Publications by authors named "Kenneth Campbell"

224 Publications

Protein Hormone Fragmentation in Intercellular Signaling: Hormones as Nested Information Systems†.

Biol Reprod 2021 Jan 5. Epub 2021 Jan 5.

Department of Biology, University of Massachusetts Boston.

This study explores the hypothesis that protein hormones are nested information systems in which initial products of gene transcription, and their subsequent protein fragments, before and after secretion and initial target cell action, play additional physiological regulatory roles. The study produced four tools and key results: 1) a problem approach that proceeds, with examples and suggestions for in vivo organismal functional tests for peptide-protein interactions, from proteolytic breakdown prediction to models of hormone fragment modulation of protein-protein binding motifs in unrelated proteins; 2) a catalog of 461 known soluble human protein hormones and their predicted fragmentation patterns; 3) an analysis of the predicted proteolytic patterns of the canonical protein hormone transcripts demonstrating near-universal persistence of 9 ± 7 peptides of 8 ± 8 amino acids even after cleavage with 24 proteases from four protease classes; and, 4) a coincidence analysis of the predicted proteolysis locations and the 1939 exon junctions within the transcripts that shows an excess (P < 0.001) of predicted proteolysis within 10 residues, especially at the exonal junction (P < 0.01). It appears all protein hormone transcripts generate multiple fragments the size of peptide hormones or protein-protein binding domains that may alter intracellular or extracellular functions by acting as modulators of metabolic enzymes, transduction factors, protein binding proteins, or hormone receptors. High proteolytic frequency at exonal junctions suggests proteolysis has evolved, as a complement to gene exon fusion, to extract structures or functions within single exons or protein segments to simplify the genome by discarding archaic one-exon genes.
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http://dx.doi.org/10.1093/biolre/ioaa234DOI Listing
January 2021

Diverse and complex muscle spindle afferent firing properties emerge from multiscale muscle mechanics.

Elife 2020 12 28;9. Epub 2020 Dec 28.

Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, United States.

Despite decades of research, we lack a mechanistic framework capable of predicting how movement-related signals are transformed into the diversity of muscle spindle afferent firing patterns observed experimentally, particularly in naturalistic behaviors. Here, a biophysical model demonstrates that well-known firing characteristics of mammalian muscle spindle Ia afferents - including movement history dependence, and nonlinear scaling with muscle stretch velocity - emerge from first principles of muscle contractile mechanics. Further, mechanical interactions of the muscle spindle with muscle-tendon dynamics reveal how motor commands to the muscle (alpha drive) versus muscle spindle (gamma drive) can cause highly variable and complex activity during active muscle contraction and muscle stretch that defy simple explanation. Depending on the neuromechanical conditions, the muscle spindle model output appears to 'encode' aspects of muscle force, yank, length, stiffness, velocity, and/or acceleration, providing an extendable, multiscale, biophysical framework for understanding and predicting proprioceptive sensory signals in health and disease.
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http://dx.doi.org/10.7554/eLife.55177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769569PMC
December 2020

Effects of the Duration of a Resting-State EEG Recording in Healthy Aging and Mild Cognitive Impairment.

Clin EEG Neurosci 2020 Dec 28:1550059420983624. Epub 2020 Dec 28.

School of Psychology, University of Ottawa, Ottawa, Ontario, Canada.

Introduction: The recording of resting-state EEG may provide a means to predict early cognitive decline associated with mild cognitive impairment (MCI). Previous studies have typically used very short recording times to avoid a confound with drowsiness that may occur in longer recordings. The effects of a longer recording have not however been systematically examined.

Methods: Eyes-closed resting-state EEG activity was recorded in 40 older adult participants (20 healthy older adults and 20 people with MCI). The recording period was a relatively long 6 minutes, divided into two equal 3-minute halves to determine if drowsiness will be more apparent as the recording progresses. The participants also completed standardized neuropsychological tasks that assessed global cognition (Montreal Cognitive Assessment) and memory (California Verbal Learning Test, Second Edition). A spectral analysis was performed on both short (2 seconds) and long (8 seconds) segments in both 3-minute halves.

Results: No differences in power density for any of the EEG frequency bands were found between the 2 halves of the study for either group. There was little evidence of increased drowsiness in the second half of the study even when frequency resolution was increased with the 8-second segmentation. Theta power density was overall larger for people with MCI compared to healthy older adults. A negative correlation was also observed between theta power and global cognition in healthy older adults.

Conclusions: The present results indicate that longer resting-state EEG recording can be reliably employed without increased risk of drowsiness.
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http://dx.doi.org/10.1177/1550059420983624DOI Listing
December 2020

Conserved Gsx2/Ind homeodomain monomer versus homodimer DNA binding defines regulatory outcomes in flies and mice.

Genes Dev 2021 Jan 17;35(1-2):157-174. Epub 2020 Dec 17.

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.

