55 research outputs found
Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute.
Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by left ventricular (LV) hypertrophy without dilatation and without apparent cause (ie, it occurs in the absence of severe hypertension, aortic stenosis, or other cardiac or systemic diseases that might cause LV hypertrophy). Numerous excellent reviews and consensus documents provide a wealth of additional background.1–8 HCM is the leading cause of sudden death in young people and leads to significant disability in survivors. It is caused by mutations in genes that encode components of the sarcomere. Cardiomyocyte and cardiac hypertrophy, myocyte disarray, interstitial and replacement fibrosis, and dysplastic intramyocardial arterioles characterize the pathology of HCM. Clinical manifestations include impaired diastolic function, heart failure, tachyarrhythmia (both atrial and ventricular), and sudden death. At present, there is a lack of understanding of how the mutations in genes encoding sarcomere proteins lead to the phenotypes described above. Current therapeutic approaches have focused on the prevention of sudden death, with implantable cardioverter defibrillator placement in high-risk patients. But medical therapies have largely focused on alleviating symptoms of the disease, not on altering its natural history. The present Working Group of the National Heart, Lung, and Blood Institute brought together clinical, translational, and basic scientists with the overarching goal of identifying novel strategies to prevent the phenotypic expression of disease. Herein, we identify research initiatives that we hope will lead to novel therapeutic approaches for patients with HCM
α−α Cross-Links Increase Fibrin Fiber Elasticity and Stiffness
Fibrin fibers, which are ∼100 nm in diameter, are the major structural component of a blood clot. The mechanical properties of single fibrin fibers determine the behavior of a blood clot and, thus, have a critical influence on heart attacks, strokes, and embolisms. Cross-linking is thought to fortify blood clots; though, the role of α–α cross-links in fibrin fiber assembly and their effect on the mechanical properties of single fibrin fibers are poorly understood. To address this knowledge gap, we used a combined fluorescence and atomic force microscope technique to determine the stiffness (modulus), extensibility, and elasticity of individual, uncross-linked, exclusively α–α cross-linked (γQ398N/Q399N/K406R fibrinogen variant), and completely cross-linked fibrin fibers. Exclusive α–α cross-linking results in 2.5× stiffer and 1.5× more elastic fibers, whereas full cross-linking results in 3.75× stiffer, 1.2× more elastic, but 1.2× less extensible fibers, as compared to uncross-linked fibers. On the basis of these results and data from the literature, we propose a model in which the α-C region plays a significant role in inter- and intralinking of fibrin molecules and protofibrils, endowing fibrin fibers with increased stiffness and elasticity
A Modular Fibrinogen Model that Captures the Stress-Strain Behavior of Fibrin Fibers
We tested what to our knowledge is a new computational model for fibrin fiber mechanical behavior. The model is composed of three distinct elements: the folded fibrinogen core as seen in the crystal structure, the unstructured α-C connector, and the partially folded α-C domain. Previous studies have highlighted the importance of all three regions and how they may contribute to fibrin fiber stress-strain behavior. Yet no molecular model has been computationally tested that takes into account the individual contributions of all these regions. Constant velocity, steered molecular dynamics studies at 0.025 Å/ps were conducted on the folded fibrinogen core and the α-C domain to determine their force-displacement behavior. A wormlike chain model with a persistence length of 0.8 nm (Kuhn length = 1.6 nm) was used to model the mechanical behavior of the unfolded α-C connector. The three components were combined to calculate the total stress-strain response, which was then compared to experimental data. The results show that the three-component model successfully captures the experimentally determined stress-strain behavior of fibrin fibers. The model evinces the key contribution of the α-C domains to fibrin fiber stress-strain behavior. However, conversion of the α-helical coiled coils to β-strands, and partial unfolding of the protein, may also contribute
Choosy Moral Punishers
The punishment of social misconduct is a powerful mechanism for stabilizing high levels of cooperation among unrelated individuals. It is regularly assumed that humans have a universal disposition to punish social norm violators, which is sometimes labelled “universal structure of human morality” or “pure aversion to social betrayal”. Here we present evidence that, contrary to this hypothesis, the propensity to punish a moral norm violator varies among participants with different career trajectories. In anonymous real-life conditions, future teachers punished a talented but immoral young violinist: they voted against her in an important music competition when they had been informed of her previous blatant misconduct toward fellow violin students. In contrast, future police officers and high school students did not punish. This variation among socio-professional categories indicates that the punishment of norm violators is not entirely explained by an aversion to social betrayal. We suggest that context specificity plays an important role in normative behaviour; people seem inclined to enforce social norms only in situations that are familiar, relevant for their social category, and possibly strategically advantageous
Persistence of strong silica-enriched domains in the Earth's lower mantle
The composition of the lower mantle—comprising 56% of Earth’s volume—remains poorly constrained. Among the major elements, Mg/Si ratios ranging from ∼0.9–1.1, such as in rocky Solar-System building blocks (or chondrites), to ∼1.2–1.3, such as in upper-mantle rocks (or pyrolite), have been proposed. Geophysical evidence for subducted lithosphere deep in the mantle has been interpreted in terms of efficient mixing, and thus homogenous Mg/Si across most of the mantle. However, previous models did not consider the effects of variable Mg/Si on the viscosity and mixing efficiency of lower-mantle rocks. Here, we use geodynamic models to show that large-scale heterogeneity associated with a 20-fold change in viscosity, such as due to the dominance of intrinsically strong (Mg, Fe)SiO3–bridgmanite in low-Mg/Si domains, is sufficient to prevent efficient mantle mixing, even on large scales. Models predict that intrinsically strong domains stabilize mantle convection patterns, and coherently persist at depths of about 1,000–2,200 km up to the present-day, separated by relatively narrow up-/downwelling conduits of pyrolitic material. The stable manifestation of such bridgmanite-enriched ancient mantle structures (BEAMS) may reconcile the geographical fixity of deep-rooted mantle upwelling centres, and geophysical changes in seismic-tomography patterns, radial viscosity, rising plumes and sinking slabs near 1,000 km depth. Moreover, these ancient structures may provide a reservoir to host primordial geochemical signatures
The heat budget of rocky planets
The loss of interior heat to space drives the internal dynamics of planetary bodies and governs long term evolution. This shapes a planet's surface environment and its prospects of habitability by dictating the rates of volcanic outgassing and recycling of volatiles into the planet interior over time. This chapter addresses how heat is acquired during planet formation and lost during the subsequent evolution, how these sources and sinks influence the surface and interior structure of the planet and explores the potential variations through our solar system and exoplanet systems
- …