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A model for the generation of movements requiring endpoint precision.

A model is proposed in which movement accuracy is regulated by means of corrective actions taken at discrete intervals throughout the course of a movement. A movement, as represented by its tangential velocity profile, cna be decomposed into a series of one or more submovements. Each submovement consists of a prototype velocity profile which can be scaled in magnitude and duration. For planar two-joint movements, we demonstrate that these submovements can be mathematically represented either in terms of velocity profiles or in terms of the underlying joint torque profiles. In either case, the submovements superimpose linearly to produce the composite movement. The model provides a very good fit to tangential velocity profiles recorded from human subjects during three-dimensional arm movements with constraints on accuracy and speed. The model assumes that when a submovement is present, its onset is associated with a change in the direction of the hand path and/or a zero crossing or inflection in at least one of the components of the velocity vector. The model is consistent with a strategy in which precision is achieved by periodic discrete actions which redirect the moving arm in order to bring the hand closer to the target. Since submovements were also observed in slow movements where accuracy constraints had been relaxed, we hypothesize that the strategy of superimposing a series of submovements to make one composite movement may be a general one. We suggest that it would be particularly appropriate for the process of learning a new motor skill.

Adult↗

Graphical and stereolithographic models of the developing human heart lumen.

Scaled physical models can be useful in analyzing stage-specific hemodynamics in the embryonic human heart to address correlations between early physical stressors and myocardial wall responses. We generated models of the cardiac blood space from reconstructions of four digitized human embryo images from Carnegie Collection at the Armed Forces Institute of Pathology. From physical scale models manufactured by stereolithography, compliant sleeves can be created for flow dynamics studies. This novel use of Carnegie collection images and graphical modeling software provides tools for broadening our understanding of normal and aberrant heart formation.

Embryonic and Fetal Development↗

The within-host cellular dynamics of bloodstage malaria: theoretical and experimental studies.

The properties of a mathematical model of bloodstage infection with a single strain of malaria were investigated. Analysing the cell population dynamics in the absence of a host immune response we demonstrate a relationship between host and parasite parameters that defines a criterion for the successful invasion and persistence of the parasite. Important parameters are the rates of merozoite production and death and those of erythrocyte production, death and invasion. We present data from experiments designed to evaluate the erythrocyte invasion rate in a rodent malaria system. The model generates patterns of parasitaemia in good qualitative agreement with those seen in Plasmodium berghei infections. The sole force behind the rise and fall in parasitaemia in the model without immunity is the density of susceptible erythrocytes, suggesting that resource availability is an important determinant of the initial pattern of infection in vivo. When we incorporate a simple immune response into the model we find that immunity against the infected cell is much more effective at suppressing parasite abundance than immunity against the merozoite. Simulations reveal oscillating temporal patterns of parasite abundance similar to P. c. chabaudi infection, challenging the concept that antigenic variation is the sole mechanism behind recrudescing patterns of infection.

Animals↗

Beyond phrenology: what can neuroimaging tell us about distributed circuitry?

Unsupervised models of how the brain identifies and categorizes the causes of its sensory input can be divided into two classes: those that minimize the mutual information (i.e., redundancy) among evoked responses and those that minimize the prediction error. Although these models have the same goal, the way that goal is attained, and the functional architectures required, are fundamentally different. This review describes the differences, in the functional anatomy of sensory cortical hierarchies, implied by the two models. We then consider how neuroimaging can be used to disambiguate between them. The key distinction reduces to whether backward connections are employed by the brain to generate a prediction of sensory inputs. To ascertain whether backward influences are evident empirically requires a characterization of functional integration among brain systems. This review summarizes the approaches to measuring functional integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations. In short, it will be shown that the conjoint manipulation of bottom-up and top-down inputs to an area can be used to test for interactions between them, in elaborating cortical responses. The conclusion, from these sorts of neuroimaging studies, points to the prevalence of top-down influences and the plausibility of generative models of sensory brain function.

Animals↗

Theoretical considerations in relation to the treatment of brain tumours by means of local hyperthermia generated by ultrasound fields.

Brain tumours comprise a significant fraction of all tumours in the human body. Despite the development of technology in clinical oncology, these tumours still present a difficult challenge. The margin between destruction of tumour and damage to normal tissue is narrow in the brain. The price paid for producing tissue damage outside the tumour is high in terms of quality of survival. Results of many experiments with ultrasound hyperthermia show that this new technique is successful for treating certain types of malignant tumours. In the case of brain tumours, applying focused fields should have the advantage of selectively destroying the tumour and leaving surrounding tissues intact. Previous attempts at applying ultrasound to the field of neurosurgery are reviewed. Those factors which have effects on the generation of thermal fields in brain tissues are considered in relation to the possible treatment of human brain tumours. Calculated thermal fields in a 2-D brain model generated by an applicator built in our laboratory are also presented.

