D389V Variant Induces Hypercontractility in Cardiac Organoids.

, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

Roles of cMyBP-C phosphorylation on cardiac contractile dysfunction in mice.

Type 2 diabetes mellitus (T2DM) is a metabolic disease and comorbidity associated with several conditions, including cardiac dysfunction leading to heart failure with preserved ejection fraction (HFpEF), in turn resulting in T2DM-induced cardiomyopathy (T2DM-CM). However, the molecular mechanisms underlying the development of T2DM-CM are poorly understood. It is hypothesized that molecular alterations in myopathic genes induced by diabetes promote the development of HFpEF, whereas cardiac myosin inhibitors can rescue the resultant T2DM-mediated cardiomyopathy.

D389V Variant Induces Hypercontractility in Cardiac Organoids.

Background: , encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in by using human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).

Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.

Unlabelled: During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function.

Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity.

Modulation of sarcomere contractility represents a new therapeutic opportunity for the treatment of heart failure by directly targeting the thick and thin filament proteins of the sarcomere to increase cardiac muscle contraction. This study compared the effect of 2 small molecules (M and T) that selectively alter myosin thick filament (M) or troponin thin filament (T) activity on overall cardiac muscle mechanics. This study revealed key differences related to the mechanism utilized by M and T to increase contractile force generation and suggests that targeting different proteins within the sarcomere may result in differentiating therapeutic profiles.

South Asian-Specific Deletion Carriers Display Hypercontraction and Impaired Diastolic Function Under Exercise Stress.

A 25-base pair (25bp) intronic deletion in the gene enriched in South Asians (SAs) is a risk allele for late-onset left ventricular (LV) dysfunction, hypertrophy, and heart failure (HF) with several forms of cardiomyopathy. However, the effect of this variant on exercise parameters has not been evaluated. As a pilot study, 10 asymptomatic SA carriers of the variant (52.

Mutations in myosin S2 alter cardiac myosin-binding protein-C interaction in hypertrophic cardiomyopathy in a phosphorylation-dependent manner.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder primarily caused by mutations in the β-myosin heavy-chain gene. The proximal subfragment 2 region (S2), 126 amino acids of myosin, binds with the C0-C2 region of cardiac myosin-binding protein-C to regulate cardiac muscle contractility in a manner dependent on PKA-mediated phosphorylation. However, it is unknown if HCM-associated mutations within S2 dysregulate actomyosin dynamics by disrupting its interaction with C0-C2, ultimately leading to HCM.

Structure, Rheology, and Electrokinetics of Soft Colloidal Suspension Electrolytes.

When ion transport in a binary liquid electrolyte is driven at potentials above the thermal voltage, an extended space charge region forms at the electrolyte/electrode interface and triggers the hydrodynamic instability termed electroconvection. We experimentally show that this instability can be completely arrested in soft colloidal suspension electrolytes composed of low concentrations of polymer-grafted nanoparticles in a liquid host. The mechanism is revealed by means of X-ray scattering, Brownian dynamics calculations, and linear stability analysis to involve overlap of the soft particles at low particle fractions to create a jammed, nanoporous medium that resists convective flow by a Darcy-Brinkman like drag on the electrolyte solvent.

Cardiac myosin binding protein-C phosphorylation regulates the super-relaxed state of myosin.

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) accelerates cardiac contractility. However, the mechanisms by which cMyBP-C phosphorylation increases contractile kinetics have not been fully elucidated. In this study, we tested the hypothesis that phosphorylation of cMyBP-C releases myosin heads from the inhibited super-relaxed state (SRX), thereby determining the fraction of myosin available for contraction.

Data on whole length myosin binding protein C stabilizes myosin S2 as measured by gravitational force spectroscopy.

Data presented in this article relates to the research article entitled "Whole length myosin binding protein C stabilizes myosin subfragment-2 (S2) flexibility as measured by gravitational force spectroscopy." (Singh et al., 2018) [1].

Whole length myosin binding protein C stabilizes myosin S2 as measured by gravitational force spectroscopy.

The mechanical stability of the myosin subfragment-2 (S2) was tested with simulated force spectroscopy (SFS) and gravitational force spectroscopy (GFS). Experiments examined unzipping S2, since it required less force than stretching parallel to the coiled coil. Both GFS and SFS demonstrated that the force required to destabilize the light meromyosin (LMM) was greater than the force required to destabilize the coiled coil at each of three different locations along S2.

A Molecularly Complete Planar Bacterial Outer Membrane Platform.

The bacterial outer membrane (OM) is a barrier containing membrane proteins and liposaccharides that fulfill crucial functions for Gram-negative bacteria. With the advent of drug-resistant bacteria, it is necessary to understand the functional role of this membrane and its constituents to enable novel drug designs. Here we report a simple method to form an OM-like supported bilayer (OM-SB), which incorporates native lipids and membrane proteins of gram-negative bacteria from outer membrane vesicles (OMVs).

Use of Infant Feeding Tube for Staged Flexor Tendon Reconstruction.

A two-stage flexor tendon reconstruction using a silicone rod in the first stage and a free tendon graft through the pseudo sheath formed around the silicone in the second stage was described by Hunter and Salisbury for a neglected and failed flexor tendon reconstruction. We are describing a technique where we have used an infant feeding tube as a substitute for silicone rods, which substantially reduces the cost of procedure but delivers the same results.

Membrane Protein Mobility and Orientation Preserved in Supported Bilayers Created Directly from Cell Plasma Membrane Blebs.

Membrane protein interactions with lipids are crucial for their native biological behavior, yet traditional characterization methods are often carried out on purified protein in the absence of lipids. We present a simple method to transfer membrane proteins expressed in mammalian cells to an assay-friendly, cushioned, supported lipid bilayer platform using cell blebs as an intermediate. Cell blebs, expressing either GPI-linked yellow fluorescent proteins or neon-green fused transmembrane P2X2 receptors, were induced to rupture on glass surfaces using PEGylated lipid vesicles, which resulted in planar supported membranes with over 50% mobility for multipass transmembrane proteins and over 90% for GPI-linked proteins.

Posterior scrotal artery flap to cover a groin defect: a new technique.

Commonly, a groin defect is reconstructed with flaps from ipsilateral thigh or lower abdomen. Here we present a case report of use of a pedicled flap from the posterior scrotum based on posterior scrotal artery to cover a groin defect exposing femoral vessels. Posterior scrotal artery, to best of our knowledge, has not been described in the literature to cover a groin defect.

Simple and effective method of heat therapy in lymphoedema.

Heat therapy is a well known conservative management for lymphoedema. We are describing here a heat therapy apparatus which is easy to make, cheap, transportable, easily reproducible and maintenance free and found to be very effective.