773 research outputs found

    Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding Kinase 1 (TBK1) to Restrain STAT3 Activity

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    Cytosolic DNA can elicit beneficial as well as undesirable immune responses. For example, viral or microbial DNA triggers cell-intrinsic immune responses to defend against infections, whereas aberrant cytosolic accumulation of self-DNA results in pathological conditions, such as autoimmunity. Given the importance of these DNA-provoked responses, a better understanding of their molecular mechanisms is needed. Cytosolic DNA engages stimulator of interferon genes (STING) to activate TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor interferon regulatory factor 3 (IRF3) to promote interferon expression. Recent studies have reported that additional transcription factors, including nuclear factor κB (NF-κB) and signal transducer and activator of transcription 6 (STAT6), are also activated by cytosolic DNA, suggesting that cytosolic DNA-induced gene expression is orchestrated by multiple factors. Here we show that cytosolic DNA activates STAT3, another member of the STAT family, via an autocrine mechanism involving interferon β (IFNβ) and IL-6. Additionally, we observed a novel cytosolic DNA-induced phosphorylation at serine 754 in the transactivation domain of STAT3. Upon cytosolic DNA stimulation, Ser 754 is directly phosphorylated by TBK1 in a STING-dependent manner. Moreover, Ser 754 phosphorylation inhibits cytosolic DNA-induced STAT3 transcriptional activity and selectively reduces STAT3 target genes that are up-regulated in response to cytosolic DNA. Taken together, our results suggest that cytosolic DNA-induced STAT3 activation via IFNβ and IL-6 is restrained by Ser 754 phosphorylation of STAT3. Our findings reveal a new signaling axis downstream of the cytosolic DNA pathway and suggest potential interactions between innate immune responses and STAT3-driven oncogenic pathways

    An Overview of 2014 SBIR Phase I and Phase II Materials Structures for Extreme Environments

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    NASA's Small Business Innovation Research (SBIR) program focuses on technological innovation by investing in development of innovative concepts and technologies to help NASA mission directorates address critical research needs for Agency programs. This report highlights nine of the innovative SBIR 2014 Phase I and Phase II projects that emphasize one of NASA Glenn Research Center's six core competencies-Materials and Structures for Extreme Environments. The technologies cover a wide spectrum of applications such as high temperature environmental barrier coating systems, deployable space structures, solid oxide fuel cells, and self-lubricating hard coatings for extreme temperatures. Each featured technology describes an innovation, technical objective, and highlights NASA commercial and industrial applications. This report provides an opportunity for NASA engineers, researchers, and program managers to learn how NASA SBIR technologies could help their programs and projects, and lead to collaborations and partnerships between the small SBIR companies and NASA that would benefit both

    An Overview of 2014 SBIR Phase 1 and Phase 2 Communications Technology and Development

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    NASA's Small Business Innovation Research (SBIR) program focuses on technological innovation by investing in development of innovative concepts and technologies to help NASA mission directorates address critical research needs for Agency programs. This report highlights eight of the innovative SBIR 2014 Phase I and Phase II projects that emphasize one of NASA Glenn Research Center's six core competencies-Communication Technology and Development. The technologies cover a wide spectrum of applications such as X-ray navigation, microsensor instrument for unmanned aerial vehicle airborne atmospheric measurements, 16-element graphene-based phased array antenna system, interferometric star tracker, ultralow power fast-response sensor, and integrated spacecraft navigation and communication. Each featured technology describes an innovation, technical objective, and highlights NASA commercial and industrial applications. This report provides an opportunity for NASA engineers, researchers, and program managers to learn how NASA SBIR technologies could help their programs and projects, and lead to collaborations and partnerships between the small SBIR companies and NASA that would benefit both

    An Overview of 2014 SBIR Phase 1 and Phase 2 Air-Breathing Propulsion

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    NASA's Small Business Innovation Research (SBIR) program focuses on technological innovation by investing in development of innovative concepts and technologies to help NASA mission directorates address critical research needs for Agency programs. This report highlights nine of the innovative SBIR 2014 Phase I and Phase II projects that emphasize one of NASA Glenn Research Center's six core competencies-Air-Breathing Propulsion. The technologies cover a wide spectrum of applications such as development of X-ray computed tomography (CT) imaging method for the measurement of complex 3D ice shapes, phased array techniques for low signal-to-noise ratio wind tunnels, compact kinetic mechanisms for petroleum-derived and alternative aviation fuels, and hybrid electric propulsion systems for a multirotor aircraft. Each featured technology describes an innovation, technical objective, and highlights NASA commercial and industrial applications. This report provides as an opportunity for NASA engineers, researchers, and program managers to learn how NASA SBIR technologies could help their programs and projects, and lead to collaborations and partnerships between the small SBIR companies and NASA that would benefit both

    Funding and Strategic Alignment Guidance for Infusing Small Business Innovation Research Technology Into Aeronautics Research Mission Directorate Projects at NASA Glenn Research Center for 2015