Brain↗

Effects of circulating renin substrate on renal function in isolated perfused rat kidney.

The effects of two different amounts of pure rat angiotensinogen were investigated in a closed circuit isolated perfused rat kidney. In response to angiotensinogen, circulating levels of angiotensin I (AI) and angiotensin II (AII) immunoreactive materials were found to increase in a time and dose-dependent manner. Vasoconstrictor and renin inhibitory effects were observed in parallel with the increase in AII. Glomerular filtration rate decreased after administration of angiotensinogen to a greater extent than renal flow and filtration fraction. The characterization by high performance liquid chromatography of peptides generated showed the liberation of AI, des-Asp1AI, AII and des-Asp1AII (AIII). These findings demonstrate that administration of angiotensinogen in an isolated perfused kidney model generates AI and that renal converting enzyme and aminopeptidases are able to convert AI to AII, AI to des-Asp1AI, and des-Asp1AI and/or AII to AIII. Changes in circulating level of angiotensinogen influence the activity of the renin-angiotensin system and, therefore, renal function.

Angiotensin I↗

On the effect of the intracellular calcium-sensitive K+ channel in the bursting pancreatic beta-cell.

Based on the observation that the calcium-activated K+ channel in the pancreatic islet cells can also be activated by the membrane potential, we have formulated a mathematical model for the electrical activity in the pancreatic beta-cell. Our model contains two types of ionic channels, which are active above the subthreshold glucose concentration in the limit-cycle region: a Ca2+-activated, voltage-gated K+ channel and voltage-gated Ca2+ channel. Numerical simulation of the model generates bursts of electrical activity in response to a variation of kCa, the rate constant for sequestration of intracellular calcium ions. The period and duration of the bursts in response to kCa are in good agreement with experiment. The model predicts that a combined spike and burst pattern can be created using only single species of inward and outward currents, the inactivation kinetics (i.e., h) in the inward current is not a necessary condition for the generation of the pattern, and a given pattern or intensity of electrical activity may produce different levels of intracellular Ca2+ depending on the set of certain electrical parameters.

Animals↗

A molecular thermodynamic approach to predict the secondary structure of homopolypeptides in aqueous systems.

Under physiological conditions, many polypeptide chains spontaneously fold into discrete and tightly packed three-dimensional structures. The folded polypeptide chain conformation is believed to represent a minimum Gibbs energy of the system, governed by the weak interactions that operate between the amino acid residues and between the residues and the solvent. A semiempirical molecular thermodynamic model is proposed to represent the Gibbs energy of folding of aqueous homopolypeptide systems. The model takes into consideration both the entropy contribution and the enthalpy contribution of folding homopolypeptide chains in aqueous solutions. The entropy contribution is derived from the Flory-Huggins expression for the entropy of mixing. It accounts for the entropy loss in folding a random-coiled polypeptide chain into a specific polypeptide conformation. The enthalpy contribution is derived from a molecular segment-based Non-Random Two Liquid (NRTL) local composition model [H. Renon and J. M. Prausnitz (1968) AIChE J., Vol. 14, pp. 135-142; C.-C. Chen and L. B. Evans (1986) AIChE J., Vol. 32, pp. 444-454], which takes into consideration of the residue-residue, residue-solvent, and solvent-solvent binary physical interactions along with the local compositions of amino acid residues in aqueous homopolypeptides. The UNIFAC group contribution method [A. Fredenslund, R. L. Jones, and J. M. Prausnitz (1975) AIChE J., 21, 1086-1099; A. Fredenslund, J. Gmehling, and P. Rasmussen (1977) Vapor-Liquid Equilibrium Using UNIFAC, Elsevier Scientific Publishing Company, Amsterdam], developed originally to estimate the excess Gibbs energy of solutions of small molecules, was used to estimate the NRTL binary interaction parameters. The model yields a hydrophobicity scale for the 20 amino acid side chains, which compares favorably with established scales [Y. Nozaki and C. Tanford (1971) Journal of Biological Chemistry, Vol. 46, pp. 2211-2217; E. B. Leodidis and T. A. Hatton (1990) Journal of Physical Chemistry, Vol. 94, pp. 6411-6420]. In addition, the model generates qualitatively correct thermodynamic constants and it accurately predicts thermodynamically favorable folding of a number of aqueous homopolypeptides from random-coiled states into alpha-helices. The model further facilitates estimation of the Zimm-Bragg helix growth parameter s and the nucleation parameter sigma for amino acid residues [B. H. Zimm and J. K. Bragg (1959) Journal of Chemical Physics, Vol. 31, pp. 526-535]. The calculated values of the two parameters fall into the ranges suggested by Zimm and Bragg.

