A Neuro-Muscular Elasto-Dynamic Model of the Human Arm Part 1: Model Development

In this paper we develop an elasto-dynamic model of the human arm for use in neuro-muscular control and dynamic interactionstudies.The motivation for this work is to present a case for developing and using non-quasistatic models of humanmusculo-skeletal biomechanics.The model is based on hybrid parameter multiple body system(HPMBS)variational projectionprinciples.In this paper,we present an overview of the HPMBS variational principle applied to the full elasto-dynamic model ofthe arm.The generality of the model allows one to incorporate muscle effects as either loads transmitted through the tendon atpoints of origin and insertion or as an effective torque at a joint.Though the technique is suitable for detailed bone and jointmodeling,we present in this initial effort only simple geometry with the bones discretized as Rayleigh beams with elongation,while allowing for large deflections.Simulations demonstrate the viability of the mcthod for use in the companion paper and infuture studies.     

A Three-Dimensional Musculoskeletal Model of the Human Knee Joint. Part 2: Analysis of Ligament Function

A three-dimensional model of the knee is used to study ligament function during anterior-posterior (a-p) draw, axial rotation, and isometric contractions of the extensor and flexor muscles. The geometry of the model bones is based on cadaver data. The contacting surfaces of the femur and tibia are modeled as deformable; those of the femur and patella are assumed to be rigid. Twelve elastic elements are used to describe the geometry and mechanical properties of the cruciate ligaments, the collateral ligaments, and the posterior capsule. The model is actuated by thirteen musculotendinous units, each unit represented as a three-element muscle in series with tendon. The calculations show that the forces applied during a-p draw are substantially different from those applied by the muscles during activity. Principles of knee-ligament function based on the results of in vitro experiments may therefore be overstated. Knee-ligament forces during straight a-p draw are determined solely by the changing geometry of the ligaments relative to the bones: ACL force decreases with increasing flexion during anterior draw because the angle between the ACL and the tibial plateau decreases as knee flexion increases; PCL force increases with increasing flexion during posterior draw because the angle between the PCL and the tibial plateau increases. The pattern of ligament loading during activity is governed by the geometry of the muscles spanning the knee: the resultant force in the ACL during isometric knee extension is determined mainly by the changing orientation of the patellar tendon relative to the tibia in the sagittal plane; the resultant force in the PCL during isometric knee flexion is dominated by the angle at which the hamstrings meet the tibia in the sagittal plane.     

A Mathematical Model of Uterine Dynamics and its Application to Human Parturition

We have developed a simple mathematical model with three physiologically significant states to describe the changes in intrauterine pressure associated with a contraction during human parturition. The myometrium is modelled as a set of smooth muscle cells, each of which is in one of three states (quiescent, contracted, refractory) at a given time. These states are occupied according to a cycle governed by three temporal parameters. The solutions of the equations describing the model show an oscillatory behavior for particular values of these parameters, which is very similar to the time dependant development of intrauterine pressure during labor. Due to its non-linear terms, our model could lead to chaotic oscillations (in the mathematical sense), whose clinical counterpart may occur in cases of dystocia. Despite its simplicity, this model appears to be a useful guide to further investigations of the oscillatory behavior of the myometrium, or other smooth muscles, in normal and pathological situations.     

皮肤的光学模型

基于人体皮肤的组织结构,光在皮肤组织中的传输特性以及皮肤各层的组织光学参数,建立了正常皮肤的光学模型,介绍了该模型中的组织光学参数的确定方法。本文建立的皮肤组织光学模型及其方法,可应用于皮肤光学基础与临床的其它研究中。     

A Three-Dimensional Musculoskeletal Model of the Human Knee Joint. Part 2: Analysis of Ligament Function

