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Modeling adaptive biological systems.

During the evolution of many systems found in nature, both the system composition and the interactions between components will vary. Equating the dimension with the number of different components, a system which adds or deletes components belongs to a class of dynamical systems with a finite dimensional phase space of variable dimension. We present two models of biochemical systems with a variable phase space, a model of autocatalytic reaction networks in the prebiotic soup and a model of the idiotypic network of the immune system. Each model contains characteristic meta-dynamical rules for constructing equations of motion from component properties. The simulation of each model occurs on two levels. On one level, the equations of motion are integrated to determine the state of each component. On a second level, algorithms which approximate physical processes in the real system are employed to change the equations of motion. Models with meta-dynamical rules possess several advantages for the study of evolving systems. First, there are no explicit fitness functions to determine how the components of the model rank in terms of survivability. The success of any component is a function of its relationship to the rest of the system. A second advantage is that since the phase space representation of the system is always finite but continually changing, we can explore a potentially infinite phase space which would otherwise be inaccessible with finite computer resources. Third, the enlarged capacity of systems with meta-dynamics for variation allows us to conduct true evolution experiments. The modeling methods presented here can be applied to many real biological systems. In the two studies we present, we are investigating two apparent properties of adaptive networks. With the simulation of the prebiotic soup, we are most interested in how a chemical reaction network might emerge from an initial state of relative disorder. With the study of the immune system, we study the self-regulation of the network including its ability to distinguish between species which are part of the network and those which are not.

Adaptation, Biological↗

Helical MR: continuously moving table axial imaging with radial acquisitions.

A technique for extended field of view MRI is presented. Similar to helical computed tomography, the method utilizes a continuously moving patient table, a 2D axial slice that remains fixed relative to the MRI magnet, and a radial k-space trajectory. A fully refocused SSFP acquisition enables spatial resolution comparable to current clinical protocols in scan times that are sufficiently short to allow a reasonable breathhold duration. RF transmission and signal reception are performed using the RF body coil and the images are reconstructed in real time. Experimental results are presented that illustrate the technique's ability to resolve small structures in the table-motion direction. Simulation experiments to study the steady-state response of the fully refocused SSFP acquisition during continuous table motion are also presented. Finally, whole body images of healthy volunteers demonstrate the high image quality achieved using the helical MRI approach.

Artifacts↗

Human reliability and confinement.

Problems inherent in the modifiability of circadian periodicity and in impoverished sensory environments were explored for the purpose of appraising attenuative effects upon human reliability. Accordingly, highly selected subjects were confined within a one-man altitude chamber for prolonged periods of time and under a variety of designed conditions. The findings relative to the modifiability of biological rhythm indicate that adjustment to a drastic revision of the 24-hour biological day was accomplished to a significant and practical extent by certain subjects, the extent of adjustment was directly related to the maintenance of high initial levels of proficiency, and just as subjects differ greatly in their adjustment to revised biological time, they differ to an equal extent in the degree of synchronization manifested by the apparent periodicities of the different physiological systems. In the investigation of impoverished sensory environments, it was found that the joint effects of impoverished sensory conditions and continuous work at an operator system drastically degraded the reliability of certain subjects. Further, neither prior experience nor knowledge acted to mitigate the degree of aberrancy experienced which in the case of one subject was so extreme as to necessitate his removal from the chamber prior to the termination of confinement period. Finally, management of certain aberrant behavior, specifically hallucinatory experiences, could be successfully achieved by those subjects who continuously attempted to maintain a diversity of sensory input.

Adaptation, Psychological↗

Mathematical modelling of the spatio-temporal response of cytotoxic T-lymphocytes to a solid tumour.

