| 1. |
- Dunne, Aisling, et al.
(författare)
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Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88
- 2003
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Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 278:42, s. 41443-41451
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Tidskriftsartikel (refereegranskat)abstract
- The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.
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| 2. |
- Glantz, H, et al.
(författare)
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Occurrence and predictors of obstructive sleep apnea in a revascularized coronary artery disease cohort
- 2013
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Ingår i: Annals of the American Thoracic Society. - : American Thoracic Society. - 2329-6933 .- 2325-6621. ; 10:4, s. 350-356
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Tidskriftsartikel (refereegranskat)abstract
- Background: Knowledge about the prevalence of obstructive sleep apnea (OSA) in coronary artery disease (CAD) is insufficient. The aim of the current report was to evaluate the occurrence and predictors of OSA among revascularized patients with CAD within the framework of a randomized controlled trial (Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnea [RICCADSA]), evaluating the impact of continuous positive airway pressure on cardiovascular outcomes in CAD patients with OSA. Material and Methods: All patients undergoing percutaneous coronary intervention or coronary artery bypass grafting between September 2005 and November 2010 (n = 1,291) were invited to participate. Anthropometrics and medical history were obtained, ambulatory sleep recording was performed, and all subjects completed the Epworth Sleepiness Scale (ESS) questionnaire. Results: In total, 662 patients participated in the sleep study. OSA, defined as an apnea–hypopnea index equal to or greater than 15/hour, was found among 422 (63.7%). The prevalence of hypertension was 55.9%; obesity (body mass index ≥ 30 kg/m2), 25.2%; diabetes mellitus, 22.1%; and current smoking, 18.9%. The patients with CAD who did not participate in the study demonstrated an almost similar anthropometric and clinical profile compared with the studied group. The majority (61.8%) of the patients with OSA were nonsleepy (ESS score < 10). Patients with OSA had a higher prevalence of obesity, hypertension, diabetes mellitus, and history of atrial fibrillation, whereas current smoking was more common in the non-OSA group. Age, male sex, body mass index, and ESS score, but not comorbidities, were independent predictors of OSA. Conclusions: The occurrence of unrecognized OSA in this revascularized CAD cohort was higher than previously reported. We suggest that OSA should be considered in the secondary prevention protocols in CAD. Read More: http://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201211-106OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&
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| 3. |
- Hardy, Matthew P., et al.
(författare)
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Characterization of the type I interferon locus and identification of novel genes
- 2004
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Ingår i: Genomics. - : Elsevier. - 0888-7543 .- 1089-8646. ; 84:2, s. 331-345
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Tidskriftsartikel (refereegranskat)abstract
- The human type I interferon (IFN) genes are clustered on human chromosome 9p21 and the mouse genes are located in the region of conserved synteny on mouse chromosome 4. We have identified two novel mouse Ifna genes (Ifna12, Ifna13) and Ifnl2 (IFN-like 2, a homologue of Limitin/IFN-like 1). Another type I IFN gene was designated Ifne1. Mouse Ifne1 was expressed in ovaries and uterus but not in tissues of hematopoietic origin. IFN-epsilon1 has general structural characteristics of a type I IFN. These studies represent the first detailed annotation of the mouse type I IFN locus, and the products of these novel genes may have important functions in reproduction and host defense.
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| 4. |
- Herlitz, Johan, et al.
(författare)
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Göteborg Metoprolol Trial : electrocardiographically estimated infarct size
- 1984
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Ingår i: American Journal of Cardiology. - : Elsevier. - 0002-9149 .- 1879-1913. ; 53:13, s. 22-26
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Tidskriftsartikel (refereegranskat)abstract
- In 236 patients with anterior myocardial infarction (MI), infarct size was estimated by analyzing the R- and Q-wave amplitude in 24 precordial leads 4 days after randomization. In 254 patients with inferior MI, the final R- and Q-wave amplitude was evaluated in leads II, III and aVF. Electrocardiographic signs of a smaller MI were observed in anterior MI in the metoprolol group compared with the placebo group when treatment was started 12 hours or less after the onset of pain, but no difference was found when treatment was started later. There was no sign of an effect of metoprolol in inferior MI. An immediate reduction in ST-segment elevation was observed after metoprolol treatment regardless of infarct localization or delay between the onset of pain and treatment.
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| 5. |
- O'Neill, Luke A. J., et al.
(författare)
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Mal and MyD88 : adapter proteins involved in signal transduction by Toll-like receptors
- 2003
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Ingår i: Journal of Endotoxin Research. - : Maney Publishing. - 0968-0519 .- 1743-2839. ; 9:1, s. 55-59
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Tidskriftsartikel (refereegranskat)abstract
- Signal transduction processes activated by Toll-like receptors (TLRs) include the important transcription factor NF-kappaB and 2 MAP kinases, p38 and Jun N-terminal kinase. These signals ultimately give rise to increased expression of a multitude of pro-inflammatory proteins. Receptor-proximal proteins involved in signalling by all TLRs include the adapter MyD88, 3 IRAKs (IRAK-4, IRAK and IRAK-2), Tollip, Traf-6 and TAK-1. Differences between signals generated by TLRs are emerging, with both TLR4 and TLR2 signalling requiring an additional adapter termed MyD88-adapter-like (Mal; also known as TIRAP). MyD88 and Mal both have a homologous Toll/IL-1 receptor (TIR) domain although they differ in their N-termini, with MyD88 possessing a death domain. In addition, structural models reveal marked differences in surface charges which, when taken with surface charge differences between TLR2 and TLR4 TIR domains, may indicate that TLR4 but not TLR2 recruits Mal directly. Another difference is that Mal can become phosphorylated. Future studies on Mal will reveal specificities in signal transduction by different TLRs, which may ultimately provide molecular explanations for specificities in the innate immune response to infection.
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| 6. |
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