A three-dimensional model of the knee is used to study ligament function during anterior-posterior (a-p) draw, axial rotation, and isometric contractions of the extensor and flexor muscles. The geometry of the model bones is based on cadaver data. The contacting surfaces of the femur and tibia are modeled as deformable; those of the femur and patella are assumed to be rigid. Twelve elastic elements are used to describe the geometry and mechanical properties of the cruciate ligaments, the collateral ligaments, and the posterior capsule. The model is actuated by thirteen musculotendinous units, each unit represented as a three-element muscle in series with tendon. The calculations show that the forces applied during a-p draw are substantially different from those applied by the muscles during activity. Principles of knee-ligament function based on the results of in vitro experiments may therefore be overstated. Knee-ligament forces during straight a-p draw are determined solely by the changing geometry of the ligaments relative to the bones: ACL force decreases with increasing flexion during anterior draw because the angle between the ACL and the tibial plateau decreases as knee flexion increases; PCL force increases with increasing flexion during posterior draw because the angle between the PCL and the tibial plateau increases. The pattern of ligament loading during activity is governed by the geometry of the muscles spanning the knee: the resultant force in the ACL during isometric knee extension is determined mainly by the changing orientation of the patellar tendon relative to the tibia in the sagittal plane; the resultant force in the PCL during isometric knee flexion is dominated by the angle at which the hamstrings meet the tibia in the sagittal plane.     

Synaptic Vesicle Dynamics: A Simple Model of Phasic Release

We present a simple model of phasic neurotransmitter release whichreproduces the salient features of chemical neurotransmission. The synapticvesicle cycle has been modelled as a set of biochemical reactionsrepresented by a system of coupled differential equations. These equationshave been solved analytically to obtain the time dependent behaviour of thesystem on perturbation from the steady state. The scheme of the synapticvesicle network has been emphasized and its role in determining some of themajor experimentally observed properties of synaptic transmission has beendiscussed, which includes the biphasic decay of the rate neurotransmitterrelease even under sustained stimulation. Another interesting outcome ofthis theoretical exercise is the saturation of total release with thecalcium dependent rate constant. The theoretically calculated values oftotal release fit very well into a sigmoidal saturating function with afourth order cooperativity exponent similar to the empiricalDodge–Rahamimoff equation. It appears that the synaptic vesiclenetwork itself is responsible for some of the major properties associatedwith chemical neurotransmission.     

Effects of Density Dependent Migrations on the Dynamics of a Predator Prey Model

We study the effects of density dependent migrations on the stability of a predator-prey model in a patchy environment which is composed with two sites connected by migration. The two patches are different. On the first patch, preys can find resource but can be captured by predators. The second patch is a refuge for the prey and thus predators do not have access to this patch. We assume a repulsive effect of predator on prey on the resource patch. Therefore, when the predator density is large on that patch, preys are more likely to leave it to return to the refuge. We consider two models. In the first model, preys leave the refuge to go to the resource patch at constant migration rates. In the second model, preys are assumed to be in competition for the resource and leave the refuge to the resource patch according to the prey density. We assume two different time scales, a fast time scale for migration and a slow time scale for population growth, mortality and predation. We take advantage of the two time scales to apply aggregation of variables methods and to obtain a reduced model governing the total prey and predator densities. In the case of the first model, we show that the repulsive effect of predator on prey has a stabilizing effect on the predator-prey community. In the case of the second model, we show that there exists a window for the prey proportion on the resource patch to ensure stability.     

荒漠麻蜥骨骼系统的解剖及与相近科属蜥蜴骨骼特征比较

采用透明骨骼染色法,观测了荒漠麻蜥Eremias przewaskii比较完整的骨骼系统,对其各部分骨骼组成、形态和位置作了详细的描述,为麻蜥属的分类及演化提供骨骼方面的基础资料。其骨骼可分为中轴骨骼(包括头骨、脊柱、胸骨和肋骨)和附肢骨骼(包括肩带、腰带、前肢骨和后肢骨)。其头骨呈三角形,眼窝与颞窝相通,不完整。颈椎8枚,胸椎5枚,腰椎13枚,荐椎2枚,尾椎44～45枚。与已报道的蜥蜴物种骨骼特征相比较,发现其前肢腕骨部位、尺骨和桡骨远端中间具1枚骨化不完全的籽骨——介间骨;在前肢腕骨与掌骨的腹面,有2块平面不规整四方形的掌籽骨,位于连接腕骨与各掌骨的韧带中间;在后肢股骨远端的关节内侧与髌骨相对的位置存在1粒籽骨,为股腓侧豆状骨;跗骨腹面下方有1枚三角形籽骨——跗籽骨。     

A Three-Dimensional Musculoskeletal Model of the Human Knee Joint. Part 1: Theoretical Construction

