Passive transverse mechanical properties of skeletal muscle under in vivo compression

The objective of the present study is to determine the passive transverse mechanical properties of skeletal muscle. Compression experiments were performed on four rat tibialis anterior muscles. To assess the stress- and strain-distributions in the muscle during the experiment, a plane stress model of the cross section was developed for each muscle. The incompressible viscoelastic Ogden model was used to describe the passive muscle behaviour. The four material parameters were determined by fitting calculated indentation forces on measured indentation forces. The elastic parameters, mu and alpha, were 15.6+/-5.4 kPa and 21.4+/-5.7, respectively. The viscoelastic parameters, delta and tau, were 0.549+/-0.056 and 6.01+/-0.42 s. When applying the estimated material parameters in a three-dimensional finite element model, the measured behaviour can be accurately simulated.     

Multiscale modeling of skeletal muscle properties and experimental validations in isometric conditions

In this article, we describe an approach to model the electromechanical behavior of the skeletal muscle based on the Huxley formulation. We propose a model that complies with a well established macroscopic behavior of striated muscles where force-length, force–velocity, and Mirsky–Parmley properties are taken into account. These properties are introduced at the microscopic scale and related to a tentative explanation of the phenomena. The method used integrates behavior ranging from the microscopic to the macroscopic scale, and allows the computation of the dynamics of the output force and stiffness controlled by EMG or stimulation parameters. The model can thus be used to simulate and carry out research to develop control strategies using electrical stimulation in the context of rehabilitation. Finally, through animal experiments, we estimated model parameters using a Sigma Point Kalman Filtering technique and dedicated experimental protocols in isometric conditions and demonstrated that the model can accurately simulate individual variations and thus take into account subject dependent behavior.     

Context modeling based lossless compression of radio-frequency data for software-based ultrasound beamforming

A new lossless compression method using context modeling for ultrasound radio-frequency (RF) data is presented. In the proposed compression method, the combination of context modeling and entropy coding is used for effectively lowering the data transfer rates for modern software-based medical ultrasound imaging systems. From the phantom and in vivo data experiments, the proposed lossless compression method provides the average compression ratio of 0.45 compared to the Burg and JPEG-LS methods (0.52 and 0.55, respectively). This result indicates that the proposed compression method is capable of transferring 64-channel 40-MHz ultrasound RF data with a 16-lane PCI-Express 2.0 bus for software beamforming in real time.     

Refinement of protein structures by iterative comparative modeling and CryoEM density fitting

We developed a method for structure characterization of assembly components by iterative comparative protein structure modeling and fitting into cryo-electron microscopy (cryoEM) density maps. Specifically, we calculate a comparative model of a given component by considering many alternative alignments between the target sequence and a related template structure while optimizing the fit of a model into the corresponding density map. The method relies on the previously developed Moulder protocol that iterates over alignment, model building, and model assessment. The protocol was benchmarked using 20 varied target-template pairs of known structures with less than 30% sequence identity and corresponding simulated density maps at resolutions from 5A to 25A. Relative to the models based on the best existing sequence profile alignment methods, the percentage of C(alpha) atoms that are within 5A of the corresponding C(alpha) atoms in the superposed native structure increases on average from 52% to 66%, which is half-way between the starting models and the models from the best possible alignments (82%). The test also reveals that despite the improvements in the accuracy of the fitness function, this function is still the bottleneck in reducing the remaining errors. To demonstrate the usefulness of the protocol, we applied it to the upper domain of the P8 capsid protein of rice dwarf virus that has been studied by cryoEM at 6.8A. The C(alpha) root-mean-square deviation of the model based on the remotely related template, bluetongue virus VP7, improved from 8.7A to 6.0A, while the best possible model has a C(alpha) RMSD value of 5.3A. Moreover, the resulting model fits better into the cryoEM density map than the initial template structure. The method is being implemented in our program MODELLER for protein structure modeling by satisfaction of spatial restraints and will be applicable to the rapidly increasing number of cryoEM density maps of macromolecular assemblies.     