In this paper a mathematical model describing the growth of a solid tumour in the presence of an immune system response is presented. In particular, attention is focused upon the attack of tumour cells by so-called tumour-infiltrating cytotoxic lymphocytes (TICLs), in a small, multicellular tumour, without necrosis and at some stage prior to (tumour-induced) angiogenesis. At this stage the immune cells and the tumour cells are considered to be in a state of dynamic equilibrium--cancer dormancy--a phenomenon which has been observed in primary tumours, micrometastases and residual disease after ablation of the primary tumour. Nonetheless, the precise biochemical and cellular mechanisms by which TICLs control cancer dormancy are still poorly understood from a biological and immunological point of view. Therefore we focus on the analysis of the spatio-temporal dynamics of tumour cells, immune cells and chemokines in an immunogenic tumour. The lymphocytes are assumed to migrate into the growing solid tumour and interact with the tumour cells in such a way that lymphocyte-tumour cell complexes are formed. These complexes result in either the death of the tumour cells (the normal situation) or the inactivation (sometimes even the death) of the lymphocytes. The migration of the TICLs is determined by a combination of random motility and chemotaxis in response to the presence of chemokines. The resulting system of four nonlinear partial differential equations (TICLs, tumour cells, complexes and chemokines) is analysed and numerical simulations are presented. We consider two different tumour geometries--multi-layered cell growth and multi-cellular spheroid growth. The numerical simulations demonstrate the existence of cell distributions that are quasi-stationary in time and heterogeneous in space. A linear stability analysis of the underlying (spatially homogeneous) ordinary differential equation (ODE) kinetics coupled with a numerical investigation of the ODE system reveals the existence of a stable limit cycle. This is verified further when a subsequent bifurcation analysis is undertaken using a numerical continuation package. These results then explain the complex heterogeneous spatio-temporal dynamics observed in the partial differential equation (PDE) system. Our approach may lead to a deeper understanding of the phenomenon of cancer dormancy and may be helpful in the future development of more effective anti-cancer vaccines.

Cell Division↗

Experimental spatial sampling study of the real-time ultrasonic pulse-echo BAI-mode imaging technique.

The ultrasonic pulse-echo backscattered amplitude integral (BAI)-mode imaging technique has been developed to inspect the seal integrity of hermetically sealed, flexible food packages. With a focused 17.3-MHz transducer acquiring radio frequency (RF) echo data in a static rectilinear stop-and-go pattern, this technique was able to reliably detect channel defects as small as 38 microm in diameter and occasionally detect 6-microm-diameter channels. This contribution presents our experimental spatial sampling study of the BAI-mode imaging technique with a continuous zigzag scanning protocol that simulates a real-time production line inspection method in continuous motion. Two transducers (f/2 17.3 MHz and f/3 20.3 MHz) were used to acquire RF echo data in a zigzag raster pattern from plastic film samples bearing rectilinear point reflector arrays of varying grid spacings. The average BAI-value difference (deltaBAI) between defective and intact regions and the contrast-to-noise ratio (CNR) were used to assess image quality as a function of three spatial sampling variables: transducer spatial scanning step size, array sample grid spacing, and transducer -6-dB pulse-echo focal beam spot size. For a given grid size, the deltaBAI and CNR degraded as scanning step size in each spatial dimension increased. There is an engineering trade-off between the BAI-mode image quality and the transducer spatial sampling. The optimal spatial sampling step size has been identified to be between one and two times the -6-dB pulse-echo focal beam lateral diameter.

Algorithms↗

Characteristics of the sleep of men in simulated space flights.

A study of the sleep of men in simulated space flight has shown that, during different effects (diminished motor activity, noise, rotation), monotony and time of the exposure is the general pathogenetic factor producing sleep disturbances. The monotony factor was responsible for typical changes in sleep function (difficulty involved in falling asleep, disturbed continuity of sleep as a process, decline in the depth, etc.), whose degree was related not only to the professional importance of the experiment but also to the individual intolerance to the main exposure. In these cases, the action of somnogenic mechanisms developed against the background of the action of analyzers (vestibular, accoustic, proprioceptive) that were under load and whose excitation during hypokinesia, noise, and rotation, especially in poorly adapted people, led to cumulation and was expressed in the phenomenon of spontaneous awakening. In addition to that, the genesis of dyssomnia, particularly during bedrest and water immersion, included hemodynamic disturbances induced by blood redistribution due to the recumbent position and monotonous motor activity. The psychosomatic feelings (congestion, edema, irresistible desire to stand up and stretch) brought about emotional strain which was later enhanced by the duration of the exposure.

Acoustic Stimulation↗

A mathematical model of particle retention in the air-spaces of human lungs.