How homeodomain proteins gain sufficient specificity to control different cell fates has been a long-standing problem in developmental biology. The conserved Gsx homeodomain proteins regulate specific aspects of neural development in animals from flies to mammals, and yet they belong to a large transcription factor family that bind nearly identical DNA sequences in vitro. Here, we show that the mouse and fly Gsx factors unexpectedly gain DNA binding specificity by forming cooperative homodimers on precisely spaced and oriented DNA sites. High-resolution genomic binding assays revealed that Gsx2 binds both monomer and homodimer sites in the developing mouse ventral telencephalon. Importantly, reporter assays showed that Gsx2 mediates opposing outcomes in a DNA binding site-dependent manner: Monomer Gsx2 binding represses transcription, whereas homodimer binding stimulates gene expression. In , the Gsx homolog, Ind, similarly represses or stimulates transcription in a site-dependent manner via an autoregulatory enhancer containing a combination of monomer and homodimer sites. Integrating these findings, we test a model showing how the homodimer to monomer site ratio and the Gsx protein levels defines gene up-regulation versus down-regulation. Altogether, these data serve as a new paradigm for how cooperative homeodomain transcription factor binding can increase target specificity and alter regulatory outcomes.
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http://dx.doi.org/10.1101/gad.343053.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778271PMC
January 2021

Fast-relaxing cardiomyocytes exert a dominant role in the relaxation behavior of heterogeneous myocardium.

Arch Biochem Biophys 2021 01 30;697:108711. Epub 2020 Nov 30.

Department of Biomedical Engineering, Yale University, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. Electronic address:

Substantial variation in relaxation rate exists among cardiomyocytes within small volumes of myocardium; however, it is unknown how this variability affects the overall relaxation mechanics of heart muscle. In this study, we sought to modulate levels of cellular heterogeneity in a computational model, then validate those predictions using an engineered heart tissue platform. We formulated an in silico tissue model composed of half-sarcomeres with varied relaxation rates, incorporating single-cell cardiomyocyte experimental data. These model tissues randomly sampled relaxation parameters from two offset distributions of fast- and slow-relaxing populations of half-sarcomeres. Isometric muscle twitch simulations predicted a complex relationship between relaxation time and the proportion of fast-versus slow-relaxing cells in heterogeneous tissues. Specifically, a 50/50 mixture of fast and slow cells did not lead to relaxation time that was the mean of the relaxation times associated with the two pure cases. Rather, the mean relaxation time was achieved at a ratio of 70:30 slow:fast relaxing cells, suggesting a disproportionate impact of fast-relaxing cells on overall tissue relaxation. To examine whether this behavior persists in vitro, we constructed engineered heart tissues from two lines of fast- and slow-relaxing human iPSC-derived cardiomyocytes. Cell tracking via fluorescent nanocrystals confirmed the presence of both cell populations in the 50/50 mixed tissues at the time of mechanical characterization. Isometric muscle twitch relaxation times of these mixed-population engineered heart tissues showed agreement with the predictions from the model, namely that the measured relaxation rate of 50/50 mixed tissues more closely resembled that of tissues made with 100% fast-relaxing cells. Our observations suggest that cardiomyocyte diversity can play an important role in determining tissue-level relaxation.
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http://dx.doi.org/10.1016/j.abb.2020.108711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785692PMC
January 2021

Titin-Truncating Mutations Associated With Dilated Cardiomyopathy Alter Length-Dependent Activation And Its Modulation Via Phosphorylation.

Cardiovasc Res 2020 Nov 2. Epub 2020 Nov 2.

National Heart and Lung Institute, Imperial College London, London, W12 0NN, UK.

Aims: Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterisations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants.

Methods And Results: We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified downregulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was upregulated in DCM patients with TTN-truncating variants.

Conclusion: Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.

Translational Perspective: Our findings may have implications in the development of new strategies for DCM treatment in patients with TTN-truncating variants as well as in the development of new drugs.
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http://dx.doi.org/10.1093/cvr/cvaa316DOI Listing
November 2020

The influence of different types of auditory change on processes associated with the switching of attention in younger and older adults.

Neurobiol Aging 2020 12 12;96:197-204. Epub 2020 Sep 12.

Bruyère Research Institute, Ottawa, Canada; School of Psychology, University of Ottawa, Ottawa, Canada. Electronic address:

Potentially highly relevant but unattended auditory stimuli may result in attention capture. The detection of stimulus change is associated with two event-related potentials: the deviant-related negativity (DRN), whose amplitude varies with the extent of change, and the P3a, which is elicited only by stimuli deemed to be highly relevant. In the present study, younger adults (aged 18-30 years) and older adults (aged 65-73 years) were presented with to-be-ignored auditory stimuli while engaged in a visual task. The auditory stimuli consisted of frequently presented standards and six different rarely presented deviants. In older adults, the amplitude of the DRN varied with the extent of deviance: it was significantly larger to the white noise and environmental sound deviants. A large P3a was elicited by these in younger adults but was much reduced in older adults. The DRN results suggest that older adults are able to compute saliency level of unattended stimulus input at an early stage of processing. However, the attenuated P3a results in older adults suggest that a potentially highly salient stimulus is not given sufficient priority to result in a switch of attention from current cognitive demands.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.012DOI Listing
December 2020

Multiscale Modeling of Cardiovascular Function Predicts That the End-Systolic Pressure Volume Relationship Can Be Targeted via Multiple Therapeutic Strategies.

Front Physiol 2020 19;11:1043. Epub 2020 Aug 19.

Department of Biomedical Engineering, Yale University, New Haven, CT, United States.

