Transient Hoogsteen base pairs in canonical duplex DNA

Sequence-directed variations in the canonical DNA double helix structure that retain Watson-Crick base-pairing play important roles in DNA recognition, topology, and nucleosome positioning. By using nuclear magnetic resonance relaxation dispersion spectroscopy in concert with steered molecular dynamics simulations, we have observed transient sequence-specific excursions away from Watson-Crick base-pairing at CA and TA steps inside canonical duplex DNA towards low-populated and short-lived A•T and G•C Hoogsteen base-pairs. The observation of Hoogsteen base-pairs in DNA duplexes specifically bound to transcription factors and in damaged DNA sites implies that the DNA double helix intrinsically codes for excited state Hoogsteen base-pairs as a means of expanding its structural complexity beyond that which can be achieved based on Watson-Crick base-pairing. The methods presented here provide a new route for characterizing transient low-populated nucleic acid structures, which we predict will be abundant in the genome and constitute a second transient layer of the genetic code. Soon after its discovery1, it was recognized that the DNA double helix could accommodate a range of conformations that retain Watson-Crick (WC) base-pairing2. Sequence-directe

Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome - Results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) study

Background: Angiotensin-converting enzyme inhibitors reduce mortality and remodeling after myocardial infarction in patients with left ventricular dysfunction. Methods: Perindopril and Remodeling in Elderly With Acute Myocardial Infarction (PREAMI), a doubleblind, randomized, parallel-group, multicenter, placebocontrolled study, determined whether similar benefits occur in elderly postinfarction patients with preserved left ventricular function. A total of 1252 patients 65 years or older with a left ventricular ejection fraction of 40% or higher and recent acute myocardial infarction were randomized to receive perindopril erbumine or placebo (8 mg/d) for 12 months. The combined primary end point was death, hospitalization for heart failure, or left ventricular remodeling. Secondary end points included cardiovascular death, hospitalization for reinfarction or angina, and revascularization. Results: The primary end point occurred in 181 patients (35%) taking perindopril and 290 patients (57%) taking placebo, with a significant absolute risk reduction of 0.22 (95% confidence interval, 0.16 to 0.28; P.001). A total of 126 patients (28%) and 226 patients (51%) in the perindopril and placebo groups, respectively, experienced remodeling. The mean increase in left ventricle end-diastolic volume was 0.7 mL with perindopril compared with 4.0 mL with placebo (P.001). In the perindopril group, 40 deaths (6%) and 22 hospitalizations (4%) for heart failure occurred, whereas 37 deaths (6%) and 30 hospitalizations (5%) occurred in the placebo group. Treatment did not affect death, whereas the hospitalization rate for heart failure was slightly reduced (absolute risk reduction, 0.01; 95% confidence interval, −0.01 to 0.02). No treatment effect on other secondary end points was detected. Conclusion:Wefound that 1-year treatment with 8mg/d of perindopril reduces progressive left ventricular remodeling that can occur even in the presence of small infarct size, but it was not associated with better clinical outcomes