Knowledge of the total and regional lung retention of particles inhaled continuously by man over long periods can be useful in understanding the potential role of inhaled particles in the pathogenesis of lung diseases. Owing to practical and ethical considerations, however, little or no experimental information exists. A mathematical model of particle retention simulating environmental and occupational exposures has therefore been developed that takes into account particle deposition, tracheobronchial clearance, and two phases of alveolar clearance in the Weibel A anatomical lung model. The derived equations of retention kinetics predict retention of particles as a function of exposure time. For a continuous exposure (simulating environmental conditions) to 4 microns particles, the model predicts that retained particles approach an equilibrium between deposited and cleared particles with the 95% level being reached in 293 days. For an intermittent exposure (simulating occupational conditions) equilibrium is approached in five years. The whole lung burden of particles is predicted to be 9% of the total mass that entered the lung after a one-year environmental exposure and 1.5% after a 25-year occupational exposure. The equilibrium surface concentration and integrated dose of particles per airway generation predict enhanced risk to the pathogenic effects of inhaled particles in the large airways and respiratory bronchioles.

Air Pollution↗

Effect of high tibial flexion osteotomy on cartilage pressure and joint kinematics: a biomechanical study in human cadaveric knees. Winner of the AGA-DonJoy Award 2004.

INTRODUCTION: Valgus high tibial osteotomy is an established treatment for unicompartmental varus osteoarthritis. However, only little is known about the effect of osteotomy in the sagittal plane on biomechanical parameters such as cartilage pressure and joint kinematics. This study investigated the effects of high tibial flexion osteotomy in a human cadaver model. MATERIALS AND METHODS: Seven fresh human cadaveric knees underwent an opening wedge osteotomy of the proximal tibia in the sagittal plane. The osteotomy was opened anteriorly, and the tibial slope of the specimen was increased gradually. An isokinetic flexion-extension motion was simulated in a kinematic knee simulator. The contact pressure and topographic pressure distribution in the medial joint space was recorded using an electronic pressure-sensitive film. Simultaneously the motion of the tibial plateau was analyzed three-dimensionally by an ultrasonic tracking system. The traction force to the quadriceps tendon which was applied by the simulator for extension of the joint was continuously measured. The experiments were carried out with intact ligaments and then after successively cutting the posterior and anterior cruciate ligaments. RESULTS: The results demonstrate that tibial flexion osteotomy leads to a significant alteration in pressure distribution on the tibial plateau. The tibiofemoral contact area and contact pressure was shifted anteriorly, which led to decompression of the posterior half of the plateau. Moreover, the increase in the slope resulted in a significant anterior and superior translation of the tibial plateau with respect to the femoral condyles. Posterior subluxation of the tibial head after cutting the posterior cruciate ligament was completely neutralized by the osteotomy. The increase in slope resulted in a significant higher quadriceps strength which was necessary for full knee extension. CONCLUSIONS: We conclude from these results that changes in tibial slope have a strong effect on cartilage pressure and kinematics of the knee. Therapeutically a flexion osteotomy may be used for decompression of the degenerated cartilage in the posterior part of the plateau, for example, after arthroscopic partial posterior meniscectomy. If a valgus osteotomy is combined with a flexion component of the proximal tibia, complex knee pathologies consisting of posteromedial cartilage damage and posterior and posterolateral instability can be addressed in one procedure, which facilitates a quicker rehabilitation of these patients.

Aged↗

Quantifying biomechanical motion using Procrustes motion analysis.

The ability to quantify and compare the movements of organisms is a central focus of many studies in biology, anthropology, biomechanics, and ergonomics. However, while the importance of functional motion analysis has long been acknowledged, quantitative methods for identifying differences in motion have not been widely developed. In this article, we present an approach to the functional analysis of motion and quantification of motion types. Our approach, Procrustes Motion Analysis (PMA) can be used to distinguish differences in cyclical, repeated, or goal-directed motions. PMA exploits the fact that any motion can be represented by an ordered sequence of postures exhibited throughout the course of a motion. Changes in posture from time step to time step form a trajectory through a multivariate data space, representing a specific motion. By evaluating the size, shape, and orientation of these motion trajectories, it is possible to examine variation in motion type within and among groups or even with respect to continuous variables. This represents a significant analytical advance over current approaches. Using simulated and digitized data representing cyclical, repeated and goal-directed motions, we show that PMA correctly identifies distinct motion tasks in these data sets.