Analysis of six protein structures predicted by comparative modeling techniques

The protein structures of six comparative modeling targets were predicted in a procedure that relied on improved energy minimization, without empirical rules, to position all new atoms. The structures of human nucleoside diphosphate kinase NM23-H2, HPr from Mycoplasma capricolum, 2Fe-2S ferredoxin from Haloarcula marismortui, eosinophil-derived neurotoxin (EDN), mouse cellular retinoic acid protein I (CRABP1), and P450eryf were predicted with root mean square deviations on Cα atoms of 0.69, 0.73, 1.11, 1.48, 1.69, and 1.73 Å, respectively, compared to the target crystal structures. These differences increased as the sequence similarity between the target and parent proteins decreased from about 60 to 20% identity. More residues were predicted than form the common region shared by the two crystal structures. In most cases insertions or deletions between the target and the related protein of known structure were not correctly positioned. One two residue insertion in CRABP1 was predicted in the correct conformation, while a nine residue insertion in EDN was predicted in the correct spatial region, although not in the correct conformation. The positions of common cofactors and their binding sites were predicted correctly, even when overall sequence similarity was low. © 1995 Wiley-Liss, Inc.     

Structured modeling of recombinant protein production in batch and fed-batch culture of baculovirus-infected insect cells

The infection of insect cells with baculovirus was described in a mathematical model as a part of the structured dynamic model describing whole animal cell metabolism. The model presented here is capable of simulating cell population dynamics, the concentrations of extracellular and intracellularviral components, and the heterologous product titers. The model describes the whole processes of viral infection and theeffect of the infection on the host cell metabolism. Dynamic simulation of the model in batch and fed-batch mode gave goodagreement between model predictions and experimental data. Optimum conditions for insect cell culture and viral infectionin batch and fed-batch culture were studied using the model.     

Diffusion of water in skeletal muscle tissue is not influenced by compression in a rat model of deep tissue injury

Sustained mechanical loading of skeletal muscle may result in the development of a severe type of pressure ulcer, referred to as deep tissue injury. Recently it was shown that the diffusion of large molecules (10–150 kDa) is impaired during deformation of tissue-engineered skeletal muscle, suggesting a role for impaired diffusion in the aetiology of deep tissue injury. However, the influence of deformation on diffusion of smaller molecules on its aetiology is less clear. This motivated the present study designed to investigate the influence of deformation of skeletal muscle on the diffusion of water, which can be measured with diffusion tensor magnetic resonance imaging (MRI). It could be predicted that this approach will provide valuable information on the diffusion of small molecules. Additionally the relationship between muscle temperature and diffusion was investigated. During deformation of the tibialis anterior a decrease of the apparent diffusion coefficient (ADC) was observed (7.2±3.9%). The use of a finite element model showed that no correlation existed between the maximum shear strain and the decrease of the ADC. The ADC in the uncompressed gastrocnemius muscle decreased with 5.9±3.7%. In an additional experiment a clear correlation was obtained between the decrease of the ADC and the relative temperature change of skeletal muscle tissue as measured by MRI. Taken together, it was concluded that (1) the decreased diffusion of water was not a direct effect of tissue deformation and (2) that it is likely that the observed decreased ADC during deformation was a result of a decreased muscle temperature. The present study therefore provides evidence that diffusion of small molecules, particularly oxygen and carbon dioxide, is not impaired during deformation of skeletal muscle tissue.     

Computational insights into the binding pattern of mitochondrial calcium uniporter inhibitor through homology modeling,molecular dynamics simulation,binding free energy prediction and density functional theory calculation

Abstract

The mitochondrial calcium uniporter (MCU) is the critical protein of the inner mitochondrial membrane that is the primary mediator for calcium uptake into the mitochondrial matrix. Herein we built the optimal homology model of human MCU which was refined through all-atom molecular dynamics simulation. Then, the binding mode of known inhibitor was predicted through molecular docking method, along with molecular dynamics simulation and binding free energy calculation to verify the docking result and stability of the protein-inhibitor complex. Finally, density functional theory (DFT) calculation enhanced our understanding of the molecular interaction of MCU inhibitor. Our research would provide a deeper insight into the interactions between human MCU and its inhibitor, which boosts to develop novel therapy against MCU related disease.

Communicated by Ramaswamy H. Sarma     

Quantum chemical modeling of Co---C bond activation in B12-dependent enzymes

Recent progress in computational modeling of the catalytic activation of cobalt–carbon bond cleavage shows that quantum chemical calculations could be an important part of coenzyme B₁₂ research. Particular emphasis has been placed on density functional theory, which is now emerging as a powerful tool to elucidate the electronic structure and spectroscopic properties of the active sites of metalloenzymes.     

