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

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

Identifying modeled ship noise hotspots for marine mammals of Canada's Pacific region

RW was supported by a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme (Project CONCEAL, FP7, PIIF-GA-2009-253407). These analyses were funded by a grant to RW and EA from Marisla Foundation.The inshore, continental shelf waters of British Columbia (BC), Canada are busy with ship traffic. South coast waters are heavily trafficked by ships using the ports of Vancouver and Seattle. North coast waters are less busy, but expected to get busier based on proposals for container port and liquefied natural gas development and expansion. Abundance estimates and density surface maps are available for 10 commonly seen marine mammals, including northern resident killer whales, fin whales, humpback whales, and other species with at-risk status under Canadian legislation. Ship noise is the dominant anthropogenic contributor to the marine soundscape of BC, and it is chronic. Underwater noise is now being considered in habitat quality assessments in some countries and in marine spatial planning. We modeled the propagation of underwater noise from ships and weighted the received levels by species-specific audiograms. We overlaid the audiogram-weighted maps of ship audibility with animal density maps. The result is a series of so-called "hotspot'' maps of ship noise for all 10 marine mammal species, based on cumulative ship noise energy and average distribution in the boreal summer. South coast waters (Juan de Fuca and Haro Straits) are hotspots for all species that use the area, irrespective of their hearing sensitivity, simply due to ubiquitous ship traffic. Secondary hotspots were found on the central and north coasts (Johnstone Strait and the region around Prince Rupert). These maps can identify where anthropogenic noise is predicted to have above-average impact on species-specific habitat, and where mitigation measures may be most effective. This approach can guide effective mitigation without requiring fleet-wide modification in sites where no animals are present or where the area is used by species that are relatively insensitive to ship noise.Publisher PDFPeer reviewe

Class I histone deacetylase inhibition for the treatment of sustained atrial fibrillation

Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N- Acetyldinaline [4-(acetylamino)-N-(2- Aminophenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra- Atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra- Atrial adipocytes, and immune cell infiltration without significant effects on cardiac function