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.

This study was undertaken to evaluate reference ranges for systolic blood pressure (SBP) in cats under conditions mimicking a clinical setting. SBP was measured in 50 healthy adult cats of various ages (range, 1.5-16 years) and body weights (range, 2.2-6.1 kg) by Doppler ultrasonic sphygmomanometry. A cuff width of 2.5 cm was used, placed on the left antebrachium, and this represented a mean cuff width of 35% limb circumference (range, 31-42%). The mean (+/-SD) SBP in the 50 cats was 162 +/- 19 mm Hg (range 124-210), with only 1 cat having a SBP > or = 200 mm Hg. No significant difference (P > .05) in SBP was found between male and female cats, and no significant correlation was found between SBP and age (r(s) = 0.075) or body weight (r(s) = 0.007). Further studies in some of these cats indicated that allowing a period of 10 minutes for acclimatization to the environment where SBP was recorded resulted in a significant decrease in SBP from 176 +/- 17 to 157 +/- 21 mm Hg (n = 7) and that use of a 3.3-cm-width cuff resulted in a significant decrease in measured SBP from 168 +/- 13 to 164 +/- 13 mm Hg (n = 10). Reproducibility of SBP measurements was evaluated in 7 cats by assessing SBP 7 times at intervals of > or = 24 hours over a 10-day period. These 7 cats had a low intraindividual coefficient of variation of SBP measurements (CV < or = 7.9%) although 2 of the 7 cats had SBP values > 200 mm Hg on at least 1 occasion.

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A population’s spatial structure affects the rate of genetic change and the outcome of natural selection. These effects can be modeled mathematically using the Birth-death process on graphs. Individuals occupy the vertices of a weighted graph, and reproduce into neighboring vertices based on fitness. A key quantity is the probability that a mutant type will sweep to fixation, as a function of the mutant’s fitness. Graphs that increase the fixation probability of beneficial mutations, and decrease that of deleterious mutations, are said to amplify selection. However, fixation probabilities are difficult to compute for an arbitrary graph. Here we derive an expression for the fixation probability, of a weakly-selected mutation, in terms of the time for two lineages to coalesce. This expression enables weak-selection fixation probabilities to be computed, for an arbitrary weighted graph, in polynomial time. Applying this method, we explore the range of possible effects of graph structure on natural selection, genetic drift, and the balance between the two. Using exhaustive analysis of small graphs and a genetic search algorithm, we identify families of graphs with striking effects on fixation probability, and we analyze these families mathematically. Our work reveals the nuanced effects of graph structure on natural selection and neutral drift. In particular, we show how these notions depend critically on the process by which mutations arise.

perturbing E-cadherin receptors also disrupts the complex. These findings suggest a mechanism by which E-cadherin may suppress EGFR signaling. They also suggest how increased tension on intercellular adhesions could override contact inhibited proliferation, to potentiate tissue growth. Our results are not only relevant to epithelia, but may have broader implications in other tissues, such as in the vascular endothelium, where VE-cadherin and VEGFR2/3 coordinately regulate endothelial proliferation and fluid shear alignment.