Most patients who develop heart failure are unable to elevate their cardiac output on demand due to impaired contractility and/or reduced ventricular filling. Despite decades of research, few effective therapies for heart failure have been developed. In part, this may reflect the difficulty of predicting how perturbations to molecular-level mechanisms that are induced by drugs will scale up to modulate system-level properties such as blood pressure. Computer modeling might help with this process and thereby accelerate the development of better therapies for heart failure. This manuscript presents a new multiscale model that uses a single contractile element to drive an idealized ventricle that pumps blood around a closed circulation. The contractile element was formed by linking an existing model of dynamically coupled myofilaments with a well-established model of myocyte electrophysiology. The resulting framework spans from molecular-level events (including opening of ion channels and transitions between different myosin states) to properties such as ejection fraction that can be measured in patients. Initial calculations showed that the model reproduces many aspects of normal cardiovascular physiology including, for example, pressure-volume loops. Subsequent sensitivity tests then quantified how each model parameter influenced a range of system level properties. The first key finding was that the End Systolic Pressure Volume Relationship, a classic index of cardiac contractility, was ∼50% more sensitive to parameter changes than any other system-level property. The second important result was that parameters that primarily affect ventricular filling, such as passive stiffness and Ca reuptake via sarco/endoplasmic reticulum Ca-ATPase (SERCA), also have a major impact on systolic properties including stroke work, myosin ATPase, and maximum ventricular pressure. These results reinforce the impact of diastolic function on ventricular performance and identify the End Systolic Pressure Volume Relationship as a particularly sensitive system-level property that can be targeted using multiple therapeutic strategies.
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http://dx.doi.org/10.3389/fphys.2020.01043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466769PMC
August 2020

Effects of mavacamten on Ca sensitivity of contraction as sarcomere length varied in human myocardium.

Br J Pharmacol 2020 Dec 21;177(24):5609-5621. Epub 2020 Oct 21.

Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington, USA.

Background And Purpose: Heart failure can reflect impaired contractile function at the myofilament level. In healthy hearts, myofilaments become more sensitive to Ca as cells are stretched. This represents a fundamental property of the myocardium that contributes to the Frank-Starling response, although the molecular mechanisms underlying the effect remain unclear. Mavacamten, which binds to myosin, is under investigation as a potential therapy for heart disease. We investigated how mavacamten affects the sarcomere-length dependence of Ca -sensitive isometric contraction to determine how mavacamten might modulate the Frank-Starling mechanism.

Experimental Approach: Multicellular preparations from the left ventricular-free wall of hearts from organ donors were chemically permeabilized and Ca activated in the presence or absence of 0.5-μM mavacamten at 1.9 or 2.3-μm sarcomere length (37°C). Isometric force and frequency-dependent viscoelastic myocardial stiffness measurements were made.

Key Results: At both sarcomere lengths, mavacamten reduced maximal force and Ca sensitivity of contraction. In the presence and absence of mavacamten, Ca sensitivity of force increased as sarcomere length increased. This suggests that the length-dependent activation response was maintained in human myocardium, even though mavacamten reduced Ca sensitivity. There were subtle effects of mavacamten reducing force values under relaxed conditions (pCa 8.0), as well as slowing myosin cross-bridge recruitment and speeding cross-bridge detachment under maximally activated conditions (pCa 4.5).

Conclusion And Implications: Mavacamten did not eliminate sarcomere length-dependent increases in the Ca sensitivity of contraction in myocardial strips from organ donors at physiological temperature. Drugs that modulate myofilament function may be useful therapies for cardiomyopathies.
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http://dx.doi.org/10.1111/bph.15271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707091PMC
December 2020

Heart Failure in Humans Reduces Contractile Force in Myocardium From Both Ventricles.

JACC Basic Transl Sci 2020 Aug 22;5(8):786-798. Epub 2020 Jul 22.

Department of Physiology, University of Kentucky, Lexington, Kentucky.

This study measured how heart failure affects the contractile properties of the human myocardium from the left and right ventricles. The data showed that maximum force and maximum power were reduced by approximately 30% in multicellular preparations from both ventricles, possibly because of ventricular remodeling (e.g., cellular disarray and/or excess fibrosis). Heart failure increased the calcium (Ca) sensitivity of contraction in both ventricles, but the effect was bigger in right ventricular samples. The changes in Ca sensitivity were associated with ventricle-specific changes in the phosphorylation of troponin I, which indicated that adrenergic stimulation might induce different effects in the left and right ventricles.
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http://dx.doi.org/10.1016/j.jacbts.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452203PMC
August 2020

Event-related potentials following gaps in noise: The effects of the intensity of preceding noise.

Brain Res 2020 12 27;1748:147078. Epub 2020 Aug 27.

School of Rehabilitation Sciences, University of Ottawa, Canada.

Auditory temporal resolution is critical for the perception of speech. It is often studied using gap detection methods in which a silent period (or "gap") is inserted in a long duration auditory stimulus. When the gap is inserted in a frequently occurring standard stimulus, it elicits a negative-going event-related potential, called the deviant-related negativity (DRN). A time-efficient multi-deviant paradigm was employed in which a standard 200 ms noise burst was presented on 50% of trials and a deviant stimulus, containing a gap, on the remaining 50% of trials. Seven different deviants were constructed by inserting a gap in the centre of the standard. The duration of the seven gaps ranged from 2 to 40 ms. In different conditions, the intensity of the noise burst was either 60 or 80 dB SPL. Ten adults watched a silent video while ignoring the auditory sequence. As expected, the amplitude of the DRN increased as gap duration became longer, regardless of the intensity of the noise in which the gap occurred. The intensity of the noise burst also affected the DRN measured peak-to-peak (DRN-to-following positivity). This was reduced when the gap occurred in the lower intensity noise burst. The time efficient multi-deviant paradigm can thus be employed to determine the effects of factors known to affect gap detection: the duration of the gap, and the intensity of the sound in which the gap is inserted.
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http://dx.doi.org/10.1016/j.brainres.2020.147078DOI Listing
December 2020

Event-related potentials following gaps in noise: The effects of the intensity of preceding noise.

