A general-purpose framework to simulate musculoskeletal system of human body: using a motion tracking approach*

Computation of muscle force patterns that produce specified movements of muscle-actuated dynamic models is an important and challenging problem. This problem is an undetermined one, and then a proper optimization is required to calculate muscle forces. The purpose of this paper is to develop a general model for calculating all muscle activation and force patterns in an arbitrary human body movement. For this aim, the equations of a multibody system forward dynamics, which is considered for skeletal system of the human body model, is derived using Lagrange–Euler formulation. Next, muscle contraction dynamics is added to this model and forward dynamics of an arbitrary musculoskeletal system is obtained. For optimization purpose, the obtained model is used in computed muscle control algorithm, and a closed-loop system for tracking desired motions is derived. Finally, a popular sport exercise, biceps curl, is simulated by using this algorithm and the validity of the obtained results is evaluated via EMG signals.     

Distribution of unselectively bound ligands along DNA

Unselective and reversible adsorption of ligands on DNA for a model of binding proposed by Zasedatelev, Gursky, and Volkenshtein is considered. In this model, the interaction between neighboring ligands located at the distance of i binding centers is characterized by the statistical weight a(i). Each ligand covers L binding centers. For this model, expressions for binding averages are represented in a new simple form. This representation is convenient for the calculation of the fraction of inter-ligand distances of i binding centers f(d)(i) and the fraction of binding centers included in the distances of i binding centers f(bc)(i) for various types of interaction between bound ligands. It is shown that, for non-cooperative binding, contact cooperativity and long-range cooperativity, the fraction of the zero inter-ligand distance f(d)(0) is maximal at any relative concentration of bound ligands (r). Calculations demonstrate that, at low r, f(d)(0) approximately r . a(o), and f(d)(i) approximately r at 1 1/r-L, then f(d)(i) rapidly decreases with i at any r for all types of inter-ligand interaction. At high ligand concentration (r is close to r(max) = L(-1)), f(d)(0) is close to unity and f(d)(i) rapidly decreases with i for any type of inter-ligand interaction. For strong contact cooperativity, f(d)(0) is close to unity in a much lager r interval ((0.5-1) . r(max)), and f(d)(1) approximately a(o)(-1) at r approximately 0.5 . r(max). In the case of long-range interaction between bound ligands, the dependence f(d)(i) is more complex and has a maximum at i approximately (1/r-L)(1/2) for anti-cooperative binding. f(bc)(i) is maximal at i approximately 1/r-L for all types of binding except the contact cooperativity. A strong asymmetry in the influence of contact cooperativity and anticooperativity on the ligand distribution along DNA is demonstrated.     

Statistical shape modelling versus linear scaling: Effects on predictions of hip joint centre location and muscle moment arms in people with hip osteoarthritis

Marker-based dynamic functional or regression methods are used to compute joint centre locations that can be used to improve linear scaling of the pelvis in musculoskeletal models, although large errors have been reported using these methods. This study aimed to investigate if statistical shape models could improve prediction of the hip joint centre (HJC) location. The inclusion of complete pelvis imaging data from computed tomography (CT) was also explored to determine if free-form deformation techniques could further improve HJC estimates. Mean Euclidean distance errors were calculated between HJC from CT and estimates from shape modelling methods, and functional- and regression-based linear scaling approaches. The HJC of a generic musculoskeletal model was also perturbed to compute the root-mean squared error (RMSE) of the hip muscle moment arms between the reference HJC obtained from CT and the different scaling methods. Shape modelling without medical imaging data significantly reduced HJC location error estimates (11.4 ± 3.3 mm) compared to functional (36.9 ± 17.5 mm, p = <0.001) and regression (31.2 ± 15 mm, p = <0.001) methods. The addition of complete pelvis imaging data to the shape modelling workflow further reduced HJC error estimates compared to no imaging (6.6 ± 3.1 mm, p = 0.002). Average RMSE were greatest for the hip flexor and extensor muscle groups using the functional (16.71 mm and 8.87 mm respectively) and regression methods (16.15 mm and 9.97 mm respectively). The effects on moment-arms were less substantial for the shape modelling methods, ranging from 0.05 to 3.2 mm. Shape modelling methods improved HJC location and muscle moment-arm estimates compared to linear scaling of musculoskeletal models in patients with hip osteoarthritis.     

