Functional Differences between the N-Terminal Domains of Mouse and Human Myosin Binding Protein-C

The N-terminus of cMyBP-C can activate actomyosin interactions in the absence of Ca2+, but it is unclear which domains are necessary. Prior studies suggested that the Pro-Ala rich region of human cMyBP-C activated force in permeabilized human cardiomyocytes, whereas the C1 and M-domains of mouse cMyBP-C activated force in permeabilized rat cardiac trabeculae. Because the amino acid sequence of the P/A region differs between human and mouse cMyBP-C isoforms (46% identity), we investigated whether species-specific differences in the P/A region could account for differences in activating effects. Using chimeric fusion proteins containing combinations of human and mouse C0, Pro-Ala, and C1 domains, we demonstrate here that the human P/A and C1 domains activate actomyosin interactions, whereas the same regions of mouse cMyBP-C are less effective. These results suggest that species-specific differences between homologous cMyBP-C isoforms confer differential effects that could fine-tune cMyBP-C function in hearts of different species

Cardiac Effects of a Single Dose of Pimobendan in Cats With Hypertrophic Cardiomyopathy; A Randomized, Placebo-Controlled, Crossover Study

Background: Pimobendan has been shown to impart a significant survival benefit in cardiomyopathic cats who receive it as part of heart failure therapy. However, use of pimobendan remains controversial in cats with hypertrophic cardiomyopathy (HCM) due to lack of pharmacodynamic data for pimobendan in cats with HCM and due to theoretical concerns for exacerbating left ventricular outflow tract obstructions. Hypothesis/Objectives: Our objective was to investigate the cardiac effects of pimobendan in cats with HCM. We hypothesized that pimobendan would not exacerbate left ventricular outflow tract obstructions and that it would improve echocardiographic measures of diastolic function. Animals: Thirteen purpose-bred cats were studied from a research colony with naturally-occurring HCM due to a variant in myosin binding protein C. Methods: Cats underwent two examinations 24 h apart with complete standard echocardiography. On their first day of evaluation, they were randomized to receive oral placebo or 1.25 mg pimobendan 1 h prior to exam. On their second examination, they were crossed over and received the remaining treatment. Investigators were blinded to all treatments. Results: The pimobendan group had a significant increase in left atrial fractional shortening (pimobendan group 41.7% ± 5.9; placebo group 36.1% ± 6.0; p = 0.04). There was no significant difference in left ventricular outflow tract (LVOT) velocities between the groups (pimobendan group 2.8 m/s ± 0.8; placebo group 2.6 m/s ± 1.0). There were no significant differences between the number of cats with LVOT obstructions between groups (12 in pimobendan group; 11 in placebo group; p = 1.00). There were no detectable differences in any systolic measures, including left ventricular fractional shortening, mitral annular plane systolic excursion, and tricuspid annular plane systolic excursion. Doppler-based diastolic function assessment was precluded by persistent tachycardia. Conclusions: Improved left atrial function in the pimobendan group could explain some of the reported survival benefit for HCM cats in CHF. Pimobendan did not exacerbate LVOT obstructions and thus may not be contraindicated in HCM cats with LVOT obstructions. Future studies are needed to better characterize other physiologic effects, particularly regarding diastolic function assessment, and to better assess safety of pimobendan over a longer time-course.Center for Companion Animal Health at the University of California Davis, School of Veterinary Medicine [2016-15-F]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Contribution of the Myosin Binding Protein C Motif to Functional Effects in Permeabilized Rat Trabeculae

Myosin binding protein C (MyBP-C) is a thick-filament protein that limits cross-bridge cycling rates and reduces myocyte power output. To investigate mechanisms by which MyBP-C affects contraction, we assessed effects of recombinant N-terminal domains of cardiac MyBP-C (cMyBP-C) on contractile properties of permeabilized rat cardiac trabeculae. Here, we show that N-terminal fragments of cMyBP-C that contained the first three immunoglobulin domains of cMyBP-C (i.e., C0, C1, and C2) plus the unique linker sequence termed the MyBP-C “motif” or “m-domain” increased Ca2+ sensitivity of tension and increased rates of tension redevelopment (i.e., ktr) at submaximal levels of Ca2+. At concentrations ≥20 μM, recombinant proteins also activated force in the absence of Ca2+ and inhibited maximum Ca2+-activated force. Recombinant proteins that lacked the combination of C1 and the motif did not affect contractile properties. These results suggest that the C1 domain plus the motif constitute a functional unit of MyBP-C that can activate the thin filament

Resuspension, Redistribution, and Deposition of Oil-Residues to Offshore Depocenters After the Deepwater Horizon Oil Spill

The focus of this study was to determine the long-term fate of oil-residues from the 2010 Deepwater Horizon (DwH) oil spill due to remobilization, transport, and re-distribution of oil residue contaminated sediments to down-slope depocenters following initial deposition on the seafloor. We characterized hydrocarbon residues, bulk sediment organic matter, ease of resuspension, sedimentology, and accumulation rates to define distribution patterns in a 14,300 km2 area southeast of the DwH wellhead (1,500 to 2,600 m water depth). Oil-residues from the DwH were detected at low concentrations in 62% of the studied sites at specific sediment layers, denoting episodic deposition of oil-residues during 2010–2014 and 2015–2018 periods. DwH oil residues exhibited a spatial distribution pattern that did not correspond with the distribution of the surface oil slick, subsurface plume or original seafloor spatial expression. Three different regions were apparent in the overall study area and distinguished by the episodic nature of sediment accumulation, the ease of sediment resuspension, the timing of oil-residue deposition, carbon content and isotopic composition and foram fracturing extent. These data indicate that resuspension and down-slope redistribution of oil-residues occurred in the years following the DwH event and must be considered in determining the fate of the spilled oil deposited on the seafloor