Animals↗

Hebbian imprinting and retrieval in oscillatory neural networks.

We introduce a model of generalized Hebbian learning and retrieval in oscillatory neural networks modeling cortical areas such as hippocampus and olfactory cortex. Recent experiments have shown that synaptic plasticity depends on spike timing, especially on synapses from excitatory pyramidal cells, in hippocampus, and in sensory and cerebellar cortex. Here we study how such plasticity can be used to form memories and input representations when the neural dynamics are oscillatory, as is common in the brain (particularly in the hippocampus and olfactory cortex). Learning is assumed to occur in a phase of neural plasticity, in which the network is clamped to external teaching signals. By suitable manipulation of the nonlinearity of the neurons or the oscillation frequencies during learning, the model can be made, in a retrieval phase, either to categorize new inputs or to map them, in a continuous fashion, onto the space spanned by the imprinted patterns. We identify the first of these possibilities with the function of olfactory cortex and the second with the observed response characteristics of place cells in hippocampus. We investigate both kinds of networks analytically and by computer simulations, and we link the models with experimental findings, exploring, in particular, how the spike timing dependence of the synaptic plasticity constrains the computational function of the network and vice versa.

Hippocampus↗

Local multidimensional scaling.

In a visualization task, every nonlinear projection method needs to make a compromise between trustworthiness and continuity. In a trustworthy projection the visualized proximities hold in the original data as well, whereas a continuous projection visualizes all proximities of the original data. We show experimentally that one of the multidimensional scaling methods, curvilinear components analysis, is good at maximizing trustworthiness. We then extend it to focus on local proximities both in the input and output space, and to explicitly make a user-tunable parameterized compromise between trustworthiness and continuity. The new method compares favorably to alternative nonlinear projection methods.

Algorithms↗

Exposure to hypomagnetic field space for multiple generations causes amnesia in Drosophila melanogaster.

This is the introduction of Drosophila into the study of learning and memory affected by removal of the geomagnetic field (GMF) for successive generations. Using the operant visual learning/memory paradigm at a flight simulator, the present study revealed that wild-type flies raised in a hypomagnetic field environment continuously for 10 successive generations were gradually impaired in visual conditioning learning and memory formation and finally the 10th generation flies became morphs of nonlearners and completely amnesiac. The control experiments show that the impairment could not be ascribed to any apparent sensorimotor problems in Drosophila. The reverse shift from hypomagnetic field (HMF) to natural GMF restored the GMF-free induced amnesia fully after six consecutive generations. Thus, our findings demonstrate conclusively that some serious, but reversible learning and memory impairment may occur for living organisms in a prolonged separation from GMF over many consecutive generations. And Drosophila has the potential to develop into a new model organism for the study of the neurobiology of magnetism for multiple generations.

Amnesia↗

Recursion equations in predicting band width under gradient elution.

The evolution of solute zone under gradient elution is a typical problem of non-linear continuity equation since the local diffusion coefficient and local migration velocity of the mass cells of solute zones are the functions of position and time due to space- and time-variable mobile phase composition. In this paper, based on the mesoscopic approaches (Lagrangian description, the continuity theory and the local equilibrium assumption), the evolution of solute zones in space- and time-dependent fields is described by the iterative addition of local probability density of the mass cells of solute zones. Furthermore, on macroscopic levels, the recursion equations have been proposed to simulate zone migration and spreading in reversed-phase high-performance liquid chromatography (RP-HPLC) through directly relating local retention factor and local diffusion coefficient to local mobile phase concentration. This new approach differs entirely from the traditional theories on plate concept with Eulerian description, since band width recursion equation is actually the accumulation of local diffusion coefficients of solute zones to discrete-time slices. Recursion equations and literature equations were used in dealing with same experimental data in RP-HPLC, and the comparison results show that the recursion equations can accurately predict band width under gradient elution.

Chromatography, High Pressure Liquid↗

Graviresponse and its regulation from the aspect of molecular levels in higher plants: growth and development, and auxin polar transport in etiolated pea seedlings under microgravity.