Brain Res 2020 12 27;1748:147078. Epub 2020 Aug 27.

School of Rehabilitation Sciences, University of Ottawa, Canada.

Auditory temporal resolution is critical for the perception of speech. It is often studied using gap detection methods in which a silent period (or "gap") is inserted in a long duration auditory stimulus. When the gap is inserted in a frequently occurring standard stimulus, it elicits a negative-going event-related potential, called the deviant-related negativity (DRN). A time-efficient multi-deviant paradigm was employed in which a standard 200 ms noise burst was presented on 50% of trials and a deviant stimulus, containing a gap, on the remaining 50% of trials. Seven different deviants were constructed by inserting a gap in the centre of the standard. The duration of the seven gaps ranged from 2 to 40 ms. In different conditions, the intensity of the noise burst was either 60 or 80 dB SPL. Ten adults watched a silent video while ignoring the auditory sequence. As expected, the amplitude of the DRN increased as gap duration became longer, regardless of the intensity of the noise in which the gap occurred. The intensity of the noise burst also affected the DRN measured peak-to-peak (DRN-to-following positivity). This was reduced when the gap occurred in the lower intensity noise burst. The time efficient multi-deviant paradigm can thus be employed to determine the effects of factors known to affect gap detection: the duration of the gap, and the intensity of the sound in which the gap is inserted.
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http://dx.doi.org/10.1016/j.brainres.2020.147078DOI Listing
December 2020

Regulation of Myofilament Contractile Function in Human Donor and Failing Hearts.

Front Physiol 2020 25;11:468. Epub 2020 May 25.

Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, United States.

Heart failure (HF) often includes changes in myocardial contractile function. This study addressed the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of contractile properties was measured in cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor ( = 7) and failing human hearts ( = 8). Permeabilized cardiac myocyte preparations were attached between a force transducer and a position motor, and both the Ca dependence and sarcomere length (SL) dependence of force, rate of force, loaded shortening, and power output were measured at 15 ± 1°C. The myocyte preparation size was similar between groups (donor: length 148 ± 10 μm, width 21 ± 2 μm, = 13; HF: length 131 ± 9 μm, width 23 ± 1 μm, = 16). The maximal Ca-activated isometric force was also similar between groups (donor: 47 ± 4 kN⋅m; HF: 44 ± 5 kN⋅m), which implicates that previously reported force declines in multi-cellular preparations reflect, at least in part, tissue remodeling. Maximal force development rates were also similar between groups (donor: = 0.60 ± 0.05 s; HF: k = 0.55 ± 0.04 s), and both groups exhibited similar Ca activation dependence of values. Human cardiac myocyte preparations exhibited a Ca activation dependence of loaded shortening and power output. The peak power output normalized to isometric force (PNPO) decreased by ∼12% from maximal Ca to half-maximal Ca activations in both groups. Interestingly, the SL dependence of PNPO was diminished in failing myocyte preparations. During sub-maximal Ca activation, a reduction in SL from ∼2.25 to ∼1.95 μm caused a ∼26% decline in PNPO in donor myocytes but only an ∼11% change in failing myocytes. These results suggest that altered length-dependent regulation of myofilament function impairs ventricular performance in failing human hearts.
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http://dx.doi.org/10.3389/fphys.2020.00468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261867PMC
May 2020

Force-dependent recruitment from myosin OFF-state increases end-systolic pressure-volume relationship in left ventricle.

Biomech Model Mechanobiol 2020 Dec 28;19(6):2683-2692. Epub 2020 Apr 28.

Department of Mechanical Engineering, University of Kentucky, 269 Ralph G. Anderson Building, Lexington, KY, 40506-0503, USA.

Finite element (FE) modeling is becoming increasingly prevalent in the world of cardiac mechanics; however, many existing FE models are phenomenological and thus do not capture cellular-level mechanics. This work implements a cellular-level contraction scheme into an existing nonlinear FE code to model ventricular contraction. Specifically, this contraction model incorporates three myosin states: OFF-, ON-, and an attached force-generating state. It has been speculated that force-dependent transitions from the OFF- to ON-state may contribute to length-dependent activation at the cellular level. The current work investigates the contribution of force-dependent recruitment out of the OFF-state to ventricular-level function, specifically the Frank-Starling relationship, as seen through the end-systolic pressure-volume relationship (ESPVR). Five FE models were constructed using geometries of rat left ventricles obtained via cardiac magnetic resonance imaging. FE simulations were conducted to optimize parameters for the cellular contraction model such that the differences between FE predicted ventricular pressures for the models and experimentally measured pressures were minimized. The models were further validated by comparing FE predicted end-systolic strain to experimentally measured strain. Simulations mimicking vena cava occlusion generated descending pressure volume loops from which ESPVRs were calculated. In simulations with the inclusion of the OFF-state, using a force-dependent transition to the ON-state, the ESPVR calculated was steeper than in simulations excluding the OFF-state. Furthermore, the ESPVR was also steeper when compared to models that included the OFF-state without a force-dependent transition. This suggests that the force-dependent recruitment of thick filament heads from the OFF-state at the cellular level contributes to the Frank-Starling relationship observed at the organ level.
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http://dx.doi.org/10.1007/s10237-020-01331-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606253PMC
December 2020

A parapithecid stem anthropoid of African origin in the Paleogene of South America.