Evaluation of Parallel Decomposition Methods for Biomechanical Optimizations

As the complexity of musculoskeletal models continues to increase, so will the computational demands of biomechanical optimizations. For this reason, parallel biomechanical optimizations are becoming more common. Most implementations parallelize the optimizer. In this study, an alternate approach is investigated that parallelizes the analysis function (i.e., a kinematic or dynamic simulation) called repeatedly by the optimizer to calculate the cost function and constraints. To evaluate this approach, a system identification problem involving a kinematic ankle joint model was solved using a gradient-based optimizer and three parallel decomposition methods: gradient calculation decomposition, analysis function decomposition, or both methods combined. For a given number of processors, analysis function decomposition exhibited the best performance despite the highest communication and synchronization overhead, while gradient calculation decomposition demonstrated the worst performance due to the fact that the necessary line searches were not performed in parallel. These findings suggest that the method of parallelization most commonly used for biomechanical optimizations may not be the most efficient, depending on the optimization algorithm used. In many applications, the best computational strategy may be to focus on parallelizing the analysis function.     

Evaluation of parallel decomposition methods for biomechanical optimizations

As the complexity of musculoskeletal models continues to increase, so will the computational demands of biomechanical optimizations. For this reason, parallel biomechanical optimizations are becoming more common. Most implementations parallelize the optimizer. In this study, an alternate approach is investigated that parallelizes the analysis function (i.e., a kinematic or dynamic simulation) called repeatedly by the optimizer to calculate the cost function and constraints. To evaluate this approach, a system identification problem involving a kinematic ankle joint model was solved using a gradient-based optimizer and three parallel decomposition methods: gradient calculation decomposition, analysis function decomposition, or both methods combined. For a given number of processors, analysis function decomposition exhibited the best performance despite the highest communication and synchronization overhead, while gradient calculation decomposition demonstrated the worst performance due to the fact that the necessary line searches were not performed in parallel. These findings suggest that the method of parallelization most commonly used for biomechanical optimizations may not be the most efficient, depending on the optimization algorithm used. In many applications, the best computational strategy may be to focus on parallelizing the analysis function.     

Musculoskeletal complaints among Italian X-ray technology students: a cross-sectional questionnaire survey

Background

There is a high prevalence of musculoskeletal disorders among healthcare professional students. Although recent studies show musculoskeletal disorders are a common problem among X-ray technologists, there are no data on these disorders among students of this healthcare profession. We have therefore estimated the prevalence of musculoskeletal complaints among a group of X-ray technology students.

Methods

The students (n = 109) currently attending the 3-year X-ray technologist school at a large University in the Apulia region of Southern Italy were recruited for the study, with a 100% participation rate. A questionnaire collected data concerning personal characteristics, physical exposure during training activities, and the presence of musculoskeletal symptoms in the neck, shoulders, low back, hand/wrist and legs.

Results

The prevalence of complaints in any body site over the previous 12 months was 37%. Low back pain was the most frequently reported symptom (27%), followed by neck (16%), shoulder (11%), leg (8%) and hand/wrist (5%) pain. Poor physical activity was associated with the complaints.

Conclusions

Our study showed prevalence rates of musculoskeletal complaints among X-ray technology students to be somewhat high, representing about half of those found in Italian technologists. The most common musculoskeletal problem was low back pain, which had also been found in research conducted among nursing students. Our research also showed a significant association between poor physical activity and the presence of musculoskeletal disorders in young university students.

     

Associative search network: A reinforcement learning associative memory

An associative memory system is presented which does not require a teacher to provide the desired associations. For each input key it conducts a search for the output pattern which optimizes an external payoff or reinforcement signal. The associative search network (ASN) combines pattern recognition and function optimization capabilities in a simple and effective way. We define the associative search problem, discuss conditions under which the associative search network is capable of solving it, and present results from computer simulations. The synthesis of sensory-motor control surfaces is discussed as an example of the associative search problem.     