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    This document is intended to enable the more effective transition of NASA Glenn Research Center (GRC) SBIR technologies funded by the Small Business Innovation Research (SBIR) program as well as its companion, the Small Business Technology Transfer (STTR) program into NASA Aeronautics Research Mission Directorate (ARMD) projects. Primarily, it is intended to help NASA program and project managers find useful technologies that have undergone extensive research and development (RRD), through Phase II of the SBIR program; however, it can also assist non-NASA agencies and commercial companies in this process. aviation safety, unmanned aircraft, ground and flight test technique, low emissions, quiet performance, rotorcraf

    Minority stress, resilience, and health in Italian and Taiwanese LGB+ people : a cross-cultural comparison

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    The present study, using a moderated mediational model, explored levels of distal/proximal stressors, rumination, resilience, and health in a group of Italian and Taiwanese LGB+ people. The study also examined the role of internalized sexual stigma (ISS) and rumination as mediators between discrimination and health, and resilience as a moderator of the relationship between discrimination and ISS, rumination, and health, respectively. An online survey was administered to 508 LGB+ participants (270 Italian and 238 Taiwanese) whose age ranged from 18 to 70 years (M = 37.93, SD = 13.53). The moderated mediation model was tested through a series of path analyses stratified by group nationality. Italian participants reported higher discrimination and resilience, but lower ISS, rumination, and health problems compared to their Taiwanese counterparts. The only common path between groups was the direct effect of discrimination on health problems. The mediating role of ISS and rumination in the relationship between discrimination and health, as well as the moderating role of resilience, were partly significant only for the Italian group. Conclusions: The findings suggest that mediators and moderators used to evaluate the effects of minority stress on health may differ between groups; further culturally sensitive research in the field of LGB+ health is needed

    Identifying gene network patterns and associated cellular immune responses in children with or without nut allergy

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    Background: Although evidence suggests that the immune system plays a key role in the pathophysiology of nut allergy, the precise immunological mechanisms of nut allergy have not been systematically investigated. The aim of the present study was to identify gene network patterns and associated cellular immune responses in children with or without nut allergy. Methods: Transcriptome profiling of whole blood cells was compared between children with and without nut allergy. Three genes were selected to be validated on a larger cohort of samples (n = 86) by reverse transcription-polymerase chain reactions (RT-qPCR). The composition of immune cells was inferred from the transcriptomic data using the CIBERSORTx algorithm. A co-expression network was constructed employing weighted gene co-expression network analysis (WGCNA) on the top 5000 most variable transcripts. The modules were interrogated with pathway analysis tools (InnateDB) and correlated with clinical phenotypes and cellular immune responses. Results: Proportions of neutrophils were positively correlated and CD4+ T-cells and regulatory T-cells (Tregs) were negatively correlated with modules of nut allergy. We also identified 2 upregulated genes, namely Interferon Induced With Helicase C Domain 1 (IFIH1), DNA damage-regulated autophagy modulator 1 (DRAM1) and a downregulated gene Zinc Finger Protein 512B (ZNF512B) as hub genes for nut allergy. Further pathway analysis showed enrichment of type 1 interferon signalling in nut allergy. Conclusions: Our findings suggest that upregulation of type 1 interferon signalling and neutrophil responses and downregulation of CD4+ T-cells and Tregs are features of the pathogenesis of nut allergy

    Antipsychotic Prescribing Pathways, Polypharmacy, and Clozapine Use in Treatment of Schizophrenia

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    Objective To ensure optimal care for patients with schizophrenia, antipsychotic medications must be appropriately prescribed and used. Therefore, the primary objectives of this study were to identify and describe pathways for antipsychotic prescribing, assess the consistency of observed pathways with treatment guidelines, and describe variability across facilities. Methods Data from Veterans Affairs administrative data sets from fiscal year (FY) 2003 to FY 2007 were gathered for analysis in this retrospective cohort study of antipsychotic prescribing pathways among 13 facilities across two regional networks. Patients with a new episode of care for schizophrenia or schizoaffective disorder in FY 2005 were identified, and antipsychotic prescribing history was obtained for two years before and after the index diagnosis. Demographic characteristics and distribution of comorbidities were assessed. Median medical center rates of polypharmacy were calculated and compared with Fisher’s exact test. Results Of 1,923 patients with a new episode of schizophrenia care, 1,003 (52%) had complete data on prescribing pathways. A majority (74%) of patients were prescribed antipsychotic monotherapy, and 19% received antipsychotic polypharmacy. Of patients receiving antipsychotic polypharmacy, 65% began polypharmacy within 90 days of starting any antipsychotic treatment. There was a fourfold difference in polypharmacy across facilities. Antipsychotic polypharmacy was not associated with geographic location or medical center patient volume. Clozapine utilization was low (0%–2%). Conclusions Retrospective examination of longitudinal prescribing patterns identified multiple antipsychotic prescribing pathways. Although most patients received guideline-concordant care, antipsychotic polypharmacy was commonly used as initial treatment, and there was substantial variability among facilities. Study findings suggest the utility of secondary data to assess treatment adaptation or switching for practical clinical trials
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