A three-dimensional model of the knee is developed to study the interactions between the muscles, ligaments, and bones during activity. The geometry of the distal femur, proximal tibia, and patella is based on cadaver data reported for an average-size knee. The shapes of the femoral condyles are represented by high-order polynomials: the tibial plateaux and patellar facets are approximated as flat surfaces. The contacting surfaces of the femur and tibia are modeled as deformable, while those of the femur and patella are assumed to be rigid. Interpenetration of the femur and tibia is taken into account by modeling cartilage as a thin, linear, elastic layer, mounted on rigid bone. Twelve elastic elements describe the geometry and mechanical properties of the cruciate ligaments, the collateral ligaments, and the posterior capsule. The model is actuated by thirteen musculotendinous units, each unit modeled as a three-element muscle in series with tendon. The path of each muscle is approximated as a straight line, except where it contacts and wraps around bone and other muscles; changes in muscle paths are taken into account using data obtained from MRI. In the first part of this paper, the model is used to simulate passive knee flexion. Quantitative comparisons of the model results with experimental data reported in the literature indicate that the relative movements of the bones and the geometry of the ligaments and muscles in the model are similar to those evident in the real knee. In Part II, the model is used to describe knee-ligament function during anterior-posterior draw, axial rotation, and isometric knee-extension and knee-flexion exercises.     

A Three-Dimensional Musculoskeletal Model of the Human Knee Joint. Part 1: Theoretical Construct

A three-dimensional model of the knee is developed to study the interactions between the muscles, ligaments, and bones during activity. The geometry of the distal femur, proximal tibia, and patella is based on cadaver data reported for an average-size knee. The shapes of the femoral condyles are represented by high-order polynomials; the tibial plateaux and patellar facets are approximated as flat surfaces. The contacting surfaces of the femur and tibia are modeled as deformable, while those of the femur and patella are assumed to be rigid. Interpenetration of the femur and tibia is taken into account by modeling cartilage as a thin, linear, elastic layer, mounted on rigid bone. Twelve elastic elements describe the geometry and mechanical properties of the cruciate ligaments, the collateral ligaments, and the posterior capsule. The model is actuated by thirteen musculotendinous units, each unit modeled as a three-element muscle in series with tendon. The path of each muscle is approximated as a straight line, except where it contacts and wraps around bone and other muscles; changes in muscle paths are taken into account using data obtained from MRI. In the first part of this paper, the model is used to simulate passive knee flexion. Quantitative comparisons of the model results with experimental data reported in the literature indicate that the relative movements of the bones and the geometry of the ligaments and muscles in the model are similar to those evident in the real knee. In Part II, the model is used to describe knee-ligament function during anterior-posterior draw, axial rotation, and isometric knee-extension and knee-flexion exercises.     

A Discrete Electromechanical Model for Human Cardiac Tissue: Effects of Stretch-Activated Currents and Stretch Conditions on Restitution Properties and Spiral Wave Dynamics

We introduce an electromechanical model for human cardiac tissue which couples a biophysical model of cardiac excitation (Tusscher, Noble, Noble, Panfilov, 2006) and tension development (adjusted Niederer, Hunter, Smith, 2006 model) with a discrete elastic mass-lattice model. The equations for the excitation processes are solved with a finite difference approach, and the equations of the mass-lattice model are solved using Verlet integration. This allows the coupled problem to be solved with high numerical resolution. Passive mechanical properties of the mass-lattice model are described by a generalized Hooke''s law for finite deformations (Seth material). Active mechanical contraction is initiated by changes of the intracellular calcium concentration, which is a variable of the electrical model. Mechanical deformation feeds back on the electrophysiology via stretch-activated ion channels whose conductivity is controlled by the local stretch of the medium. We apply the model to study how stretch-activated currents affect the action potential shape, restitution properties, and dynamics of spiral waves, under constant stretch, and dynamic stretch caused by active mechanical contraction. We find that stretch conditions substantially affect these properties via stretch-activated currents. In constantly stretched medium, we observe a substantial decrease in conduction velocity, and an increase of action potential duration; whereas, with dynamic stretch, action potential duration is increased only slightly, and the conduction velocity restitution curve becomes biphasic. Moreover, in constantly stretched medium, we find an increase of the core size and period of a spiral wave, but no change in rotation dynamics; in contrast, in the dynamically stretching medium, we observe spiral drift. Our results may be important to understand how altered stretch conditions affect the heart''s functioning.     

