Cardiovascular disease-induced thermal responses during passive heat stress: an integrated computational study.

The cardiovascular system plays a crucial role in human thermoregulation; cardiovascular diseases may lead to significantly degrading the thermoregulation ability for patients during exposure to heat stress. To evaluate the thermal responses of patients with common chronic cardiovascular diseases, we here propose an integrated computational model by coupling a two-node thermoregulation model with a closed-loop, multi-compartment, lumped-parameter cardiovascular model. This bioheat transfer model is validated, capable to predict cardiovascular functions and thermal responses under varying environmental conditions. Our results demonstrate that the cardiovascular disease-induced reduction in cardiac output and skin blood flow causes extra elevation in core temperature during hyperthermic challenges. In addition, a combination of aging, obesity, and cardiovascular diseases shows a pronounced increase in core temperature during heat exposure, which implies that such combined effect may increase the risk of heat-related morbidity and mortality. Copyright © 2016 John Wiley & Sons, Ltd.

Analysis of the equine ovarian structure during the first twelve months of life by three-dimensional internal structure microscopy.

A three-dimensional internal structure microscopy (3D-ISM) can clarify the anatomical arrangement of internal structures of equine ovaries. In this study, morphological changes of the equine ovary over the first 12 months of life were investigated by 3D-ISM in 59 fillies and by histological analysis in 2 fillies. The weight and volume of the paired ovaries initially decreased from 0 to 1 months to 2 to 3 months of age and then significantly increased at 8 to 12 months of age. The ovulation fossa was first observed around the 3rd month and became evident after the 6th month. The number of follicles with a diameter of ≥10 mm and the diameter of the largest follicle increased gradually after 6 months of age. On a volume basis, the medulla accounted for nearly 90% of the whole ovary at 0 to 1 months of age, but significantly decreased from 2 to 3 months of age. The volume of the cortex increased progressively after birth and reached approximately 60% of the total volume at 8 to 12 months of age. This significant development of the cortex coincided with the increased number and size of large follicles observed from 6 months of age. These results suggest that the development of the cortex plays a role in the maturation of the follicles and the equine ovary undergoes substantial morphological changes postnatally until puberty.

Binding free-energy calculation is a powerful tool for drug optimization: calculation and measurement of binding free energy for 7-azaindole derivatives to glycogen synthase kinase-3ß.

Present computational lead (drug)-optimization is lacking in thermodynamic tactics. To examine whether calculation of binding free-energy change (ΔG) is effective for the lead-optimization process, binding ΔGs of 7-azaindole derivatives to the ATP binding site of glycogen synthase kinase-3ß (GSK-3ß) were calculated. The result was a significant correlation coefficient of r = 0.895 between calculated and observed ΔGs. This indicates that calculated ΔG reflects the inhibitory activities of 7-azaindole derivatives. In addition to quantitative estimation of activity, ΔG calculation characterizes the thermodynamic behavior of 7-azaindole derivatives, providing also useful information for inhibitor optimization on affinity to water molecules.

The activation time-course of contractile elements estimated from in vivo fascicle behaviours during twitch contractions.

To better understand the cascade from neural activation up to force production within in vivo contracting muscle-tendon units, we estimated activation of contractile elements from experimentally measured human fascicle length change and force using a Hill-type muscle model. The experiment was conducted with respect to twitch contractions of the tibialis anterior muscle at three joint angles. As muscle contractile element force is a function of its length and velocity, the activation of contractile elements was calculated using a Hill-type muscle model and measured data. The results were able to reproduce the continuous rising activation of contractile elements after termination of electromyographic activity, the earlier shift of peak activation in time compared to twitch force, and the differences in time-course activation at three different joint angles. These findings are consistent with the predicted change in the activation of contractile elements from previous reports. Also, the results suggest that the time-course of the activation of contractile elements was greatly influenced by the change in force generating capacities related to both length and velocity, even in fixed end contractions, which could result from muscle-tendon interaction.

A computational model of the cardiovascular system coupled with an upper-arm oscillometric cuff and its application to studying the suprasystolic cuff oscillation wave, concerning its value in assessing arterial stiffness.

