High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells

The best-characterized type 1 interferon (IFN) signaling pathway depends on signal transducer and activator of transcription 1 (STAT1) and STAT2. The cytokines can, however, conditionally activate all STATs. Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-γ induction, and NK cells are major producers of this cytokine. We report that NK cells have high basal STAT4 levels and sensitivity to type 1 IFN–mediated STAT4 activation for IFN-γ production. Increases in STAT1, driven during viral infection by either type 1 IFN or IFN-γ, are associated with decreased STAT4 access. Both STAT1 and STAT2 are important for antiviral defense, but STAT1 has a unique role in protecting against sustained NK cell IFN-γ production and resulting disease. The regulation occurs with an NK cell type 1 IFN receptor switch from a STAT4 to a STAT1 association. Thus, a fundamental characteristic of NK cells is high STAT4 bound to the type 1 IFN receptor. The conditions of infection result in STAT1 induction with displacement of STAT4. These studies elucidate the critical role of STAT4 levels in predisposing selection of specific signaling pathways, define the biological importance of regulation within particular cell lineages, and provide mechanistic insights for how this is accomplished in vivo

Pulmonary arterial remodeling induced by a Th2 immune response

Pulmonary arterial remodeling characterized by increased vascular smooth muscle density is a common lesion seen in pulmonary arterial hypertension (PAH), a deadly condition. Clinical correlation studies have suggested an immune pathogenesis of pulmonary arterial remodeling, but experimental proof has been lacking. We show that immunization and prolonged intermittent challenge via the airways with either of two different soluble antigens induced severe muscularization in small- to medium-sized pulmonary arteries. Depletion of CD4+ T cells, antigen-specific T helper type 2 (Th2) response, or the pathogenic Th2 cytokine interleukin 13 significantly ameliorated pulmonary arterial muscularization. The severity of pulmonary arterial muscularization was associated with increased numbers of epithelial cells and macrophages that expressed a smooth muscle cell mitogen, resistin-like molecule α, but surprisingly, there was no correlation with pulmonary hypertension. Our data are the first to provide experimental proof that the adaptive immune response to a soluble antigen is sufficient to cause severe pulmonary arterial muscularization, and support the clinical observations in pediatric patients and in companion animals that muscularization represents one of several injurious events to the pulmonary artery that may collectively contribute to PAH

Biomarkers of Disease and Treatment in Murine and Cynomolgus Models of Chronic Asthma

Background Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. Objective Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. Methods The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. Results Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. Conclusions and clinical relevance These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination

Fostering Persistence in Science, Technology, Engineering, and Mathematics (STEM): Creating an Equitable Environment That Addresses the Needs of Undergraduate Students

Student retention is a critical issue for universities, and nearly half of the students who start degree programs in science, technology, engineering, and mathematics (STEM) do not complete them. The current study tracks the progress of STEM students taking part in an entry-to-graduation program designed to build community, provide academic and social support, and promote engagement in academically purposeful activities. Although it had no effect on the number of students who changed their major, the program more than doubled the number of students who graduated in their original major. Black or Hispanic students taking part in the program also graduated at twice the rate of comparator students, largely attributable to the success of women in these groups. The results provide needed real-world insights into how to create an equitable environment that promotes the persistence and graduation of students, including those from groups historically underrepresented in STEM

Essential Human Virology 1st Edition

Essential Human Virology is written for the undergraduate level with case studies integrated into each chapter. The structure and classification of viruses will be covered, as well as virus transmission and virus replication strategies based upon type of viral nucleic acid. Several chapters will focus on notable and recognizable viruses and the diseases caused by them, including influenza, HIV, hepatitis viruses, poliovirus, herpesviruses, and emerging and dangerous viruses. Additionally, how viruses cause disease, or pathogenesis, will be highlighted during the discussion of each virus family, and a chapter on the immune response to viruses will be included. Further, research laboratory assays and viral diagnosis assays will be discussed, as will vaccines, anti-viral drugs, gene therapy, and the beneficial uses of viruses. By focusing on general virology principles, current and future technologies, familiar human viruses, and the effects of these viruses on humans, this textbook will provide a solid foundation in virology while keeping the interest of undergraduate students. Focuses on the human diseases and cellular pathology that viruses cause Highlights current and cutting-edge technology and associated issues Presents real case studies and current news highlights in each chapter Features dynamic illustrations, chapter assessment questions, key terms, and summary of concepts, as well as an instructor website with lecture slides, test bank, and recommended activitieshttps://digitalcommons.kennesaw.edu/facbooks2016/1026/thumbnail.jp