The mutated subsequence problem and locating conserved genes

MOTIVATION: For the purpose of locating conserved genes in a whole genome scale, this paper proposes a new structural optimization problem called the Mutated Subsequence Problem, which gives consideration to possible mutations between two species (in the form of reversals and transpositions) when comparing the genomes. RESULTS: A practical algorithm called mutated subsequence algorithm (MSS) is devised to solve this optimization problem, and it has been evaluated using different pairs of human and mouse chromosomes, and different pairs of virus genomes of Baculoviridae. MSS is found to be effective and efficient; in particular, MSS can reveal >90% of the conserved genes of human and mouse that have been reported in the literature. When compared with existing softwares MUMmer and MaxMinCluster, MSS uncovers 14 and 7% more genes on average, respectively. Furthermore, this paper shows a hybrid approach to integrate MUMmer or MaxMinCluster with MSS, which has better performance and reliability.     

Comparative analysis of dermal collagen and lipids in cereblon ablated mice using a multimodal nonlinear optical system

By utilizing a multimodal nonlinear optical system that combines coherent anti-Stokes Raman scattering and second harmonic generation to investigate biological characteristics of dermal tissues ex vivo, we demonstrate the potential feasibility of using this optical approach as a powerful new investigative tool for future biomedical research. For this study, our optical system was utilized for the first time to analyze lipid and collagen profiles in cereblon knockout (KO) mouse skin, and we were able to discover significant alterations in the number of carbon–carbon double bonds (wild-type vs. cereblon KO; N_CC: 0.75 vs. 0.85) of skin fatty acids in triacylglycerides as well as changes in dermal collagen fibers (25% reduction in cereblon KO). By adopting our optical system to biological studies, we provide researchers with another diagnostic approach to validate their experimental results, which will significantly advance the state of biomedical research.     

Structure of the fronts of strong collisional shock waves in an ideal two-temperature electron-ion plasma with ions of arbitrary charge

Solutions in the form of plane running waves are investigated numerically in the framework of a two-temperature hydrodynamic model of a fully ionized ideal plasma with ions of arbitrary charge number Z₀. Most simulations were carried out for simple boundary conditions corresponding to a cold immobile plasma at the front of a running wave. All the solutions obtained have a discontinuity in the form of an isoelectronic-thermal jump, whose parameters relax to their steady-state values in the course of calculation. The problem of finding numerical solutions in which all the quantities at infinity take on finite (equilibrium) values actually reduces to the problem of the front structure of a strong shock wave. For a plasma with singly changed ions (Z₀ = 1), numerical solutions were found to coincide with the previously known solution. For a plasma with arbitrarily charged ions (Z₀ > 1), numerical solutions were obtained for the first time on the basis of justified formulas for the electron thermal conductivity.     

Electric dipole theory and thermodynamics of actomyosin molecular motor in muscle contraction

Movements in muscles are generated by the myosins which interact with the actin filaments. In this paper we present an electric theory to describe how the chemical energy is first stored in electrostatic form in the myosin system and how it is then released and transformed into work. Due to the longitudinal polarized molecular structure with the negative phosphate group tail, the ATP molecule possesses a large electric dipole moment (p(0)), which makes it an ideal energy source for the electric dipole motor of the actomyosin system. The myosin head contains a large number of strongly restrained water molecules, which makes the ATP-driven electric dipole motor possible. The strongly restrained water molecules can store the chemical energy released by ATP binding and hydrolysis processes in the electric form due to their myosin structure fixed electric dipole moments (p(i)). The decrease in the electric energy is transformed into mechanical work by the rotational movement of the myosin head, which follows from the interaction of the dipoles p(i) with the potential field V(0) of ATP and with the potential field Psi of the actin. The electrical meaning of the hydrolysis reaction is to reduce the dipole moment p(0)-the remaining dipole moment of the adenosine diphosphate (ADP) is appropriately smaller to return the low negative value of the electric energy nearly back to its initial value, enabling the removal of ADP from the myosin head so that the cycling process can be repeated. We derive for the electric energy of the myosin system a general equation, which contains the potential field V(0) with the dipole moment p(0), the dipole moments p(i) and the potential field psi. Using the previously published experimental data for the electric dipole of ATP (p(0) congruent with 230 debye) and for the amount of strongly restrained water molecules (N congruent with 720) in the myosin subfragment (S1), we show that the Gibbs free energy changes of the ATP binding and hydrolysis reaction steps can be converted into the form of electric energy. The mechanical action between myosin and actin is investigated by the principle of virtual work. An electric torque always appears, i.e. a moment of electric forces between dipoles p(0) and p(i)(/M/ > or = 16 pN nm) that causes the myosin head to function like a scissors-shaped electric dipole motor. The theory as a whole is illustrated by several numerical examples and the results are compared with experimental results.     

