Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways

Distinct effects of two hearing loss-associated mutations in the sarcomeric myosin MYH7b

For decades, sarcomeric myosin heavy chain proteins were assumed to be restricted to striated muscle where they function as molecular motors that contract muscle. However, MYH7b, an evolutionarily ancient member of this myosin family, has been detected in mammalian nonmuscle tissues, and mutations in MYH7b are linked to hereditary hearing loss in compound heterozygous patients. These mutations are the first associated with hearing loss rather than a muscle pathology, and because there are no homologous mutations in other myosin isoforms, their functional effects were unknown. We generated recombinant human MYH7b harboring the D515N or R1651Q hearing loss-associated mutation and studied their effects on motor activity and structural and assembly properties, respectively. The D515N mutation had no effect on steady-state actin-activated ATPase rate or load-dependent detachment kinetics, but increased actin sliding velocity due to an increased displacement during the myosin working stroke. Furthermore, we found that the D515N mutation caused an increase in the proportion of myosin heads that occupy the disordered-relaxed state, meaning more myosin heads are available to interact with actin. Although we found no impact of the R1651Q mutation on myosin rod secondary structure or solubility, we observed a striking aggregation phenotype when this mutation was introduced into nonmuscle cells. Our results suggest that each mutation independently affects MYH7b function and structure. Together, these results provide the foundation for further study of a role for MYH7b outside of the sarcomere

SARS-CoV-2 infects human engineered heart tissues and models COVID-19 myocarditis

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease

SARS-CoV-2 Infects Human Engineered Heart Tissues and Models COVID-19 Myocarditis.

There is ongoing debate as to whether cardiac complications of coronavirus disease-2019 (COVID-19) result from myocardial viral infection or are secondary to systemic inflammation and/or thrombosis. We provide evidence that cardiomyocytes are infected in patients with COVID-19 myocarditis and are susceptible to severe acute respiratory syndrome coronavirus 2. We establish an engineered heart tissue model of COVID-19 myocardial pathology, define mechanisms of viral pathogenesis, and demonstrate that cardiomyocyte severe acute respiratory syndrome coronavirus 2 infection results in contractile deficits, cytokine production, sarcomere disassembly, and cell death. These findings implicate direct infection of cardiomyocytes in the pathogenesis of COVID-19 myocardial pathology and provides a model system to study this emerging disease

Functional divergence of the sarcomeric myosin, MYH7b, supports species-specific biological roles.

Myosin heavy chain 7b (MYH7b) is an evolutionarily ancient member of the sarcomeric myosin family, which typically supports striated muscle function. However, in mammals alternative splicing prevents MYH7b protein production in cardiac and most skeletal muscles and limits expression to a subset of specialized muscles and certain non-muscle environments. In contrast, MYH7b protein is abundant in python cardiac and skeletal muscles. Although the MYH7b expression pattern diverges in mammals versus reptiles, MYH7b shares high sequence identity across species. So, it remains unclear how mammalian MYH7b function may differ from that of other sarcomeric myosins and whether human and python MYH7b motor functions diverge as their expression patterns suggest. Thus, we generated recombinant human and python MYH7b protein and measured their motor properties to investigate any species-specific differences in activity. Our results reveal that despite having similar working strokes, the MYH7b isoforms have slower actin-activated ATPase cycles and actin sliding velocities than human cardiac β-MyHC. Furthermore, python MYH7b is tuned to have slower motor activity than human MYH7b due to slower kinetics of the mechanochemical cycle. We found that the MYH7b isoforms adopt a higher proportion of myosin heads in the ultra-slow, super-relaxed state compared to human cardiac β-MyHC. These findings are supported by molecular dynamics simulations that predict MYH7b preferentially occupies myosin active site conformations similar to those observed in the structurally inactive state. Together, these results suggest that MYH7b is specialized for slow, energy-conserving motor activity and that differential tuning of MYH7b orthologs contributes to species-specific biological roles. [Abstract copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Subglacial geology and geomorphology of the Pensacola-Pole Basin, East Antarctica

The East Antarctic Ice Sheet (EAIS) is underlain by a series of low‐lying subglacial sedimentary basins. The extent, geology and basal topography of these sedimentary basins are important boundary conditions governing the dynamics of the overlying ice sheet. This is particularly pertinent for basins close to the grounding line wherein the EAIS is grounded below sea level, and therefore potentially vulnerable to rapid retreat. Here, we analyze newly acquired airborne geophysical data over the Pensacola‐Pole Basin (PPB), a previously unexplored sector of the EAIS. Using a combination of gravity, magnetic and ice‐penetrating radar data, we present the first detailed subglacial sedimentary basin model for the PPB. Radar data reveal that the PPB is defined by a topographic depression situated ~500 m below sea level. Gravity and magnetic depth‐to‐source modeling indicate that the southern part of the basin is underlain by a sedimentary succession 2–3 km thick. This is interpreted as an equivalent of the Beacon Supergroup and associated Ferrar dolerites that are exposed along the margin of East Antarctica. However, we find that similar rocks appear to be largely absent from the northern part of the basin, close to the present‐day grounding line. In addition, the eastern margin of the basin is characterized by a major geological boundary and a system of overdeepened subglacial troughs. We suggest that these characteristics of the basin may reflect the behavior of past ice sheets and/or exert an influence on the present‐day dynamics of the overlying EAIS

The (Dis)similarity of a Minority Religion to Its Broader Religious Context: The Case of American Jews

While much research shows the relationship between individual-level variables, such as Jewish background, education, age, and income and an individual’s Jewish identity, very little research has systematically addressed the question of community context, either general or Jewish, as a factor influencing Jewish religious or ethnic identity. This lack of research has been partially a result of the lack of an adequate data set to facilitate such analysis. Using the newly-aggregated Decade 2000 data set, with its 19,800 cases spread across 22 Jewish communities, we find that despite the anecdotal evidence and the logic that suggests that environment impacts behavior, the environmental impact on Jewish identity is clearly weak. Individual characteristics are much stronger than community context in explaining variations in the strength of Jewish identity