Clomipramine and Related Structures as Inhibitors of the Skeletal Sarcoplasmic Reticulum Ca2+ Pump

The Ca²⁺-pumping activity of skeletal sarcoplasmic reticulum vesicles is half-maximallyinhibited by 120 M clomipramine, 250 M desipramine, and 500 M imipramine or trimipramine.The inhibition is attributed to the dihydrodibenzazepine moiety, since3-(dimethylamino)propionitrile, reproducing the aliphatic amine chain, has no inhibitory action. The inhibitionis shown as a marked decrease of Ca²⁺ binding at equilibrium in theabsence of ATP and asa reduction of phosphorylation of the Ca²⁺-free conformation byinorganic phosphate. Therefore,the drug effect is consistent with preferential interaction of tricyclic antidepressants withthe Ca²⁺-free conformation of the nonphosphorylated enzyme. An additional decrease in theapparent rate constant of enzyme dephosphorylation, i.e., in the release of phosphate fromATP during enzyme cycling was also noticed.     

Molecular Dynamics Study of the Human Beta-defensins 2 and 3 Chimeric Peptides with the Cell Membrane Model of Pseudomonas aeruginosa

International Journal of Peptide Research and Therapeutics - Pseudomonas aeruginosa is a unique microorganism among the antibiotic-resistant microbial pathogens. Among the various therapeutic...     

Model-free Analysis of Protein Dynamics: Assessment of Accuracy and Model Selection Protocols Based on Molecular Dynamics Simulation

The popular model-free approach to analyze NMR relaxation measurements has been examined using artificial amide (15)N relaxation data sets generated from a 10 nanosecond molecular dynamics trajectory of a dihydrofolate reductase ternary complex in explicit water. With access to a detailed picture of the underlying internal motions, the efficacy of model-free analysis and impact of model selection protocols on the interpretation of NMR data can be studied. In the limit of uncorrelated global tumbling and internal motions, fitting the relaxation data to the model-free models can recover a significant amount of quantitative information on the internal dynamics. Despite a slight overestimation, the generalized order parameter is quite accurately determined. However, the model-free analysis appears to be insensitive to the presence of nanosecond time scale motions with relatively small magnitude. For such cases, the effective correlation time can be significantly underestimated. As a result, proteins appear to be more rigid than they really are. The model selection protocols have a major impact on the information one can reliably obtain. The commonly employed protocol based on step-up hypothesis testing has severe drawbacks of oversimplification and underfitting. The consequences are that the order parameter is more severely overestimated and the correlation time more severely underestimated. Instead, model selection based on Bayesian Information Criteria (BIC), recently introduced to the model-free analysis by d'Auvergne and Gooley (2003), provides a better balance between bias and variance. More appropriate models can be selected, leading to improved estimate of both the order parameter and correlation time. In addition, the computational cost is significantly reduced and subjective parameters such as the significance level are unnecessary.     

A Compare-and-Contrast NMR Dynamics Study of Two Related RRMs: U1A and SNF

The U1A/U2B″/SNF family of small nuclear ribonucleoproteins uses a phylogenetically conserved RNA recognition motif (RRM1) to bind RNA stemloops in U1 and/or U2 small nuclear RNA (snRNA). RRMs are characterized by their α/β sandwich topology, and these RRMs use their β-sheet as the RNA binding surface. Unique to this RRM family is the tyrosine-glutamine-phenylalanine (YQF) triad of solvent-exposed residues that are displayed on the β-sheet surface; the aromatic residues form a platform for RNA nucleobases to stack. U1A, U2B″, and SNF have very different patterns of RNA binding affinity and specificity, however, so here we ask how YQF in Drosophila SNF RRM1 contributes to RNA binding, as well as to domain stability and dynamics. Thermodynamic double-mutant cycles using tyrosine and phenylalanine substitutions probe the communication between those two residues in the free and bound states of the RRM. NMR experiments follow corresponding changes in the glutamine side-chain amide in both U1A and SNF, providing a physical picture of the RRM1 β-sheet surface. NMR relaxation and dispersion experiments compare fast (picosecond to nanosecond) and intermediate (microsecond-to-millisecond) dynamics of U1A and SNF RRM1. We conclude that there is a network of amino acid interactions involving Tyr-Gln-Phe in both SNF and U1A RRM1, but whereas mutations of the Tyr-Gln-Phe triad result in small local responses in U1A, they produce extensive microsecond-to-millisecond global motions throughout SNF that alter the conformational states of the RRM.     

