QTY code designed thermostable and water-soluble chimeric chemokine receptors with tunable ligand affinity.

Chemokine receptors are of great interest as they play a critical role in many immunological and pathological processes. The ability to study chemokine receptors in aqueous solution without detergent would be significant because natural receptors require detergents to become soluble. We previously reported using the QTY code to design detergent-free chemokine receptors.

Normalization of connexin 43 protein levels prevents cellular and functional signs of dystrophic cardiomyopathy in mice.

Duchenne muscular dystrophy (DMD) associated cardiomyopathy remains incurable. Connexin 43 (Cx43) is upregulated and remodeled in the hearts of mdx mice, a mouse model of DMD. Hearts from Wild Type, mdx, and mdx:Cx43(+/-) mice were studied before (4-6 months) and after (10-15 months) the onset of cardiomyopathy to assess the impact of decreasing Cx43 levels on cardiac pathology in dystrophic mice.

Deficit in PINK1/PARKIN-mediated mitochondrial autophagy at late stages of dystrophic cardiomyopathy.

Aims: Duchenne muscular dystrophy (DMD) is an inherited devastating muscle disease with severe and often lethal cardiac complications. Emerging evidence suggests that the evolution of the pathology in DMD is accompanied by the accumulation of mitochondria with defective structure and function. Here, we investigate whether defects in the housekeeping autophagic pathway contribute to mitochondrial and metabolic dysfunctions in dystrophic cardiomyopathy.

The concerted movement of the switch region of Troponin I in cardiac muscle thin filaments as tracked by conventional and pulsed (DEER) EPR.

The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn. Spin labels were placed on the switch region of Troponin I and distances measured to Troponin C.

Fluorescent Protein-Based Ca2+ Sensor Reveals Global, Divalent Cation-Dependent Conformational Changes in Cardiac Troponin C.

Cardiac troponin C (cTnC) is a key effector in cardiac muscle excitation-contraction coupling as the Ca2+ sensing subunit responsible for controlling contraction. In this study, we generated several FRET sensors for divalent cations based on cTnC flanked by a donor fluorescent protein (CFP) and an acceptor fluorescent protein (YFP). The sensors report Ca2+ and Mg2+ binding, and relay global structural information about the structural relationship between cTnC's N- and C-domains.

Pivotal role of miR-448 in the development of ROS-induced cardiomyopathy.

Aims: Nicotinamide adenine dinucleotide oxidases (NOXs) are important contributors to cellular oxidative stress in the cardiovascular system. The NOX2 isoform is upregulated in numerous disorders, including dystrophic cardiomyopathy, where it drives the progression of the disease. However, mechanisms underlying NOX2 overexpression are still unknown.

Slowed Dynamics of Thin Filament Regulatory Units Reduces Ca-Sensitivity of Cardiac Biomechanical Function.

Actomyosin kinetics in both skinned skeletal muscle fibers at maximum Ca-activation and unregulated motility assays are modulated by solvent microviscosity in a manner consistent with a diffusion limited process. Viscosity might also influence cardiac thin filament Ca-regulatory protein dynamics. motility assays were conducted using thin filaments reconstituted with recombinant human cardiac troponin and tropomyosin; solvent microviscosity was varied by addition of sucrose or glucose.

Tropomyosin flexural rigidity and single ca(2+) regulatory unit dynamics: implications for cooperative regulation of cardiac muscle contraction and cardiomyocyte hypertrophy.

Striated muscle contraction is regulated by dynamic and cooperative interactions among Ca(2+), troponin, and tropomyosin on the thin filament. While Ca(2+) regulation has been extensively studied, little is known about the dynamics of individual regulatory units and structural changes of individual tropomyosin molecules in relation to their mechanical properties, and how these factors are altered by cardiomyopathy mutations in the Ca(2+) regulatory proteins. In this hypothesis paper, we explore how various experimental and analytical approaches could broaden our understanding of the cooperative regulation of cardiac contraction in health and disease.