In STS-95 space experiments we have demonstrated that microgravity conditions resulted in automorphosis in etiolated pea (Pisum sativum L. cv. Alaska) seedlings (Ueda et al. 1999). Automorphosis-like growth and development in etiolated pea seedlings were also induced under simulated microgravity conditions on a 3-dimensional (3-D) clinostat, epicotyls being the most oriented toward the direction far from the cotyledons. Detail analysis of epicotyl bending revealed that within 36 h after watering, no significant difference in growth direction of epicotyls was observed in between seedlings grown on the 3-D clinostat and under 1 g conditions, differential growth near the cotyledonary node resulting in epicotyl bending of ca. 45 degrees toward the direction far from the cotyledons. Thereafter epicotyls continued to grow almost straightly keeping this orientation on the 3-D clinostat. On the other hand, the growth direction in etiolated seedlings changed to antigravity direction by negative gravitropic response under 1 g conditions. Automorphological epicotyl bending was also phenocopied by the application of auxin polar transport inhibitors such as 9-hydroxyfluorene-9-carboxylic acid, N-(1-naphtyl)phthalamic acid and 2,3,5-triiodobenzoic acid. These results together with the fact that auxin polar transport activity in etiolated pea epicotyls was substantially reduced in space suggested that reduced auxin polar transport is closely related to automorphosis. Strenuous efforts to learn how gravity contributes to the auxin polar transport in etiolated pea epicotyls in molecular bases resulted in successful identification of PsPIN2 and PsAUX1 encoding putative auxin-efflux and influx carrier proteins, respectively. Based on the results of these gene expression under simulated microgravity conditions, a possible role of PsPIN2 and PsAUX1 genes for auxin polar transport in etiolated pea seedlings will be discussed.

Arabidopsis Proteins↗

Characteristics and limits of tolerance in repeated subarachnoid hemorrhage in dogs.

The effects of repeated subarachnoid hemorrhages have been investigated experimentally in dogs. The main objectives were to determine the tolerance to repeated hemorrhage and to study the changes occurring during the repeated bleeds, in intracranial pressure, EEG, ECG, systemic arterial pressure and respiration. The natural course of an intracranial hemorrhage was simulated by shunting blood from a femoral artery through a drop recorder into five different sites in the craniospinal system: the chiasmatic cistern, a lateral ventricle, the cisterna magna, the lumbar subarachnoid space and into the cerebral tissue of the left frontal lobe. The hemorrhage was allowed to continue until it stopped spontaneously. Each bleed resulted in a transient rise in intracranial pressure to the level of the arterial pressure, followed by a return to a steady state value. The time taken for the attainment of the steady state was increasingly prolonged. The final steady state pressure increased with each bleed. Ultimately, a stage was reached where the hemorrhage resulted in a sustained high pressure at the level of the arterial blood pressure, producing failure of vital functions and an irreversibly isoelectric electroencephalogram. The average number of bleeds necessary to produce this state in the case of hemorrhage into brain parenchyma was 3 (range 2-4), into the lateral ventricle, 4 range 3-5), and into the cisterna chiasmatica, 5 (range 2-7). After 5 hemorrhages into the cisterna magna and the spinal subarachnoid space, a local resistance at the bleeding site was built up which prevented further bleeding.

Animals↗

Effect of soil moisture dynamics on dense nonaqueous phase liquid (DNAPL) spill zone architecture in heterogeneous porous media.