Muscle force recruitment and biomechanical modeling: an analysis of masseter muscle function during mastication in Macaca fascicularis.

The main purpose of this study is to test the hypothesis that as subjects chew with increasing levels of force, the ratio of the working- to balancing-side jaw-muscle force (W/B) decreases and begins to approach 1.0. We did this by analyzing relative masseter force in Macaca fascicularis using both strain gage and surface electromyographic (EMG) techniques. In addition, we also analyzed: 1) the relationship between jaw position using cineradiographic techniques and relative masseter force, 2) the timing differences between relative masseter force from the working and balancing sides, and 3) the loading and unloading characteristics of the masseter muscle. Our findings indicate that when macaques increase the amount of overall masticatory force during chewing, the W/B ratio for masseter force frequently (but not always) decreases and begins to approach 1.0. Therefore, our working hypothesis is not completely supported because the W/B ratio does not decrease with increasing levels of force in all subjects. The data also demonstrate timing differences in masseter force. During apple-skin mastication, the average peak masseter force on the working side occurs immediately at or slightly after the initial occurrence of maximum intercuspation, whereas the average peak masseter force on the balancing side occurs well before maximum intercuspation. On average, we found that peak force from the balancing-side masseter precedes the working-side masseter by about 26 msec. The greater the asynchrony between working- and balancing-side masseter force, the greater the difference in the relative magnitude of these forces. For example, in the subject with the greatest asynchrony, the balancing-side masseter had already fallen to about one-half of peak force when the working-side masseter reached peak force. Our data also indicate that the loading and unloading characteristics of the masseter differ between the working and balancing sides. Loading (from 50 to 100% of peak force) and unloading (from 100 to 50% of peak force) for the balancing-side masseter tends to be rather symmetrical. In contrast, the working-side masseter takes much longer to load from 50 to 100% of peak force than it does to unload from 100 to 50% of peak force. Finally, it takes on average about 35 msec for the working-side zygoma and 42 msec for the balancing-side zygoma to unload from 100 to 50% of peak force during apple-skin mastication, indicating that the unloading characteristics of the macaque masseter during mastication closely approximates its relaxation characteristics (as determined by muscle stimulation).     

Heme-based sensors: theoretical modeling of heme-ligand–protein interactions

Heme proteins are uniquely adapted to bind the important diatomic molecules O(2), NO and CO. An increasing number of heme proteins are being discovered that sense these molecules and thereby regulate a variety of biochemical responses. The interactions of diatomic molecules with heme, and with the surrounding protein, are therefore of great interest. Recent theoretical modeling, using density functional theory, captures many features of these interactions, as exemplified by the well-characterized heme protein myoglobin. Important details, however, especially the mutual influence of the bound diatomic molecule and the proximal ligand, remain to be clarified.     

Prediction and validation of HIV-1 gp41 ecto-transmembrane domain post-fusion trimeric structure using molecular modeling

Abstract

The glycoproteins on the surface of human immunodeficiency virus (HIV) undergoes cascade of conformational transitions to evade the human immune system. The virus replicates inside the host and infects the T-cells instigating acquired immunodeficiency syndrome (AIDS). The glycoprotein 41 (gp41) of HIV helps to mediate the fusion of virus and host membranes. The detailed mechanism of host cell invasion by virus remains obscure due to the unavailability of experimental structure of complete gp41. In the current study, the post-fusion (PoF) trimeric structure of ecto-domain including transmembrane domain of gp41 was modeled using multiple homologous templates of Simian immunodeficiency virus (SIV) and HIV-1. In order to validate the gp41 model, interactions of three peptide inhibitors: T20, C37 and C34; were studied using all-atom molecular dynamics (MD) simulations, binding free-energy calculation and per-residue energy decomposition analysis. The binding free energy calculated using MM-PBSA (Molecular Mechanics Poisson-Boltzmann surface area) method predicts maximum affinity for C34 and minimum by T20 for gp41, which is in good agreement with the available computational and experimental studies. The van der Waals interaction is a dominant contributor for the peptide-gp41 complexes. The per-residue decomposition of energy confirmed the role of Trp117, Trp120 and Ile124, present in C34 and C37, for the strong hydrophobic interactions with the deep pocket localized around the N-terminal of gp41, which is lacking in T20. The HIV-1 gp41 structure developed in this work can be used in future study to gain insight into the mechanism of virus invasion and probing potent inhibitor to eliminate AIDS.

