein 1 spliced (XBP1s) arm of the Unfolded Protein Response (UPR) producing inflammation, metabolic adaptation and cellular plasticity, yet the mechanisms how the UPR potentiates inflammation are not well understood...

Innate immune responses (IIR) of the epithelium play a critical role in the initiation and progression of asthma. The core of the IIR is an intracellular signaling pathway activated by pattern recognition receptors (PRRs) to limit the spread of infectious organisms. This chapter will focus on the epithelium as the major innate sentinel cell and its role in acute exacerbations (AEs). Although the pathways of how the IIR activates the NFκB transcription factor, triggering cytokine secretion, dendritic cell activation, and Th2 polarization are well-described, recent exciting work has developed mechanistic insights into how chronic activation of the IIR is linked to mucosal adaptive responses...

INTRODUCTION: Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In the context of airway viral infection, BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream epithelial plasticity. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not well understood...

Successful translation involves the coupled application of knowledge - generating research with product development to advance a device, drug, diagnostic, or evidence-based intervention for clinical adoption to improve human health. Critical to the success of the CTSA consortium, translation can be more effectively accomplished by training approaches that focus on improving team-emergent knowledge skills and attitudes (KSAs) linked to performance. We earlier identified 15 specific evidence-informed, team-emergent competencies that facilitate translational team (TT) performance...

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INTRODUCTION: This study describes a needs assessment of clinical and translational research (CTR) scientists at a large, distributed, School of Medicine within a public university and affiliated clinics. METHOD: We performed an Exploratory Conversion Mixed-Methods analysis using a quantitative survey and qualitative interviews with CTR scientists across the training continuum, from early-career scholars, mid-career mentors, and senior administrators at the University of Wisconsin and Marshfield Clinics...

A translational team (TT) is a specific type of interdisciplinary team that seeks to improve human health. Because high-performing TTs are critical to accomplishing CTSA goals, a greater understanding of how to promote TT performance is needed. Previous work by a CTSA Workgroup formulated a taxonomy of 5 interrelated team-emergent competency "domains" for successful translation: 1). affect, 2). communication, 3). management, 4). collaborative problem-solving, and 5). leadership. These Knowledge Skills and Attitudes (KSAs) develop within teams from the team's interactions...

Epithelial mesenchymal plasticity (EMP) is a complex cellular reprogramming event that plays a major role in tissue homeostasis. Recently we observed the unfolded protein response (UPR) triggers EMP through the inositol-requiring protein 1 (IRE1α)-X-box-binding protein 1 spliced (XBP1s) axis, enhancing glucose shunting to protein N glycosylation. To better understand the genomic targets of XBP1s, we identified its genomic targets using Cleavage Under Targets and Release Using Nuclease (CUT&RUN) of a FLAG-epitope tagged XBP1s in RSV infection...

Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood. Based on its interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing...

RNA viruses are responsible for substantial morbidity and health burden [...].

Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells...

No abstract text is available yet for this article.

Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and secretion of the extracellular matrix (ECM). Because the presence of matrix metalloproteinases and matricellular growth factors (TGF) is associated with severe LRTI, we studied the effect of RSV on ECM remodeling and found that RSV enhances the deposition of fibronectin-rich ECM by small airway epithelial cells in a manner highly dependent on the inositol requiring kinase (IRE1α)-XBP1 arm of the UPR...

Respiratory syncytial virus (RSV), or human orthopneumovirus, is a negative-sense RNA virus that is the causative agent of severe lower respiratory tract infections in children and is associated with exacerbations of adult lung disease. The mechanisms how severe and/or repetitive virus infections cause declines in pulmonary capacity are not fully understood. We have recently discovered that viral replication triggers epithelial plasticity and metabolic reprogramming involving the hexosamine biosynthetic pathway (HBP)...

Idiopathic pulmonary fibrosis is a lethal disease driven by myofibroblast expansion. Currently no therapies exist that target the epigenetic mechanisms controlling myofibroblast transdifferentiation, which is responsible for unregulated extracellular matrix (ECM) production. We have recently shown that bromodomain-containing protein 4 (BRD4), an epigenetic regulator that forms a scaffold for nuclear activators and transcription factors, is essential for TGFβ-induced myofibroblast transdifferentiation. However, its role in the development and progression of pulmonary fibrosis in vivo has not been established...