A variety of methods have been proposed to noninvasively assess arterial stiffness using single or multiple oscillometric cuffs. A common pitfall of most of such methods is that the individual-specific accuracy of assessment is not clearly known due to an insufficient understanding of the relationships between the characteristics of cuff oscillometry and cardiovascular properties. To provide a tool for quantitatively investigating such relationships, we developed a computational model of the cardiovascular system coupled with an oscillometric cuff wrapped around the left upper arm. The model was first examined by simulating the inflation-deflation process of the cuff. The simulated results reasonably reproduced the well-established characteristics of cuff oscillometry. The model was then applied to study the oscillation wave generated by a suprasystolic cuff that is currently under considerable debate regarding its validity for assessing aortic stiffness. The simulated results confirmed the experimental observations that the suprasystolic cuff oscillation wave resembles the blood pressure wave in the proximal brachial artery and is characterised by the presence of two systolic peaks. A systemic analysis on the simulation results for various cardiovascular/physiological conditions revealed that neither the time lag nor the height difference between the two peaks is a direct indicator of aortic stiffness. These findings provided useful evidence for explaining the conflicts among previous studies. Finally, it was stressed that although the emphasis of this study has been placed on a suprasystolic upper-arm cuff, the model could be employed to address more issues related to oscillometric cuffs.

Transcriptome tomography for brain analysis in the web-accessible anatomical space.

Increased information on the encoded mammalian genome is expected to facilitate an integrated understanding of complex anatomical structure and function based on the knowledge of gene products. Determination of gene expression-anatomy associations is crucial for this understanding. To elicit the association in the three-dimensional (3D) space, we introduce a novel technique for comprehensive mapping of endogenous gene expression into a web-accessible standard space: Transcriptome Tomography. The technique is based on conjugation of sequential tissue-block sectioning, all fractions of which are used for molecular measurements of gene expression densities, and the block- face imaging, which are used for 3D reconstruction of the fractions. To generate a 3D map, tissues are serially sectioned in each of three orthogonal planes and the expression density data are mapped using a tomographic technique. This rapid and unbiased mapping technique using a relatively small number of original data points allows researchers to create their own expression maps in the broad anatomical context of the space. In the first instance we generated a dataset of 36,000 maps, reconstructed from data of 61 fractions measured with microarray, covering the whole mouse brain (ViBrism: http://vibrism.riken.jp/3dviewer/ex/index.html) in one month. After computational estimation of the mapping accuracy we validated the dataset against existing data with respect to the expression location and density. To demonstrate the relevance of the framework, we showed disease related expression of Huntington's disease gene and Bdnf. Our tomographic approach is applicable to analysis of any biological molecules derived from frozen tissues, organs and whole embryos, and the maps are spatially isotropic and well suited to the analysis in the standard space (e.g. Waxholm Space for brain-atlas databases). This will facilitate research creating and using open-standards for a molecular-based understanding of complex structures; and will contribute to new insights into a broad range of biological and medical questions.

Three-dimensional microscopic elemental analysis using an automated high-precision serial sectioning system.

The elemental composition and microscopic-level shape of inclusions inside industrial materials are considered important factors in fracture analytical studies. In this work, a three-dimensional (3D) microscopic elemental analysis system based on a serial sectioning technique was developed to observe the internal structure of such materials. This 3D elemental mapping system included an X-ray fluorescence analyzer and a high-precision milling machine. Control signals for the X-ray observation process were automatically sent from a data I/O system synchronized with the precision positioning on the milling machine. Composite specimens were used to confirm the resolution and the accuracy of 3D models generated from this system. Each of the two specimens was composed of three metal wires of 0.5 mm diameter braided into a single twisted wire that was placed inside a metal pipe; the pipe was then filled with either epoxy resin or Sn. The milling machine was used to create a mirror-finish cross-sectional surface on these specimens, and elemental analyses were performed. The twisted wire structure was clearly observed in the resulting 3D models. This system enables automated investigation of the 3D internal structure of materials as well as the identification of their elemental components.

Stereolithographic biomodeling of equine ovary based on 3D serial digitizing device.

The 3D internal structure microscopy (3D-ISM) was applied to the equine ovary, which possesses peculiar structural characteristics. Stereolithography was applied to make a life-sized model by means of data obtained from 3D-ISM. Images from serially sliced surfaces contributed to a successful 3D reconstruction of the equine ovary. Photopolymerized resin models of equine ovaries produced by stereolithography can clearly show the internal structure and spatial localizations in the ovary. The understanding of the spatial relationship between the ovulation fossa and follicles and/or corpora lutea in the equine ovary was a great benefit. The peculiar structure of the equine ovary could be thoroughly observed and understood through this model.

