A framework for evolutionary systems biology

<p>Abstract</p> <p>Background</p> <p>Many difficult problems in evolutionary genomics are related to mutations that have weak effects on fitness, as the consequences of mutations with large effects are often simple to predict. Current systems biology has accumulated much data on mutations with large effects and can predict the properties of knockout mutants in some systems. However experimental methods are too insensitive to observe small effects.</p> <p>Results</p> <p>Here I propose a novel framework that brings together evolutionary theory and current systems biology approaches in order to quantify small effects of mutations and their epistatic interactions <it>in silico</it>. Central to this approach is the definition of fitness correlates that can be computed in some current systems biology models employing the rigorous algorithms that are at the core of much work in computational systems biology. The framework exploits synergies between the realism of such models and the need to understand real systems in evolutionary theory. This framework can address many longstanding topics in evolutionary biology by defining various 'levels' of the adaptive landscape. Addressed topics include the distribution of mutational effects on fitness, as well as the nature of advantageous mutations, epistasis and robustness. Combining corresponding parameter estimates with population genetics models raises the possibility of testing evolutionary hypotheses at a new level of realism.</p> <p>Conclusion</p> <p>EvoSysBio is expected to lead to a more detailed understanding of the fundamental principles of life by combining knowledge about well-known biological systems from several disciplines. This will benefit both evolutionary theory and current systems biology. Understanding robustness by analysing distributions of mutational effects and epistasis is pivotal for drug design, cancer research, responsible genetic engineering in synthetic biology and many other practical applications.</p

Update on hypertrophic cardiomyopathy and a guide to the guidelines

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 individuals worldwide. Existing epidemiological studies might have underestimated the prevalence of HCM, however, owing to limited inclusion of individuals with early, incomplete phenotypic expression. Clinical manifestations of HCM include diastolic dysfunction, left ventricular outflow tract obstruction, ischaemia, atrial fibrillation, abnormal vascular responses and, in 5% of patients, progression to a 'burnt-out' phase characterized by systolic impairment. Disease-related mortality is most often attributable to sudden cardiac death, heart failure, and embolic stroke. The majority of individuals with HCM, however, have normal or near-normal life expectancy, owing in part to contemporary management strategies including family screening, risk stratification, thromboembolic prophylaxis, and implantation of cardioverter-defibrillators. The clinical guidelines for HCM issued by the ACC Foundation/AHA and the ESC facilitate evaluation and management of the disease. In this Review, we aim to assist clinicians in navigating the guidelines by highlighting important updates, current gaps in knowledge, differences in the recommendations, and challenges in implementing them, including aids and pitfalls in clinical and pathological evaluation. We also discuss the advances in genetics, imaging, and molecular research that will underpin future developments in diagnosis and therapy for HCM

Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries

Experiments were designed to determine whether endothelial injury contributes to augmented coronary vascular tone seen during myocardial reperfusion. Canine left anterior descending coronary arteries were exposed to ischemia followed by reperfusion (60 minutes each). Rings (3-4 mm) of the reperfused artery and of normal left circumflex (control) coronary artery segments were prepared. Rings were suspended for isometric force measurement in organ chamber containing modified Krebs' Ringer bicarbonate solution (37°C, 95%, O2-5% CO2). Endothelium-independent contractions to KCl and prostaglandin F(2α) were unaltered after reperfusion. Endothelium-dependent relaxations to nitric oxide, sodium nitroprusside, and isoproterenol were comparable in control and reperfused arteries. However, reperfused coronary arteries contracted with prostaglandin F(2α) lost the ability to express endothelium-dependent relaxations to aggregating platelets. Reperfused arterial rings also exhibited impaired endothelium-dependent relaxations to acetylcholine, the calcium ionophore A23187, and the platelet-derived compounds ADP and serotonin. Quiescent (noncontracted) reperfused arterial rings exhibited larger conractions than controls when exposed to aggregating platelets. In such quiescent rings, the endothelium-dependent increase in tension to hemoglobin was unaltered after reperfusion. Thus, coronary reperfusion impairs the normal endothelium-dependent relaxations to aggregating platelets and vasoactive drugs. This impairment of platelet-mediated coronary relaxtion could help explain the increased vascular tone and tendency toward vasospasm commonly observed after reperfusion of the coronary arteries.link_to_subscribed_fulltex

Acute impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries

Experiments were designed to determine whether endothelial injury contributes to augmented coronary vascular tone seen during myocardial reperfusion. Canine left anterior descending coronary arteries were exposed to ischemia followed by reperfusion (60 minutes each). Rings (3-4 mm) of the reperfused artery and of normal left circumflex (control) coronary artery segments were prepared. Rings were suspended for isometric force measurement in organ chamber containing modified Krebs' Ringer bicarbonate solution (37°C, 95%, O2-5% CO2). Endothelium-independent contractions to KCl and prostaglandin F(2α) were unaltered after reperfusion. Endothelium-dependent relaxations to nitric oxide, sodium nitroprusside, and isoproterenol were comparable in control and reperfused arteries. However, reperfused coronary arteries contracted with prostaglandin F(2α) lost the ability to express endothelium-dependent relaxations to aggregating platelets. Reperfused arterial rings also exhibited impaired endothelium-dependent relaxations to acetylcholine, the calcium ionophore A23187, and the platelet-derived compounds ADP and serotonin. Quiescent (noncontracted) reperfused arterial rings exhibited larger conractions than controls when exposed to aggregating platelets. In such quiescent rings, the endothelium-dependent increase in tension to hemoglobin was unaltered after reperfusion. Thus, coronary reperfusion impairs the normal endothelium-dependent relaxations to aggregating platelets and vasoactive drugs. This impairment of platelet-mediated coronary relaxtion could help explain the increased vascular tone and tendency toward vasospasm commonly observed after reperfusion of the coronary arteries.link_to_subscribed_fulltex

Augmented endothelium-dependent constriction to hypoxia early and late following reperfusion of the canine coronary artery

1. Canine coronary arteries with intact endothelium respond to hypoxaemia or serotonin infusion with dilatation, but when the endothelium is injured dysfunctional, these stimuli can cause constriction. The present studies investigated whether or not regional ischaemia and reperfusion alter endothelium-dependent responsiveness of canine coronary arteries in vivo and in vitro. 2. In organ chamber experiments, isolated control and reperfused coronary artery rings were contracted with prostaglandin F(2α) and exposed to hypoxia (PO2 less than 5 mmHg). 3. Hypoxia augmented the response of reperfused arteries more than that of controls. The hypoxic augmentation was blocked by N(G)-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis from L-arginine. 4. These findings demonstrate that early following coronary reperfusion the hypoxic augmentation, which is mediated by a nitric oxide-dependent pathway in the endothelium, is facilitated. 5. In vivo studies revealed hyperconstriction of reperfused arteries in response to hypoxaemia (PO2 = 30-40 mmHg) and administration of either serotonin or ergonovine. 6. Twelve weeks following reperfusion injury, coronary arteries still exhibited augmented endothelium-dependent hypoxic augmentations in vitro, which were inhibited by N(G)-monomethyl-L-arginine. 7. Furthermore, resting coronary segments with endothelium displayed hypoxia-induced contractions that could not be inhibited by indomethacin, the lipoxygenase inhibitor AA861, superoxide dismutase plus catalase, deferoxamine, ouabain, or N(G)-monomethyl-L-arginine. 8. These endothelium-dependent hypoxic response may play a role in the pathogenesis of hyperconstriction (vasospasm) following coronary reperfusion.link_to_subscribed_fulltex