Science 2020 04;368(6487):194-197

Department of Vertebrate Zoology, Natural History Museum of Los Angeles County, Los Angeles, CA 90007, USA.

Phylogenetic evidence suggests that platyrrhine (or New World) monkeys and caviomorph rodents of the Western Hemisphere derive from source groups from the Eocene of Afro-Arabia, a landmass that was ~1500 to 2000 kilometers east of South America during the late Paleogene. Here, we report evidence for a third mammalian lineage of African origin in the Paleogene of South America-a newly discovered genus and species of parapithecid anthropoid primate from Santa Rosa in Amazonian Perú. Bayesian clock-based phylogenetic analysis nests this genus () deep within the otherwise Afro-Arabian clade Parapithecoidea and indicates that transatlantic rafting of the lineage leading to likely took place between ~35 and ~32 million years ago, a dispersal window that includes the major worldwide drop in sea level that occurred near the Eocene-Oligocene boundary.
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http://dx.doi.org/10.1126/science.aba1135DOI Listing
April 2020

Physical interactions between Gsx2 and Ascl1 balance progenitor expansion versus neurogenesis in the mouse lateral ganglionic eminence.

Development 2020 04 10;147(7). Epub 2020 Apr 10.

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA

The Gsx2 homeodomain transcription factor promotes neural progenitor identity in the lateral ganglionic eminence (LGE), despite upregulating the neurogenic factor Ascl1. How this balance in maturation is maintained is unclear. Here, we show that Gsx2 and Ascl1 are co-expressed in subapical progenitors that have unique transcriptional signatures in LGE ventricular zone (VZ) cells. Moreover, whereas Ascl1 misexpression promotes neurogenesis in dorsal telencephalic progenitors, the co-expression of Gsx2 with Ascl1 inhibits neurogenesis. Using luciferase assays, we found that Gsx2 reduces the ability of Ascl1 to activate gene expression in a dose-dependent and DNA binding-independent manner. Furthermore, Gsx2 physically interacts with the basic helix-loop-helix (bHLH) domain of Ascl1, and DNA-binding assays demonstrated that this interaction interferes with the ability of Ascl1 to bind DNA. Finally, we modified a proximity ligation assay for tissue sections and found that Ascl1-Gsx2 interactions are enriched within LGE VZ progenitors, whereas Ascl1-Tcf3 (E-protein) interactions predominate in the subventricular zone. Thus, Gsx2 contributes to the balance between progenitor maintenance and neurogenesis by physically interacting with Ascl1, interfering with its DNA binding and limiting neurogenesis within LGE progenitors.
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http://dx.doi.org/10.1242/dev.185348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157596PMC
April 2020

Cardiac myosin regulatory light chain kinase modulates cardiac contractility by phosphorylating both myosin regulatory light chain and troponin I.

J Biol Chem 2020 04 21;295(14):4398-4410. Epub 2020 Feb 21.

Randall Centre for Cell and Molecular Biophysics and British Heart Foundation Centre of Research Excellence, King's College London, London SE1 1UL, United Kingdom

Heart muscle contractility and performance are controlled by posttranslational modifications of sarcomeric proteins. Although myosin regulatory light chain (RLC) phosphorylation has been studied extensively and , the precise role of cardiac myosin light chain kinase (cMLCK), the primary kinase acting upon RLC, in the regulation of cardiomyocyte contractility remains poorly understood. In this study, using recombinantly expressed and purified proteins, various analytical methods, and kinase assays, and mechanical measurements in isolated ventricular trabeculae, we demonstrate that human cMLCK is not a dedicated kinase for RLC but can phosphorylate other sarcomeric proteins with well-characterized regulatory functions. We show that cMLCK specifically monophosphorylates Ser of human cardiac troponin I (cTnI) in isolation and in the trimeric troponin complex and in the native environment of the muscle myofilament lattice. Moreover, we observed that human cMLCK phosphorylates rodent cTnI to a much smaller extent and , suggesting species-specific adaptation of cMLCK. Although cMLCK treatment of ventricular trabeculae exchanged with rat or human troponin increased their cross-bridge kinetics, the increase in sensitivity of myofilaments to calcium was significantly blunted by human TnI, suggesting that human cTnI phosphorylation by cMLCK modifies the functional consequences of RLC phosphorylation. We propose that cMLCK-mediated phosphorylation of TnI is functionally significant and represents a critical signaling pathway that coordinates the regulatory states of thick and thin filaments in both physiological and potentially pathophysiological conditions of the heart.
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http://dx.doi.org/10.1074/jbc.RA119.011945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135997PMC
April 2020

The Heart by Numbers.

Biophys J 2019 12 29;117(12):E1-E3. Epub 2019 Nov 29.

Department of Medicine and Division of Cardiology, University of California, Los Angeles, Los Angeles, California.

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http://dx.doi.org/10.1016/j.bpj.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990371PMC
December 2019

Identification of Human Very Small Embryonic like Stem Cells (VSELS) in Human Heart Tissue Among Young and Old Individuals.

Stem Cell Rev Rep 2020 02;16(1):181-185

Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.