Multi-scale modeling of the human cardiovascular system with applications to aortic valvular and arterial stenoses.

A computational model of the entire cardiovascular system is established based on multi-scale modeling, where the arterial tree is described by a one-dimensional model coupled with a lumped parameter description of the remainder. The resultant multi-scale model forms a closed loop, thus placing arterial wave propagation into a global hemodynamic environment. The model is applied to study the global hemodynamic influences of aortic valvular and arterial stenoses located in various regions. Obtained results show that the global hemodynamic influences of the stenoses depend strongly on their locations in the arterial system, particularly, the characteristics of hemodynamic changes induced by the aortic valvular and aortic stenoses are pronounced, which imply the possibility of noninvasively detecting the presence of the stenoses from peripheral pressure pulses. The variations in aortic pressure/flow pulses with the stenoses play testimony to the significance of modeling the entire cardiovascular system in the study of arterial diseases.

Application of MDGRAPE-3, a special purpose board for molecular dynamics simulations, to periodic biomolecular systems.

We describe the application of a special purpose board for molecular dynamics simulations, named MDGRAPE-3, to the problem of simulating periodic bio-molecular systems. MDGRAPE-3 is the latest board in a series of hardware accelerators designed to calculate the nonbonding long-range interactions much more rapidly than normal processors. So far, MDGRAPEs were mainly applied to isolated systems, where very many nonbonded interactions were calculated without any distance cutoff. However, in order to regulate the density and pressure during simulations of membrane embedded protein systems, one has to evaluate interactions under periodic boundary conditions. For this purpose, we implemented the Particle-Mesh Ewald (PME) method, and its approximation with distance cutoffs and charge neutrality as proposed by Wolf et al., using MDGRAPE-3. When the two methods were applied to simulations of two periodic biomolecular systems, a single MDGRAPE-3 achieved 30-40 times faster computation times than a single conventional processor did in the both cases. Both methods are shown to have the same molecular structures and dynamics of the systems.

Simulations of needle insertion by using a Eulerian hydrocode FEM and the experimental validations.

In this paper, simulations for needle insertion were performed by using a novel Eulerian hydrocode FEM, which was adaptive for large deformation and tissue fracture. We also performed experiments for the same needle insertion with silicon rubbers and needles, which had conical tips of different angles in order to investigate the accuracy of the simulations. The resistance forces in the simulations accurately followed those in the experiments until the conical portion of the needle was inside the rubbers, and the validation of the Eulerian hydrocode was revealed. However, the present simulation showed that after the conical portion was inside the tissue, the simulated resistance forces became lower than the experimental ones. The proportional increase of the friction forces and the roughly flatness of the tip force along the time were simulated. It was predicted that the tightening force along the needle side was underestimated.

Development of high-resolution 4D in vivo-CT for visualization of cardiac and respiratory deformations of small animals.

The interest in small animal models of human diseases has generated a need to design a computed tomography (CT) system that operates at a microscopic level. It is particularly important to be able to visualize the dramatic rhythmical motion of organs such as the heart and lungs. In order to evaluate the motion of the heart and lungs of small animals (rats and mice), we developed in the present study a high-resolution 4D in vivo-CT system for small animals that uses synchrotron radiation. To reduce motion artifacts and the radiation dose, the projections were synchronized with airway pressure, the ECG, the x-ray shutter and the CCD shutter. For cardiovascular imaging, a blood pool contrast agent was injected and the data sets were acquired at several ECG points during the end-expiratory phase. For imaging of the lungs, the data sets were acquired at several airway pressures during diastole. The dynamic motion of the cardiovascular system (the ventricles and coronary arteries) and small airways (diameter > 250 microm of rats and 125 microm of mice) was visualized. This high-resolution imaging tool may be very useful for the development of novel drugs in murine models, in addition to its use in the study of cardiovascular and respiratory physiology.

Finite element analysis of blood flow and heat transfer in an image-based human finger.