Interdisciplinary differences in hybrid courses: A study in biology & communication

This study addressed disciplinary differences in hybrid courses using lecture videos to support in-person class discussions. Our results suggested that disciplinary differences existed, students\u27 perceived importance of lecture videos may have had a stronger influence on viewership and audience retention rate than other factors, and procrastination of video consumption correlated with lower exam scores. Building on existing research in hybrid course design, the use of online lectures, and student engagement, our findings suggest that purposeful integration of online videos in the hybrid class should be a consideration of faculty members designing hybrid classes with a heavy reliance on online lectures

MicroRNAs Expressed during Viral Infection: Biomarker Potential and Therapeutic Considerations

MicroRNAs (miRNAs) are short sequences of noncoding single-stranded RNAs that exhibit inhibitory effects on complementary target mRNAs. Recently, it has been discovered that certain viruses express their own miRNAs, while other viruses activate the transcription of cellular miRNAs for their own benefit. This review summarizes the viral and/or cellular miRNAs that are transcribed during infection, with a focus on the biomarker and therapeutic potential of miRNAs (or their antagomirs). Several human viruses of clinical importance are discussed, namely, herpesviruses, polyomaviruses, hepatitis B virus, hepatitis C virus, human papillomavirus, and human immunodeficiency virus

Interleukin-19: a constituent of the regulome that controls antigen presenting cells in the lungs and airway responses to microbial products.

Interleukin (IL)-19 has been reported to enhance chronic inflammatory diseases such as asthma but the in vivo mechanism is incompletely understood. Because IL-19 is produced by and regulates cells of the monocyte lineage, our studies focused on in vivo responses of CD11c positive (CD11c+) alveolar macrophages and lung dendritic cells.IL-19-deficient (IL-19-/-) mice were studied at baseline (naïve) and following intranasal challenge with microbial products, or recombinant cytokines. Naïve IL-19-/- mixed background mice had a decreased percentage of CD11c+ cells in the bronchoalveolar-lavage (BAL) due to the deficiency in IL-19 and a trait inherited from the 129-mouse strain. BAL CD11c+ cells from fully backcrossed IL-19-/- BALB/c or C57BL/6 mice expressed significantly less Major Histocompatibility Complex class II (MHCII) in response to intranasal administration of lipopolysaccharide, Aspergillus antigen, or IL-13, a pro-allergic cytokine. Neurogenic-locus-notch-homolog-protein-2 (Notch2) expression by lung monocytes, the precursors of BAL CD11c+ cells, was dysregulated: extracellular Notch2 was significantly decreased, transmembrane/intracellular Notch2 was significantly increased in IL-19-/- mice relative to wild type. Instillation of recombinant IL-19 increased extracellular Notch2 expression and dendritic cells cultured from bone marrow cells in the presence of IL-19 showed upregulated extracellular Notch2. The CD205 positive subset among the CD11c+ cells was 3-5-fold decreased in the airways and lungs of naïve IL-19-/- mice relative to wild type. Airway inflammation and histological changes in the lungs were ameliorated in IL-19-/- mice challenged with Aspergillus antigen that induces T lymphocyte-dependent allergic inflammation but not in IL-19-/- mice challenged with lipopolysaccharide or IL-13.Because MHCII is the molecular platform that displays peptides to T lymphocytes and Notch2 determines cell fate decisions, our studies suggest that endogenous IL-19 is a constituent of the regulome that controls both processes in vivo