利用果蝇模型研究人类心脏早期发育的分子机理(英文)

近年来 ,果蝇心脏特化的遗传机制已初步研究清楚 ,但控制人类心脏早期发育的基因尚待鉴定。因为调控果蝇和脊椎动物早期心脏细胞命运定型的途径具有保守性 ,果蝇是一种探讨人类心脏早期发育的分子机理的理想动物模式。为此目的 ,我们采用P转座子和EMS诱变技术建立了约 3 0 0 0个隐性致死基因平衡系。通过心脏前体细胞特异性抗体免疫组化筛选 ,我们检出 2 0 0余个表现心脏突变表型的平衡致死系。我们进一步利用RNAi技术对一些基因的功能进行了初步的研究 ,证明这些基因表现RNAi的突变表型 ,该类突变表型与基因突变时表现的表型相似 ,即心管呈缺陷型或无心脏前体细胞形成。利用果蝇和人类基因组计划获得的成果 ,我们从果蝇心脏侯选基因中初步克隆和鉴定了 5 0个人类同源基因 ,其中 2 0个是新基因。Northen印迹分析表明 ,一部分人类基因在心脏组织中有表达 ,从而为研究这些基因在人类心脏早期发育中的作用提供了信息。目前 ,我们正在建立转基因果蝇 ,以此为模型研究这些基因是否对心肌细胞发生或心肌功能起调控作用。产生心肌细胞突变类型的基因如果类似于人类心脏病综合症 ,则可以作为人类心脏疾病侯选基因作进一步的分析。     

An Interactive Model of Human and Companion Animal Dynamics: The Ecology and Economics of Dog Overpopulation and the Human Costs of Addressing the Problem

Companion animal overpopulation is a problem of human creation with significant human costs that can only be addressed through human action. A model was constructed to understand the dynamics of canine overpopulation and the effectiveness of various policy options for reducing euthanasia. The model includes economic and ecological factors in human and dog populations. According to the model, a no-kill society is an achievable goal at an acceptable human cost. Spay/neuter programs were generally found to be the most effective, with increasing adoptions also being an effective option. However, spay/neuter policies need to be evaluated over a very long time horizon since full impact may not be achieved for 30 years or more. Spay/neuter efforts can have a large impact even if they only effect a small portion of the human population. Adoption and spay/neuter programs were found to work well in combination, and to continue being effective as society approaches no-kill dynamics.     

单种群生长的广义Logistic模型中参数的一种估值方法

本文提出种群生长的实测数据与广义Logistic模型的相容性条件,给出估计环境容纳量K的数学方法,利用常微分方程反问题的处理方法与麦夸特方法,对模型中参数进行近似估计与优化估计,其方法简便、通用性强．     

Human CDK2 Inhibition Modifies the Dynamics of Chromatin-Bound Minichromosome Maintenance Complex and Replication Protein A

Minichromosome maintenance (MCM) proteins form a complex and possess helicase activity to unwind the DNA duplex and establish a replication fork. To assure that origins only fire once per cell cycle, the MCM complex is removed from chromatin and inactivated as cells exit S phase. In this report, we demonstrate that CDK2 depletion in human cells leads to an overall phosphorylation defect at mitosis with increased rereplication, correlated with the accumulation of chromatin-bound MCM proteins. We show that CDK2 suppression results in decreased MCM4 phosphorylation at multiple serine and threonine sites. In addition, CDK2 inhibition induces an increase in chromatin-bound replication protein A (RPA) which should bindto single-stranded DNA regions, possibly establishing a replication intermediate that activates the ATR cascade. Finally, we observe that loss of CDK2 function in G1 delays replication initiation while it promotes rereplication in G2/M. Thus, by modulating the phospho-status of MCM4 and regulating origin firing, S phase CDK2 appears to be an integrated component of cellular machinery required for temporally controlling replication activity and maintaining genomic stability.