Efficient calculation of interval scores for DNA copy number data analysis.

DNA amplifications and deletions characterize cancer genome and are often related to disease evolution. Microarray-based techniques for measuring these DNA copy-number changes use fluorescence ratios at arrayed DNA elements (BACs, cDNA, or oligonucleotides) to provide signals at high resolution, in terms of genomic locations. These data are then further analyzed to map aberrations and boundaries and identify biologically significant structures. We develop a statistical framework that enables the casting of several DNA copy number data analysis questions as optimization problems over real-valued vectors of signals. The simplest form of the optimization problem seeks to maximize phi(I) = Sigmanu(i)/radical|I| over all subintervals I in the input vector. We present and prove a linear time approximation scheme for this problem, namely, a process with time complexity O (nepsilon(-2)) that outputs an interval for which phi(I) is at least Opt/alpha(epsilon), where Opt is the actual optimum and alpha(epsilon) --> 1 as epsilon --> 0. We further develop practical implementations that improve the performance of the naive quadratic approach by orders of magnitude. We discuss properties of optimal intervals and how they apply to the algorithm performance. We benchmark our algorithms on synthetic as well as publicly available DNA copy number data. We demonstrate the use of these methods for identifying aberrations in single samples as well as common alterations in fixed sets and subsets of breast cancer samples.     

Electroporative fast pore-flickering of the annexin V-lipid surface complex, a novel gating concept for ion transport

In contact with lipid bilayers and Ca2+-ions, the intracellular protein human annexin V (wild-type), Mr = 35,800, forms two types of cation-selective channels for the transport of Ca2+-, K+-, Na+- and Mg2+-ions, depending on the protein concentration [AN]. Type (I) channel events are large and predominant at high values [AN] > or = K = 5 nM at 296 K. At 50 mM Ca2+, symmetrical on both membrane sides, AN added at the cis side, the conductance is gCa(I) = 22 +/- 2 pS and at symmetrical 0.1 M K+-conditions: gK(I) = 32 +/- 3 pS, associated with two mean open-times tau1(I) = 0.68 +/- 0.2 ms and tau2(I) = 31 +/- 2 ms. Monoclonal anti-AN antibodies added to the trans-side first increase the mean open-times and then abolish the channel activity, suggesting that type (I) channels refer to a membrane spanning protein complex, probably a trimer T, which at [AN] > K changes its membrane organization to a higher oligomer, probably to the side-by-side double-trimer T2. The smaller type (II) channel events are predominant at low [AN] < or = K and refer to the (electroporative) adsorption complex of the monomer. The conductances g(i)(II) for symmetrical concentrations depend non-linearly on the voltage Um = Uext + U(AN), where U(AN) = 0.02 +/- 0.002 V is the electrostatic contribution of the Ca2+-AN complex and Uext the externally applied voltage. There is only one mean open-time tau(o)(II) which is voltage-dependent according to a functional of b x Um2 where b = 113.9 +/- 15 V(-2), yielding an activation Gibbs free energy of Ga = RT x b x Um2. The conformational flicker probability f(i)(II) in g(i)(II) = g(i)0(II) x gamma(i) x f(i)(II) is non-linearly voltage-dependent according to a functional of a x Um2. The Nernst term gamma(i) refers to asymmetrical ion concentrations. From a = 50 V(-2), independent of the ion type, we obtain f(i)0(II) = 0.03 +/- 0.002 and the conductances for the fully open-channel states: gCa0(II) = 69 +/- 3 pS (0.05 M Ca2+) and gK0(II) = 131 +/- 5 pS (1.2 M K+). From the electroporation term a = pi[r(p)2]epsilon0(epsilon(w) - epsilon(m))/(2 kTd) we determine the mean pore radius of the complex in its fully open state as r(p)= 0.86 +/- 0.05 nm. The adsorbed annexin V (Ca2+) monomer appears to electrostatically facilitate the electric pore formation at the contact interface between the protein and the lipid phase. The complex rapidly flickers and thus limits the ion transport in a voltage-dependent manner.     