Models, Molecular↗

Optimisation of transcutaneous cardiac pacing by three-dimensional finite element modelling of the human thorax.

The goal of the study is to determine by finite element analysis (FE) the optimal electrode placement, size and electrolyte resistivity that minimise the pain experienced by patients during successful transcutaneous cardiac pacing (TCP). The three-dimensional FE model generated for this purpose has 55,388 nodes, 50,913 hexahedral elements and simulated 16 different organs and tissues, as well as the properties of the electrolyte. The model uses a non-uniform mesh with an average spatial resolution of 0.8 cm in all three dimensions. To validate this model, the voltage across 3 cm2 Ag-AgCl electrodes is measured when currents of 5 mA at 50 kHz are injected into a subject's thorax through the same electrodes. For the same electrode placements and sizes and the same injected current, the FE analysis produced results in good agreement with the experimental data. The optimisation analysis tested seven different electrode placements, five different electrode sizes and six different electrolyte resistivities. The analysis indicates that the anterior-posterior electrode placement, electrode sizes of about 90 cm2 and electrolytes with resistivity of about 800 omega.cm yield the most uniform current distribution through the skin, thus having the best chances to minimise the pain delivered to the patient during successful TCP. The anterior-anterior electrode placement is the second most efficient.

Cardiac Pacing, Artificial↗

[Geometrical modeling of the spine and the thorax for the biomechanical analysis of scoliotic deformities using the finite element method].

In order to study the biomechanical behavior of the whole human spine and thorax, as well as orthopaedic treatment effects, a new generation model is proposed, which includes a precise functional representation of the posterior part of the spine, while respecting computational capabilities. This paper presents the geometrical aspects of this model. The latter is built using an hybrid method which combines steroradiographic 3-D reconstructions of the spine and thorax [1] to serial CT scan 3-D reconstructions of typical human vertebrae and sternum [4] and published morphometric data of ribs [2, 3]. These anatomical structures were deformed in order to fit as well as possible the personalized data of scoliotic patients using geometrical transformations as well as interpolation or extrapolation techniques. In the posterior part, articular facets are modelled and parameterized as elementary surface shapes (plane, cylinder, sphere). For the articular facet geometry of a given normal subject, results revealed that the zygapophyseal facets are better represented by planes for T1 to T11 and by portions of cylinders for T12 to L5, which is in concordance with the literature [5, 6]. Evaluation of this modelling approach was done on 2 cadaveric vertebral segments. Parametric data obtained from the model were compared to precise measurements done on the vertebrae using a 3-D digitizer, and concordance was found. These personalized geometric informations were then used to build a finite element model [7], which will be useful to study scoliotic deformities as well as personalized orthopaedic treatments.

Humans↗

Extending the multiple indicator dilution method to include slow intracellular diffusion.

The traditional multiple indicator dilution (MID) method is extended to incorporate cytoplasmic concentration gradients due to slow intracellular diffusion of the permeable molecule. The new model is governed by a system of partial differential equations that are solved using Laplace transformation. An analysis of the transformed solution shows that the traditional MID method is a special case of the extended model. We then use simulation analysis to show that the traditional MID model and the new diffusion model generate similar outflow curves. However, when the traditional MID equations were used to analyze outflow curves generated using a system in which intracellular diffusion is slow compared to other transport processes, the recovered rate constants for the transmembrane and excretion processes were incorrect. The diffusion model permits estimation of the rate of intracellular transport of amphipathic molecules from suitable indicator dilution data.

Animals↗

Non-peptide angiotensin II receptor antagonists: chemical feature based pharmacophore identification.

