RESUMEN
In mathematical phylogenetics, the Sackin index, measuring the sum of path lengths between leaves and the root, is one of the most frequently used measures of balance for phylogenetic trees. The uniform model, in which all rooted binary labeled trees for a given set of leaf labels are assumed to be equiprobable, is one of the most frequently used models for describing a probability distribution on the set of rooted binary labeled trees. This note provides a simple new derivation of the mean value of the Sackin index of tree balance under the uniform model on rooted binary labeled trees. The new derivation suggests a simple form of the mean Sackin index in terms of the Catalan numbers, quickly enabling a verification of the asymptotic value for the mean.
Asunto(s)
Algoritmos , Modelos Genéticos , Filogenia , ProbabilidadRESUMEN
Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.
Asunto(s)
Arrestinas/química , Proteínas de Unión al GTP/química , Receptor de Angiotensina Tipo 1/química , Transducción de Señal , Regulación Alostérica , Humanos , Simulación de Dinámica Molecular , Conformación ProteicaRESUMEN
STUDY OBJECTIVE: Use of contrast-enhanced computed tomography (CT) of the pulmonary arteries to evaluate for pulmonary embolism has increased, raising concern about radiation and contrast toxicity. We sought to measure the frequency of repeat CT pulmonary angiography in emergency department (ED) patients. METHODS: This was a prospective, longitudinal follow-up of ED patients who underwent first-time CT pulmonary angiography as part of a research protocol for diagnosis of pulmonary embolism in 2001 to 2002. Two authors (DMB and MCK) searched electronic medical record databases to measure the frequency of repeated CT scans performed within 5 years. Primary outcome was greater than or equal to 1 repeated CT pulmonary angiography examination. Radiologist-written interpretations of CT pulmonary angiography were categorized by 2 observers (DMB and JAK). Cox regression was used to estimate hazard ratios for 24 clinical variables. RESULTS: A cohort of 675 ED patients was observed for a median of 1,989 days: 226 of 675 (33%) had at least 1 additional CT pulmonary angiography scan, and 60 died with no repeated CT pulmonary angiography, leading to a mortality-adjusted frequency of repeated CT pulmonary angiography scanning of 226 of 615, or 37%. Seventy-three percent of the cohort had 1 or more subsequent CT scans of any body part, and 31 patients (5%) had 5 or more repeated CT pulmonary angiography scans. The pulmonary embolism (positive) prevalence was 57 of 675 (8.4%; 95% confidence interval [CI] 6.5% to 10.8%) on the first CT pulmonary angiography versus 8 of 226 (3.5%; 95% CI 1.5% to 6.9%) on the second CT pulmonary angiography scan. Hazard ratios indicated that respiratory rate, active malignancy, previous coronary artery disease, and previous or new diagnosis of venous thromboembolism were positively associated with repeated CT pulmonary angiography scanning. CONCLUSION: At least one third of ED patients who undergo CT pulmonary angiography scanning will have a second CT pulmonary angiography result that will be negative for pulmonary embolism. New methods are needed to exclude pulmonary embolism recurrence without use of ionizing radiation.