Qualitative theory of stochastic dynamical systems—Applications to life sciences

Qualitative theory for multidimensional stochastic dynamical models is presented where the random influences ξ may be white or colored, i.e. a (possibly bounded) diffusion process. We concentrate on transience, stationary solutions and boundary behavior and discuss a set-up for reliable simulations. The method consists in associating a deterministic control system where the (approximate) controllability properties determine the qualitative behavior of the stochastic system. Applications to some biological systems indicate the usefulness of qualitative theory in life sciences.     

Different forms of the oxysterol-binding protein. Binding kinetics and stability

Based upon measurements of the sedimentation coefficient and the Stokes radii, three forms of the oxysterol-binding protein were identified. The unliganded binding protein was the largest (7.7 S, Stokes radius = 71.6 A, Mr = 236,000) was relatively asymmetric (f/f0 = 1.7), and was composed of at least three subunits. Binding of 25-hydroxycholesterol was associated with a reduction in the size of the protein (7.5 S, Stokes radius = 50 A, Mr approximately 169,000) and an increase in symmetry (f/f0 = 1.4), due to the loss of a subunit of Mr approximately 67,000. At pH 6 or lower, the Mr = 169,000 sterol-protein complex was altered so that reversible dissociation to give a smaller (4.2 S, Stokes radius = 53 A, Mr = 97,000) more asymmetric (f/f0 = 1.8) sterol-protein complex occurred when it was sedimented in a sucrose gradient buffered at pH 7.4 containing 0.3 M KCl and 2.5 M urea. Irreversible dissociation of the 7.5 S, Mr = 169,000 form to a 4.2 S form occurred spontaneously when the complex in whole cytosol buffered at pH 7.8 was allowed to stand overnight at 0 degree C, or when the partially purified complex was incubated at pH 5.5 at 0 degree C for several days. The partially purified, unliganded binding protein was unstable at 0 degree C (approximately 75% loss of binding activity in 24 h) whereas the liganded protein was stable for 7 days at 0 degree C although irreversible conversion to a 4.2 S form occurred under some conditions. Rates of sterol binding and dissociation were increased in the presence of 2.5 M urea at pH 7.4 or when the pH was lowered to 5.5 Kd values were not greatly altered under the various incubation conditions.     

DFBAlab: a fast and reliable MATLAB code for dynamic flux balance analysis

Background

Dynamic Flux Balance Analysis (DFBA) is a dynamic simulation framework for biochemical processes. DFBA can be performed using different approaches such as static optimization (SOA), dynamic optimization (DOA), and direct approaches (DA). Few existing simulators address the theoretical and practical challenges of nonunique exchange fluxes or infeasible linear programs (LPs). Both are common sources of failure and inefficiencies for these simulators.

Results

DFBAlab, a MATLAB-based simulator that uses the LP feasibility problem to obtain an extended system and lexicographic optimization to yield unique exchange fluxes, is presented. DFBAlab is able to simulate complex dynamic cultures with multiple species rapidly and reliably, including differential-algebraic equation (DAE) systems. In addition, DFBAlab’s running time scales linearly with the number of species models. Three examples are presented where the performance of COBRA, DyMMM and DFBAlab are compared.