Very Small Embryonic-Like (VSEL) stem cells are a proposed pluripotent population, residing in adult tissues. VSELs have been described in multiple tissues including bone marrow, cord blood, and gonads. They exhibit multiple characteristics of embryonic stem cells including the ability to differentiate into cellular lineages of all three germ layers, including cardiomyocytes and vascular endothelial cells. However, their presence in adult solid organs such as heart in humans has not been established. VSELs are valuable source of stem cells for tissue regeneration and replacement of cells for turnover and usual wear-and-tear. The purpose of our study was to explore the existence of human VSELs (huVSELs) in human heart tissue and examine the changes in their prevalence with aging and cardiac disease. Human heart tissue, collected from healthy and ischemic heart disease subjects was examined for the prevalence of VSELS, defined as CD45-/CD133+/SSEA4+. Both epicardial and endocardial tissues were examined comparing VSEL numbers across different age groups. Our data confirm the existence of huVSELs in adult hearts with decreasing prevalence during aging. This is the first evidence of huVSELs in adult cardiac tissue. Cardiac huVSELs could be further explored in future studies to characterize their primitive potential and therapeutic potential in regenerative studies.
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http://dx.doi.org/10.1007/s12015-019-09923-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027381PMC
February 2020

Diabetic microcirculatory disturbances and pathologic erythropoiesis are provoked by deposition of amyloid-forming amylin in red blood cells and capillaries.

Kidney Int 2020 01 5;97(1):143-155. Epub 2019 Sep 5.

Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA; Department of Neurology, University of Kentucky, Lexington, Kentucky, USA. Electronic address:

In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications.
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http://dx.doi.org/10.1016/j.kint.2019.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943180PMC
January 2020

EAES and SAGES 2018 consensus conference on acute diverticulitis management: evidence-based recommendations for clinical practice.

Surg Endosc 2019 09 27;33(9):2726-2741. Epub 2019 Jun 27.

Department of Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Acute diverticulitis (AD) presents a unique diagnostic and therapeutic challenge for general surgeons. This collaborative project between EAES and SAGES aimed to summarize recent evidence and draw statements of recommendation to guide our members on comprehensive AD management.

Methods: Systematic reviews of the literature were conducted across six AD topics by an international steering group including experts from both societies. Topics encompassed the epidemiology, diagnosis, management of non-complicated and complicated AD as well as emergency and elective operative AD management. Consensus statements and recommendations were generated, and the quality of the evidence and recommendation strength rated with the GRADE system. Modified Delphi methodology was used to reach consensus among experts prior to surveying the EAES and SAGES membership on the recommendations and likelihood to impact their practice. Results were presented at both EAES and SAGES annual meetings with live re-voting carried out for recommendations with < 70% agreement.

Results: A total of 51 consensus statements and 41 recommendations across all six topics were agreed upon by the experts and submitted for members' online voting. Based on 1004 complete surveys and over 300 live votes at the SAGES and EAES Diverticulitis Consensus Conference (DCC), consensus was achieved for 97.6% (40/41) of recommendations with 92% (38/41) agreement on the likelihood that these recommendations would change practice if not already applied. Areas of persistent disagreement included the selective use of imaging to guide AD diagnosis, recommendations against antibiotics in non-complicated AD, and routine colonic evaluation after resolution of non-complicated diverticulitis.

Conclusion: This joint EAES and SAGES consensus conference updates clinicians on the current evidence and provides a set of recommendations that can guide clinical AD management practice.
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http://dx.doi.org/10.1007/s00464-019-06882-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684540PMC
September 2019

Muscle thixotropy-where are we now?

J Appl Physiol (1985) 2019 06 9;126(6):1790-1799. Epub 2019 May 9.

Department of Physiology, College of Medicine, University of Kentucky , Lexington, Kentucky.

Relaxed skeletal muscle has an inbuilt resistance to movement. In particular, the resistance manifests itself as a substantial stiffness for small movements. The stiffness is impermanent, because it forms only when the muscle is stationary for some time and is reduced upon active or passive movement. Because the resistance to movement increases with time at rest and is reduced by movement, this behavior has become known as muscle thixotropy. In this short review, we describe the phenomenon of thixotropy and illustrate its significance in postural control with particular emphasis on human standing. We show how thixotropy came to be unambiguously associated with muscle mechanics and we review present knowledge of the molecular basis of thixotropic behavior. Specifically, we examine how recent knowledge about titin, and about the control of cross-bridge cycling, has impacted on the role of non-cross-bridge mechanisms and cross-bridge mechanisms in explaining thixotropy. We describe how thixotropic changes in muscle stiffness that occur during transitions from posture to movement can be tracked by analyzing physiological tremor. Finally, because skeletal muscle contains sensory receptors, and because some of these receptors are themselves thixotropic, we outline some of the consequences of muscle thixotropy for proprioception.
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http://dx.doi.org/10.1152/japplphysiol.00788.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734056PMC
June 2019

Disentangling specific inhibitory versus general decision-making processes during sleep deprivation using a Go/NoGo ERP paradigm.

Int J Psychophysiol 2019 07 23;141:18-27. Epub 2019 Apr 23.

School of Psychology, University of Ottawa, Canada.

