ABSTRACT
Signal transduction proteins containing a pLxIS motif induce interferon (IFN) responses central to antiviral immunity. Apart from their established roles in activating the IFN regulator factor (IRF) transcription factors, the existence of additional pathways and functions associated with the pLxIS motif is unknown. Using a synthetic biology-based platform, we identified two orphan pLxIS-containing proteins that stimulate IFN responses independent of all known pattern-recognition receptor pathways. We further uncovered a diversity of pLxIS signaling mechanisms, where the pLxIS motif represents one component of a multi-motif signaling entity, which has variable functions in activating IRF3, the TRAF6 ubiquitin ligase, IκB kinases, mitogen-activated protein kinases, and metabolic activities. The most diverse pLxIS signaling mechanisms were associated with the highest antiviral activities in human cells. The flexibility of domains that regulate IFN signaling may explain their prevalence in nature.
Subject(s)
Interferon Regulatory Factor-3 , Interferons , Signal Transduction , TNF Receptor-Associated Factor 6 , Humans , Interferons/metabolism , HEK293 Cells , Interferon Regulatory Factor-3/metabolism , Interferon Regulatory Factor-3/genetics , TNF Receptor-Associated Factor 6/metabolism , TNF Receptor-Associated Factor 6/genetics , I-kappa B Kinase/metabolism , I-kappa B Kinase/genetics , Protein Domains , Animals , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Amino Acid Motifs , Mitogen-Activated Protein Kinases/metabolismABSTRACT
The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is â¼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.
Subject(s)
Glycerol-3-Phosphate Dehydrogenase (NAD+) , Kidney Neoplasms , Lipids , Humans , Glycerol/metabolism , Glycerol-3-Phosphate Dehydrogenase (NAD+)/genetics , Glycerol-3-Phosphate Dehydrogenase (NAD+)/metabolism , Glycerolphosphate Dehydrogenase/genetics , Glycerolphosphate Dehydrogenase/metabolism , Kidney Neoplasms/genetics , Kidney Neoplasms/metabolism , Lipids/biosynthesis , NAD/metabolism , Oxidation-Reduction , Phosphates/metabolismABSTRACT
OBJECTIVE: To elicit feedback on the acceptability, usability, and dissemination options for the bMOREsafe smartphone application (app). Participants: Forty-nine students and six service-providers provided feedback on the bMOREsafe app between April 2015 and March 2016. Methods: Students responded to an anonymous online survey and providers participated in semi-structured interviews. Descriptive and thematic analyses were completed. Results: Students rated the app as useful, however less applicable to themselves and their peers. Students stated they would be most receptive to recommendations about the app from peers and social media. Qualitative data from service providers fell into three main categories: trauma-informed aspects; inclusivity vs. specificity; and within an app, language matters. Conclusions: Smartphone technology can provide confidential information and resources to help students make decisions related to sexual assault or intimate partner violence care. While students and providers identified apps as a useful strategy for sharing this information, dissemination challenges remain.
Subject(s)
Intimate Partner Violence , Mobile Applications , Humans , Smartphone , Students , Universities , ViolenceSubject(s)
Dental Instruments/history , Dentistry/trends , Forecasting , History, 20th Century , Humans , Oral HygieneABSTRACT
OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.