The amount, location, and form of NAPL in contaminated vadose zones are controlled by the spatial distribution of water saturation and soil permeability, the NAPL spill scenario, water infiltration events, and vapor transport. To evaluate the effects of these processes, we used the three-phase flow simulator STOMP, which includes a new permeability-liquid saturation-capillary pressure (k-S-P) constitutive model. This new constitutive model considers three NAPL forms: free, residual, and trapped. A 2-D vertical cross-section with five stratigraphic layers was assumed, and simulations were performed for seven cases. The conceptual model of the soil heterogeneity was based upon the stratigraphy at the Hanford carbon tetrachloride (CT) spill site. Some cases considered co-disposal of NAPL with large volumes of wastewater, as also occurred at the Hanford CT site. In these cases, the form and location of NAPL were most strongly influenced by high water discharge rates and NAPL evaporation to the atmosphere. In order to investigate the impact of heterogeneity, the hydraulic conductivity within the lower permeability layer was modeled as a realization of a random field having three different classes. For six extreme cases of 100 realizations, the CT mass that reached the water table varied by a factor of two, and was primarily controlled by the degree of lateral connectivity of the low conductivity class within the lowest permeability layer. The grid size at the top boundary had a dramatic impact on NAPL diffusive flux just after the spill event when the NAPL was present near the ground surface. NAPL evaporation with a fine grid spacing at the top boundary decreased CT mass that reached the water table by 74%, compared to the case with a coarse grid spacing, while barometric pumping had a marginal effect for the case of a continuous NAPL spill scenario considered in this work. For low water infiltration rate scenarios, the distribution of water content prior to a NAPL spill event decreased CT mass that reached the water table by 98% and had a significant impact on the formation of trapped NAPL. For all cases simulated, use of the new constitutive model that allows the formation of residual NAPL increased the amount of NAPL retained in the vadose zone. Density-driven advective gas flow from the ground surface controlled vapor migration in strongly anisotropic layers, causing NAPL mass flux to the lower layer to be reduced. These simulations indicate that consideration of the formation of residual and trapped NAPLs and dynamic boundary conditions (e.g., areas, rates, and periods of different NAPL and water discharge and fluctuations of atmospheric pressure) in the context of full three-phase flow are needed, especially for NAPL spill events at the ground surface. In addition, NAPL evaporation, density-driven gas advection, and NAPL vertical movement enhanced by water flow must be considered in order to predict NAPL distribution and migration in the vadose zone.

Carbon Tetrachloride↗

A three-dimensional vertex dynamics cell model of space-filling polyhedra simulating cell behavior in a cell aggregate.

We developed a three-dimensional (3D) cell model of a multicellular aggregate consisting of several polyhedral cells to investigate the deformation and rearrangement of cells under the influence of external forces. The polyhedral cells fill the space in the aggregate without gaps or overlaps, consist of contracting interfaces and maintain their volumes. The interfaces and volumes were expressed by 3D vertex coordinates. Vertex movements obey equations of motion that rearrange the cells to minimize total free energy, and undergo an elementary process that exchanges vertex pair connections when vertices approach each other. The total free energy includes the interface energy of cells and the compression or expansion energy of cells. Computer simulations provided the following results: An aggregate of cells becomes spherical to minimize individual cell surface areas; Polygonal interfaces of cells remain flat; Cells within the 3D cell aggregate can move and rearrange despite the absence of free space. We examined cell rearrangement to elucidate the viscoelastic properties of the aggregate, e.g. when an external force flattens a cell aggregate (e.g. under centrifugation) its component cells quickly flatten. Under a continuous external force, the cells slowly rearrange to recover their original shape although the cell aggregate remains flat. The deformation and rearrangement of individual cells is a two-step process with a time lag. Our results showed that morphological and viscoelastic properties of the cell aggregate with long relaxation time are based on component cells where minimization of interfacial energy of cells provides a motive force for cell movement.

Animals↗

Maintenance of complex performance during a 135-day spaceflight simulation.

BACKGROUND: The maintenance of crew performance during extended space missions has been a major concern because of the problems associated with prolonged isolation and confinement. Previous research has failed to address this problem by not using appropriate performance tests. METHOD: Three Russian cosmonauts were tested on a PC-based simulation of a spacecraft's life support system during a 135-d simulation of a MIR spaceflight. A complex multiple-task environment was used to examine a comprehensive range of task management variables, including both primary and secondary task performance, control activity and information sampling behavior. Subjective state variables were also measured. RESULTS: The data suggested an overall successful adjustment to isolation and confinement, though some indications of temporary disruptions of some performance indicators were observed. Information sources were sampled less frequently with increasing mission length while system control activities showed a tendency to increase. CONCLUSION: Suggestions are made to address the problem of continuous learning during repeated testing sessions. Using well-designed computer simulations of complex task environments appears to be a promising approach for the evaluation of crew member performance.

Adult↗