Conclusions

Lexicographic optimization is used to determine unique exchange fluxes which are necessary for a well-defined dynamic system. DFBAlab does not fail during numerical integration due to infeasible LPs. The extended system obtained through the LP feasibility problem in DFBAlab provides a penalty function that can be used in optimization algorithms.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-014-0409-8) contains supplementary material, which is available to authorized users.     

Constraint Logic Programming approach to protein structure prediction

Background  

The protein structure prediction problem is one of the most challenging problems in biological sciences. Many approaches have been proposed using database information and/or simplified protein models. The protein structure prediction problem can be cast in the form of an optimization problem. Notwithstanding its importance, the problem has very seldom been tackled by Constraint Logic Programming, a declarative programming paradigm suitable for solving combinatorial optimization problems.     

Maintenance and growth requirements in the metabolism of Debaryomyces hansenii performing xylose-to-xylitol bioconversion in corncob hemicellulose hydrolyzate

In order to improve the biotechnological production of xylitol, the metabolism of Debaryomyces hansenii NRRL Y-7426 in corncob hemicellulose hydrolyzate has been investigated under different conditions, where either maintenance or growth requirements predominated. For this purpose, the experimental results of two sets of batch bioconversions carried out alternatively varying the starting xylose concentration in the hydrolyzate (65.6 < or = S(0) < or = 154.7 g L(-1)) or the initial biomass level (3.0 < or = X(0) < or = 54.6 g(DM) L(-1)) were used to fit a metabolic model consisting of carbon material and ATP balances based on five main activities, namely fermentative assimilation of pentoses, semi-aerobic pentose-to-pentitol bioconversion, biomass growth on pentoses, catabolic oxidation of pentoses, and acetic acid and NADH regeneration by the electron transport system. Such an approach allowed separately evaluating the main bioenergetic constants of this microbial system, that is, the specific rates of ATP and xylose consumption due to maintenance (m(ATP) = 21.0 mmol(ATP) C-mol(DM) (-1)h(-1); m(Xyl) = 6.5 C-mmol(Xyl) C-mol(DM) (-1)h(-1)) and the true yields of biomass on ATP (Y(ATP) (max) = 0.83 C-mol(DM) mol(ATP) (-1)) and on xylose (Y(Xyl) (max) = 0.93 C-mol(DM) C-mol(Xyl) (-1)). The results of this study highlighted that the system, at very high S(0) and X(0) values, dramatically increased its energy requirements for cell maintenance, owing to the occurrence of stressing conditions. In particular, for S(0) > 130 g L(-1), these activities required an ATP consumption of about 2.1 mol(ATP) L(-1), that is, a value about seven- to eightfold that observed at low substrate concentration. Such a condition led to an increase in the fraction of ATP addressed to cell maintenance from 47% to 81%. On the other hand, the very high percentage of ATP addressed to maintenance (> 96%) at very high cell concentration (X(0) > or = 25 g(DM) L(-1)) was likely due to the insufficient substrate to sustain the growth.     

Visible Raman excitation laser induced power and exposure dependent effects in red blood cells

We present results of Raman spectroscopic studies carried out on optically trapped red blood cells with Raman excitation wavelength in Q‐band region of the hemoglobin (Hb) absorption spectrum. The results obtained suggest that when exposed to the Raman excitation laser the RBCs get deoxygenated due to photo‐dissociation of oxygen from hemoglobin. For smaller exposure durations (5 s) the level of deoxygenation increases with an increase in power. However, for longer exposure durations the deoxygenated hemoglobin in the cells gets irreversibly oxidized to form a low spin ferric derivative of hemoglobin. The rate of oxidation depends upon the initial level of deoxygenation; higher the initial level of deoxygenation, higher is the rate of oxidation. However, the RBCs deoxygenated via oxygen deprivation (i.e. N₂ purging) were found to be very stable against any laser induced effect. These observations suggests that in case of laser induced deoxygenation of RBCs the free oxygen generated by photo‐dissociation acts as the oxidizing agent and leads to oxidative damage of the RBCs.