This study used a Go/NoGo ERP paradigm in which Go and NoGo stimuli occurred rarely and equally often in an attempt to determine if sleep deprivation has a general effect on decision-making or a more specific effect on inhibition. A Go/NoGo task was administered six times to eleven participants during 36 h of sleep deprivation and once again post recovery sleep. In the Go condition, the participant was asked to respond to the rare stimulus. In the separate NoGo condition, the participant was asked to withhold the response to the rare stimulus. ERPs were recorded to the rare stimuli. The NoGo P3 should be attenuated if sleep loss mainly affects inhibitory processes. Both Go and NoGo P3 should be attenuated if sleep loss affects general detection processes. During sleep loss, accuracy decreased for both tasks. RT also gradually increased for the Go task. Performance during the NoGo task was more complex and was better accounted by a speed-accuracy trade-off. Overall, findings indicate that sleep deprivation did not have specific effects on inhibition. However, the amplitude of the Go P3 occurred as early as 12 h after waking and might reflect an effect of task repetition rather than true sleep deprivation. In contrast, the NoGo P3 amplitude was not significantly reduced until after 24 and 36 h of wakefulness, suggesting a true sleep deprivation effect. Both Go and NoGo P3 post recovery sleep did not return to baseline levels, possibly due to residual sleep inertia.
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http://dx.doi.org/10.1016/j.ijpsycho.2019.04.007DOI Listing
July 2019

Sleep deprivation moderates neural processes associated with passive auditory capture.

Brain Cogn 2019 06 30;132:89-97. Epub 2019 Mar 30.

School of Psychology, University of Ottawa, Ottawa, Canada; Brain and Mind Institute, University of Ottawa, Ottawa, Canada.

Sleep loss has a major effect on cognitive tasks that are dependent on the maintenance of active sustained attention. This study examines the effects of sleep deprivation on automatic information processing, more specifically, its effect on processes leading to involuntary auditory attention capture by task-irrelevant auditory events. Two experiments were run. In the first, 13 participants were totally sleep-deprived (TSD); in the second, 16 participants were partially sleep-deprived (PSD), sleeping only four hours. Event-related potentials were recorded while participants discriminated the duration of equiprobable short and long auditory tones. At rare times, a small change to the pitch of these stimuli occurred. This deviant was however irrelevant to the duration detection task. As expected, TSD had a significant effect on the attention-dependent duration detection task; performance was worse and the P3b, associated with ease of detection, was attenuated. PSD had a similar, but reduced effect. Critically, the small pitch deviant resulted in less behavioural distraction following TSD compared to normal sleep.Consistent with this, the P3a, associated with the attention capture process, was significantly reduced following both TSD and PSD. Processes related to the passive switching of attention to potentially critical, but unattended, stimulus events are moderated by sleep deprivation.
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http://dx.doi.org/10.1016/j.bandc.2019.03.004DOI Listing
June 2019

A time-efficient multi-deviant paradigm to determine the effects of gap duration on the mismatch negativity.

Hear Res 2019 06 7;377:34-43. Epub 2019 Mar 7.

School of Rehabilitation Sciences, University of Ottawa, Ottawa, Canada.

The insertion of a silent period (or gap) in a frequently occurring standard stimulus elicits a negative-going event-related potential (ERP), called the Deviant-Related Negativity (DRN). This is often studied using a single-deviant paradigm. To study the effects of gaps with multiple durations, a different sequence would be required for each gap. A more time-efficient multi-deviant paradigm has been developed in which stimuli of various gap widths are included in a single sequence. In the present study, 14 young adults watched a silent video while ignoring an auditory sequence. A single run of a multi-deviant sequence was presented in which 6 different rare deviants alternated with a standard stimulus. The standard was a 200-ms white noise burst. The deviants were constructed by inserting a gap in the standard. The duration of the 6 gaps ranged from 2 to 40 ms. Participants were also presented with multiple runs of single-deviant sequences. Each of the 3 deviants was run in a separate sequence. The amplitude of the DRN elicited by the deviant increased as gap duration became longer, although it did plateau for the longer duration gaps. The amplitudes of the DRNs were larger in the single-deviant paradigm than in the multi-deviant paradigm. However, the difference was only significant when the mastoid reference was used. Behavioural data showed a mean d' of 2.1 for the 5-ms gap. None of the participants were able to detect the 2-ms gap. There was no correlation between d' and the DRN amplitude. Still, the effects of gap duration on the amplitude of the DRN were similar between the single and multi-deviant sequences. This makes the multi-deviant paradigm a possible time-saving alternative to the single-deviant paradigm.
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http://dx.doi.org/10.1016/j.heares.2019.03.004DOI Listing
June 2019

Event-related potentials associated with auditory attention capture in younger and older adults.

Neurobiol Aging 2019 05 24;77:20-25. Epub 2019 Jan 24.

School of Psychology, University of Ottawa, Ottawa, Canada; Bruyère Research Institute, Ottawa, Canada. Electronic address:

A deviant-related negativity (DRN), mismatch negativity (MMN), and P3a are electrophysiological measures thought to reflect processes involved in the involuntary switching of attention to a task-irrelevant stimulus. The purpose of this article was to determine whether healthy older adults involuntarily detect unattended auditory stimuli as efficiently as younger adults. To test this, 20 younger adults (aged 18-30 years) and 20 older adults (aged 65+ years) were presented with to-be-ignored auditory sequences consisting of frequently presented 80 dB SPL standards and rarely presented increments (+10 dB) and decrements (-20 dB). The MMN to the decrement did not differ between the 2 groups. On the other hand, the DRN to the increment was significantly reduced in the older adults. Importantly, the P3a was also significantly reduced in the older adults. This reduced P3a may reflect a deficit in the involuntary shift of attention from current cognitive demands to a potentially more critical event.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.01.012DOI Listing
May 2019

Evidence of P3a During Sleep, a Process Associated With Intrusions Into Consciousness in the Waking State.