The human finger is said to be the extension of the brain and can convey the information on mechanical, thermal, and tissue damaging. The quantitative prediction of blood flow rate and heat generation are of great importance for diagnosing blood circulation illness and for the noninvasive measurement of blood glucose. In this study, we developed a coupled thermofluid model to simulate blood flow in large vessels and living tissue. The finite element (FE) model to analyze the blood perfusion and heat transport in the human finger was developed based on the transport theory in porous media. With regard to the blood flow in the large arteries and veins, the systemic blood circulation in the upper limb was modeled based on the one-dimensional flow in an elastic tube. The blood pressure and velocity in each vessel were first computed and the corresponding values for the large vessels in the finger were subsequently transferred to the FE model as the boundary conditions. The realistic geometric model for the human finger was constructed based on the MRI image data. After computing the capillary pressure and blood velocity in the tissue, the temperatures in the large vessels and the tissue of the finger were computed simultaneously by numerically solving the energy equation in porous media. The computed blood flow in tissues is in agreement with the anatomical structure and the measurement. It is believed that this analysis model will have extensive applications in the prediction of peripheral blood flow, temperature variation, and mass transport.

Expression analysis for inverted effects of serotonin transporter inactivation.

Inactivation of serotonin transporter (HTT) by pharmacologically in the neonate or genetically increases risk for depression in adulthood, whereas pharmacological inhibition of HTT ameliorates symptoms in depressed patients. The differing role of HTT function during early development and in adult brain plasticity in causing or reversing depression remains an unexplained paradox. To address this we profiled the gene expression of adult Htt knockout (Htt KO) mice and HTT inhibitor-treated mice. Inverted profile changes between the two experimental conditions were seen in 30 genes. Consistent results of the upstream regulatory element search and the co-localization search of these genes indicated that the regulation may be executed by Pax5, Pax7 and Gata3, known to be involved in the survival, proliferation, and migration of serotonergic neurons in the developing brain, and these factors are supposed to keep functioning to regulate downstream genes related to serotonin system in the adult brain.

New physiological model of serum creatine phosphokinase activity in acute myocardial infarction. Estimation of the total creatine phosphokinase release.

In this report, we introduce a new physiological model of the serum creatine phosphokinase (CPK) activity change, that is useful for estimating the total CPK release accurately even with reduced blood sampling frequency. The physiological model was applied to the serum CPK activity change of patients who suffered acute myocardial infarction (AMI), and the model showed good agreement with the serum CPK activity. In addition, the calculated value of total CPK release agreed well with that calculated using the conventional technique.

Computation of the kinematics and the minimum peak joint moments of sit-to-stand movements.

BACKGROUND: A sit-to-stand (STS) movement requires muscle strength higher than that of other daily activities. There are many elderly people, who experience difficulty when standing up from a chair. The muscle strength required (or the load on the joints) during a STS task is determined by the kinematics (movement pattern). The purpose of this study was to evaluate the kinematics and resultant joint moments of people standing up from a chair in order to determine the minimum peak joint moments required for a STS task. METHODS: This study consisted of three steps. In the first step, kinematic data of lower extremity joint angles (hip, knee and ankle) during STS movements were experimentally collected from human subjects. Eighty-five sets of STS kinematic data were obtained. In the second step, the experimentally collected kinematic data and a link segment model of the human body were used to generate more than 5,000,000 computed STS movements. In the third step, using inverse dynamics method, joint moments of the lower extremity were calculated for all movements obtained through the preceding steps. From the outputs of the third step, the optimal kinematics (movement pattern) in terms of minimized peak joint moment for the hip, knee and ankle was determined. RESULTS: The peak hip joint moment ranged from 0.24 to 1.92 N.m/kg. The peak knee joint moment ranged from 0.51 to 1.97 N.m/kg, and the peak ankle joint moment ranged from -0.11 to 1.32 N.m/kg. The optimal movement patterns differed depending on which minimized joint moment index was selected (hip, knee or ankle). However, the sum of the peak hip joint moment and peak knee joint moment was always approximately 1.53 N.m/kg regardless of which minimized joint moment index was selected. CONCLUSION: The most important finding of this study was that the relation between the peak joint moments at the hip and knee joints was complementary and the sum of those moments needed to be greater than 1.53 N.m/kg in order to perform a successful STS. A combined hip-knee value of 1.5 N.m/kg or lower may indicate the need for physical rehabilitation and/or exercise to increase muscular force.

In vivo behavior of muscle fascicles and tendinous tissues in human tibialis anterior muscle during twitch contraction.