Communicated by Ramaswamy H. Sarma     

KATP channels process nucleotide signals in muscle thermogenic response

Uniquely gated by intracellular adenine nucleotides, sarcolemmal ATP-sensitive K⁺ (K_ATP) channels have been typically assigned to protective cellular responses under severe energy insults. More recently, K_ATP channels have been instituted in the continuous control of muscle energy expenditure under non-stressed, physiological states. These advances raised the question of how K_ATP channels can process trends in cellular energetics within a milieu where each metabolic system is set to buffer nucleotide pools. Unveiling the mechanistic basis of the K_ATP channel-driven thermogenic response in muscles thus invites the concepts of intracellular compartmentalization of energy and proteins, along with nucleotide signaling over diffusion barriers. Furthermore, it requires gaining insight into the properties of reversibility of intrinsic ATPase activity associated with K_ATP channel complexes. Notwithstanding the operational paradigm, the homeostatic role of sarcolemmal K_ATP channels can be now broadened to a wider range of environmental cues affecting metabolic well-being. In this way, under conditions of energy deficit such as ischemic insult or adrenergic stress, the operation of K_ATP channel complexes would result in protective energy saving, safeguarding muscle performance and integrity. Under energy surplus, downregulation of K_ATP channel function may find potential implications in conditions of energy imbalance linked to obesity, cold intolerance and associated metabolic disorders.     

Regulation and dysregulation of fibrosis in skeletal muscle

In response to skeletal muscle injury, distinct cellular pathways are activated to repair the damaged tissue. Activation and restriction of these pathways must be temporally coordinated in a precise sequence as regeneration progresses if muscle integrity and homeostasis are to be restored. However, if tissue injury persists, as in severe muscular dystrophies, the repair process becomes uncontrolled leading to the substitution of myofibers by a non-functional mass of fibrotic tissue. In this review, we provide an overview of how muscle responds to damage and aging, with special emphasis on the cellular effectors and the regulatory and inflammatory pathways that can shift normal muscle repair to fibrosis development.     

藏羚羊骨骼肌肌红蛋白含量及乳酸脱氢酶、苹果酸脱氢酶活力的研究

目的:探讨藏羚羊骨骼肌对低氧环境的适应机制。方法:以生活在同海拔高度(4 300 m)的藏绵羊和低海拔绵羊(1 800 m)为对照,用分光光度法测定三种动物骨骼肌中肌红蛋白(Mb)含量、乳酸(LA)含量,酶活力法测定三种动物骨骼肌中乳酸脱氢酶(LDH)和苹果酸脱氢酶(MDH)活力。结果:藏羚羊骨骼肌中Mb含量明显高于藏绵羊和低海拔绵羊(P<0.05),而藏绵羊和低海拔绵羊间无明显差异。LA含量和LDH活力明显低于藏绵羊和低海拔绵羊(P<0.05),而MDH活力及MDH/LDH比值显著高于藏绵羊和低海拔绵羊(P<0.05),藏绵羊和低海拔绵羊间无明显差异。结论:藏羚羊可能通过增加骨骼肌中Mb的含量,提高其在低氧环境获取氧的能力,且藏羚羊骨骼肌组织中有氧代谢比例高,这可能与肌肉中Mb含量较高有关,推测藏羚羊较高的Mb含量可能是其适应高原缺氧条件的分子基础之一。     

Investigation of the role of interneurons and their modulation by centrifugal fibers in a neural model of the olfactory bulb

Olfactory bulb processing results from the interaction of relay neurons with two main categories of interneurons which mediate inhibition in two distinct layers: periglomerular cells and granule cells. We present here a neural model of the mammalian olfactory bulb which allows to separately investigate the functional consequences of the two types of interneurons onto the relay neurons responsiveness to odors. The model, although built with simplified representations of neural elements generates various aspects of neural dynamics from the cellular to the populational level. We propose that the combined action of centrifugal control at two different layers of processing is complementary: reduction of the number of active relay neurons responding to a given odorant through increased activity of periglomerular cells, and an increase of response intensity of active mitral cells through decrease of granule cell inhibition.