Front Neurosci 2018 10;12:1028. Epub 2019 Jan 10.

School of Psychology, University of Ottawa, Ottawa, ON, Canada.

The present study examines processes associated with intrusions into consciousness during an unconscious state, natural sleep. The definition of sleep is still much debated. Almost all researchers agree that sleep onset represents a gradual loss of consciousness of the external environment. For sleep to be beneficial, it needs to remain as undisturbed as possible. Nevertheless, unlike other unconsciousness states, sleep is reversible. For purposes of survival, it is critical that the sleeper be able to "detect" and perhaps become conscious of highly relevant biological or personal information. Therefore, even in sleep, the brain must decide whether a new incoming stimulus is relevant and if so, may require an arousal to wakefulness, or whether it is irrelevant and can be gated to prevent disruption of sleep. Event-related potentials (ERPs) were used to measure the extent processing of auditory stimuli some of which elicited an ERP component, the P3a, in the waking state. The P3a is associated with processes resulting in the interruption of frontal central executive, leading to conscious awareness. Very little research has focused on the occurrence of the P3a during sleep. A multi-feature paradigm was used to examine the processing of a frequently occurring "standard" stimulus and six rarely occurring different "deviant" stimuli during wakefulness, NREM, and REM sleep. A P3a was elicited by novel environmental sounds and white noise bursts in the waking state, replicating previous studies. Other deviant stimuli (changes in pitch, intensity, duration) failed to do so. The ERPs indicated that processing of the stimuli that did not elicit a P3a in wakefulness were much inhibited during both NREM and REM sleep. Surprisingly, those deviants that did elicit a P3a in wakefulness continued to do so in stage N2 and REM sleep. The subject did not, however, awaken. These results suggest processes leading to consciousness in wakefulness may still remain active during sleep possibly allowing subjects to act on potentially highly relevant input. This may also explain how sleep can be reversed if the stimulus input is sufficiently critical.
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http://dx.doi.org/10.3389/fnins.2018.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335993PMC
January 2019

Closing the therapeutic loop.

Arch Biochem Biophys 2019 03 9;663:129-131. Epub 2019 Jan 9.

Department of Mechanical Engineering and Department of Surgery, University of Kentucky, United States.

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http://dx.doi.org/10.1016/j.abb.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377839PMC
March 2019

Deletion of Glucocorticoid Receptors in Forebrain GABAergic Neurons Alters Acute Stress Responding and Passive Avoidance Behavior in Female Mice.

Front Behav Neurosci 2018 21;12:325. Epub 2018 Dec 21.

Department of Pharmacology and Systems Physiology, University of Cincinnati, Cincinnati, OH, United States.

The glucocorticoid receptor (GR) is critically involved in regulation of stress responses [inhibition of the hypothalamic-pituitary-adrenal (HPA) axis], emotional behavior and cognition interactions with forebrain corticolimbic circuity. Work to date has largely focused on GR actions in forebrain excitatory neurons; however, recent studies suggest a potential role mediated by interneurons. Here, we targeted GR deletion in forebrain GABAergic neurons, including the cortical interneurons, using a Dlx5/6-Cre driver line to test the role of forebrain interneuronal GR in HPA axis regulation and behavior. Our data indicate that GR deletion in GABAergic neurons causes elevated corticosterone stress responsiveness and decreased cross-over latencies in a passive avoidance task in females, but not males. Dlx5/6-Cre driven gene deletion caused loss of GR in interneurons in the prefrontal cortex (PFC) and hippocampus, but also in select diencephalic GABAergic neurons (including the reticular thalamic nucleus and dorsomedial hypothalamus). Our data suggest that GR signaling in interneurons is differentially important in females, which may have implications for GR-directed therapies for stress-related affective disease states.
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http://dx.doi.org/10.3389/fnbeh.2018.00325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309161PMC
December 2018

A short history of the development of mathematical models of cardiac mechanics.

J Mol Cell Cardiol 2019 02 29;127:11-19. Epub 2018 Nov 29.

Departments of Biomedical Engineering and Cellular and Molecular Physiology, Yale University, New Haven, USA.

Cardiac mechanics plays a crucial role in atrial and ventricular function, in the regulation of growth and remodelling, in the progression of disease, and the response to treatment. The spatial scale of the critical mechanisms ranges from nm (molecules) to cm (hearts) with the fastest events occurring in milliseconds (molecular events) and the slowest requiring months (growth and remodelling). Due to its complexity and importance, cardiac mechanics has been studied extensively both experimentally and through mathematical models and simulation. Models of cardiac mechanics evolved from seminal studies in skeletal muscle, and developed into cardiac specific, species specific, human specific and finally patient specific calculations. These models provide a formal framework to link multiple experimental assays recorded over nearly 100 years into a single unified representation of cardiac function. This review first provides a summary of the proteins, physiology and anatomy involved in the generation of cardiac pump function. We then describe the evolution of models of cardiac mechanics starting with the early theoretical frameworks describing the link between sarcomeres and muscle contraction, transitioning through myosin-level models to calcium-driven systems, and ending with whole heart patient-specific models.
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http://dx.doi.org/10.1016/j.yjmcc.2018.11.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525149PMC
February 2019