In this study we investigated the time course of length and velocity of muscle fascicles and tendinous tissues (TT) during isometric twitch contraction, and examined how their interaction relates to the time course of external torque and muscle fascicle force generation. From seven males, supra-maximal twitch contractions (singlet) of the tibialis anterior muscle were induced at 30 degrees , 10 degrees and -10 degrees plantar flexed positions. The length and velocity of fascicles and TT were determined from a series of their transverse ultrasound images. The maximal external torque appeared when the shortening velocity of fascicles was zero. The fascicle and TT length, and external torque showed a 10-30 ms delay of each onset, with a significant difference in half relaxation times at -10 degrees . The time course of TT elongation, and fascicle and tendinous velocities did not differ between joint angles. Curvilinear length-force properties, whose slope of quasi-linear part was ranged from -15.0 to -5.9 N/mm for fascicles and 5.4 to 14.3N/mm for TT, and a loop-like pattern of velocity-force properties, in which the mean power was ranged from 0.14 to 0.80 W for fascicles, and 0.14 to 0.81 W for TT were also observed. These results were attributed to the muscle-tendon interaction, depending on the slack and non-linearity of length-force relationship of compliant TT. We conclude that the mechanical interaction between fascicles and TT, are significant determinants of twitch force and time characteristics.

Small airway changes in healthy and ovalbumin-treated mice during quasi-static lung inflation.

Previously, we developed a synchrotron radiation CT system to evaluate the morphometric changes (length and diameter, D) and small airway compliance (sC(aw)) of euthanized mice under quasi-static inflation [Sera, T., Uesugi, K., Yagi, N., 2005. Localized morphometric deformations of small airways and alveoli in intact mouse lungs under quasi-static inflation. Respir. Physiol. Neurobiol. 147, 51-63). Using this system, this study compared normal and asthmatic small airways. Ovalbumin-treated mice were used as an asthma model. Compared with the values at functional residual capacity, D of normal and asthmatic small airways (D<200microm) increased by 48% and 36% at the end of tidal inspiration. For larger airways (D>500microm), the increases were 23% and 20%, respectively. The ratio of the sC(aw) of asthmatic small airways to that of healthy small airways was 0.57, and the ratio was 0.70 for larger airways. The morphometric changes and sC(aw) in asthma model mice were significantly lower than those of healthy mice. The differences in sC(aw) between healthy and asthma model mice were greater for smaller airways.

Exploration and grading of possible genes from 183 bacterial strains by a common protocol to identification of new genes: Gene Trek in Prokaryote Space (GTPS).

A large number of complete microorganism genomes has been sequenced and submitted to the public database and then incorporated into our complete genome database, Genome Information Broker (GIB, http://gib.genes.nig.ac.jp/). However, when comparative genomics is carried out, researchers must be aware that there are protein-coding genes not confirmed by homology or motif search and that reliable protein-coding genes are missing. Therefore, we developed a protocol (Gene Trek in Prokaryote Space, GTPS) for finding possible protein-coding genes in bacterial genomes. GTPS assigns a degree of reliability to predicted protein-coding genes. We first systematically applied the protocol to the complete genomes of all 123 bacterial species and strains that were publicly available as of July 2003, and then to those of 183 species and strains available as of September 2004. We found a number of incorrect genes and several new ones in the genome data in question. We also found a way to estimate the total number of orthologous genes in the bacterial world.

Influence of vision and static stretch of the calf muscles on postural sway during quiet standing.

The purpose of this experimental study was to evaluate the effects of vision and stretching of the calf muscles on postural sway during quiet standing. Under pre-stretch conditions, participants stood on a force plate for 30s and the sway of the ground reaction force center of pressure was recorded. The following postural sway variables were calculated off-line: sweep speed, sway speed, standard deviation, maximal mediolateral range, maximal anteroposterior range, mean mediolateral position and mean anteroposterior position. For post-stretch conditions, participants stood quietly on a device that was utilized to impose a static 3 min ankle joint dorsiflexion stretch. Immediately thereafter, participants moved onto the force platform where postural sway parameters were again recorded. Randomized eyes-open and eyes-closed conditions were tested in both cases. Results showed that postural sway significantly increased due to stretch (sweep speed, sway speed, standard deviation, maximal anteroposterior range, mean anteroposterior position), as well as eye closure (sweep speed, sway speed, standard deviation, maximal mediolateral range, maximal anteroposterior range). The interaction between stretch and eye closure was also significant (sweep speed, sway speed, standard deviation, maximal mediolateral range), suggesting that there were only minor increases in postural sway after stretch under the eyes-open condition. It was suggested that stretching of the calf muscles has the effect of increasing postural sway, although this effect can be greatly compensated for when vision is included.