Molecular Markers of Biogenic and Oil-Derived Hydrocarbons in Deep-Sea Sediments Following the Deepwater Horizon Spill

Following the Deepwater Horizon oil spill (DWHOS), the formation of an unexpected and extended sedimentation event of oil-associated marine snow (MOSSFA: Marine Oil Snow Sedimentation and Flocculent Accumulation) demonstrated the importance of biology on the fate of contaminants in the oceans. We used a wide range of compound-specific data (aliphatics, hopanes, steranes, triaromatic steroids, polycyclic aromatics) to chemically characterize the MOSSFA event containing abundant and multiple hydrocarbon sources (e.g., oil residues and phytoplankton). Sediment samples were collected in 2010–2011 (ERMA-NRDA programs: Environmental Response Management Application – Natural Resource Damage Assessment) and 2018 (REDIRECT project: Resuspension, Redistribution and Deposition of Deepwater Horizon recalcitrant hydrocarbons to offshore depocenter) in the northern Gulf of Mexico to assess the role of biogenic and chemical processes on the fate of oil residues in sediments. The chemical data revealed the deposition of the different hydrocarbon mixtures observed in the water column during the DWHOS (e.g., oil slicks, submerged-plumes), defining the chemical signature of MOSSFA relative to where it originated in the water column and its fate in deep-sea sediments. MOSSFA from surface waters covered 90% of the deep-sea area studied and deposited 32% of the total oil residues observed in deep-sea areas after the DWHOS while MOSSFA originated at depth from the submerged plumes covered only 9% of the deep-sea area studied and was responsible for 15% of the total deposition of oil residues. In contrast, MOSSFA originated at depth from the water column covered only 1% of the deep-sea area studied (mostly in close proximity of the DWH wellhead) but was responsible for 53% of the total deposition of oil residues observed after the spill in this area. This study describes, for the first time, a multi-chemical method for the identification of biogenic and oil-derived inputs to deep-sea sediments, critical for improving our understanding of carbon inputs and storage at depth in open ocean systems

Source Coding Optimization for Distributed Average Consensus

Consensus is a common method for computing a function of the data distributed among the nodes of a network. Of particular interest is distributed average consensus, whereby the nodes iteratively compute the sample average of the data stored at all the nodes of the network using only near-neighbor communications. In real-world scenarios, these communications must undergo quantization, which introduces distortion to the internode messages. In this thesis, a model for the evolution of the network state statistics at each iteration is developed under the assumptions of Gaussian data and additive quantization error. It is shown that minimization of the communication load in terms of aggregate source coding rate can be posed as a generalized geometric program, for which an equivalent convex optimization can efficiently solve for the global minimum. Optimization procedures are developed for rate-distortion-optimal vector quantization, uniform entropy-coded scalar quantization, and fixed-rate uniform quantization. Numerical results demonstrate the performance of these approaches. For small numbers of iterations, the fixed-rate optimizations are verified using exhaustive search. Comparison to the prior art suggests competitive performance under certain circumstances but strongly motivates the incorporation of more sophisticated coding strategies, such as differential, predictive, or Wyner-Ziv coding.Comment: Master's Thesis, Electrical Engineering, North Carolina State Universit

Species-specific differences in the Pro-Ala rich region of cardiac myosin binding protein-C

Cardiac myosin binding protein-C (cMyBP-C) is an accessory protein found in the A-bands of vertebrate sarcomeres and mutations in the cMyBP-C gene are a leading cause of familial hypertrophic cardiomyopathy. The regulatory functions of cMyBP-C have been attributed to the N-terminus of the protein, which is composed of tandem immunoglobulin (Ig)-like domains (C0, C1, and C2), a region rich in proline and alanine residues (the Pro-Ala rich region) that links C0 and C1, and a unique sequence referred to as the MyBP-C motif, or M-domain, that links C1 and C2. Recombinant proteins that contain various combinations of the N-terminal domains of cMyBP-C can activate actomyosin interactions in the absence of Ca2+, but the specific sequences required for these effects differ between species; the Pro-Ala region has been implicated in human cMyBP-C whereas the C1 and M-domains appear important in mouse cMyBP-C. To investigate whether species-specific differences in sequence can account for the observed differences in function, we compared sequences of the Pro-Ala rich region in cMyBP-C isoforms from different species. Here we report that the number of proline and alanine residues in the Pro-Ala rich region varies significantly between different species and that the number correlates directly with mammalian body size and inversely with heart rate. Thus, systematic sequence differences in the Pro-Ala rich region of cMyBP-C may contribute to observed functional differences in human versus mouse cMyBP-C isoforms and suggest that the Pro-Ala region may be important in matching contractile speed to cardiac function across species