Chemical feature based pharmacophore models were elaborated for angiotensin II receptor subtype 1 (AT(1)) antagonists using both a quantitative and a qualitative approach (Catalyst HypoGen and HipHop algorithms, respectively). The training sets for quantitative model generation consisted of 25 selective AT(1) antagonists exhibiting IC(50) values ranging from 1.3 nM to 150 microM. Additionally, a qualitative pharmacophore hypothesis was derived from multiconformational structure models of the two highly active AT(1) antagonists 4u (IC(50) = 0.2 nM) and 3k (IC(50) = 0.7 nM). In the case of the quantitative model, the best pharmacophore hypothesis consisted of a five-features model (Hypo1: seven points, one hydrophobic aromatic, one hydrophobic aliphatic, a hydrogen bond acceptor, a negative ionizable function, and an aromatic plane function). The best qualitative model consisted of seven features (Hypo2: 11 points, two aromatic rings, two hydrogen bond acceptors, a negative ionizable function, and two hydrophobic functions). The obtained pharmacophore models were validated on a wide set of test molecules. They were shown to be able to identify a range of highly potent AT(1) antagonists, among those a number of recently launched drugs and some candidates presently undergoing clinical tests and/or development phases. The results of our study provide confidence for the utility of the selected chemical feature based pharmacophore models to retrieve structurally diverse compounds with desired biological activity by virtual screening.

Acrylates↗

A dimension reduction framework for understanding cortical maps.

We argue that cortical maps, such as those for ocular dominance, orientation and retinotopic position in primary visual cortex, can be understood in terms of dimension-reducing mappings from many-dimensional parameter spaces to the surface of the cortex. The goal of these mappings is to preserve as far as possible neighbourhood relations in parameter space so that local computations in parameter space can be performed locally in the cortex. We have found that, in a simple case, certain self-organizing models generate maps that are near-optimally local, in the sense that they come close to minimizing the neuronal wiring required for local operations. When these self-organizing models are applied to the task of simultaneously mapping retinotopic position and orientation, they produce maps with orientation vortices resembling those produced in primary visual cortex. This approach also yields a new prediction, which is that the mapping of position in visual cortex will be distorted in the orientation fracture zones.

Animals↗

Lateral arm fascial flap: microarterial anatomy and potential clinical applications.

Previously, muscle flaps and the omentum have been used to indirectly vascularize tissues. Induction of synangiogenesis, or indirect vascularization through the formation of collateral vessels, occurs through the development of vascular connections at the interface between the donor and recipient tissues. Unfortunately, muscle and omental flaps are bulky and, when used to salvage ischemic hands and digits, may limit digital range of motion. Additionally, disadvantages to using omentum include a requirement for an intraabdominal procedure and a lack of subsequent donor tissue if the contralateral limb becomes involved at a later time. The purpose of this anatomic study was to develop a customized lateral arm fascial flap (LAFF) which may be used for flap prefabrication or synangiogenesis of non-bypassable ischemia. Detailed anatomic dissections were performed to more thoroughly define the microvascular anatomy of the LAFF. Computer analysis of the data was performed to demonstrate the potential clinical application of using the LAFF. Dissections revealed a consistent pattern of vessels branching within the lateral arm fascia and to the neighboring musculature. In order to optimize the surgical use of available tissue, computer-aided design techniques were used to model a reliable fascial free flap for inducing synangiogenesis while imparting minimal donor-site morbidity. Anatomic studies of the LAFF revealed pitfalls in flap dissection, while computer-generated models illustrated the detailed microarterial anatomy of the LAFF and potential limitations in flap design. Potential clinical applications for use of this low-profile fasciovascular conduit are noted.

Arm↗

Experimental verification of a mathematical model for pelleted growth of Streptomyces coelicolor A3(2) in submerged batch culture.

A published mathematical model for growth of pellets of filamentous microorganisms has been tested by comparison of model predictions with experimental data on growth of Streptomyces coelicolor in liquid batch culture. The original model considered the classification of pellets into a range of size classes. Growth resulted in movement of pellets to classes of increasing size, while shear forces produced mycelial fragments which entered the smallest size class, from which they grew to form further pellets. This model did not correctly describe changes in pellet size distributions during growth and was therefore modified in two ways. In the first, new pellets were assumed to be formed by the break-up, by shear forces, of existing pellets into two pellets of equal size, rather than removal of small hyphal fragments from the pellet surface. The second modification assumed that the outer shell of active mycelial biomass had a density less than 1 g cm-3 and that hyphal density within this shell decreased with distance from the pellet centre. The modified model generated predictions which agreed closely with experimental data on biomass concentration, pellet size distribution, pellet number and pellet radius during batch growth, thereby supporting the assumptions on which the model was based. The model did not accurately describe final biomass concentration, through lack of consideration of autolysis of mycelia at the centre of larger pellets in which growth was limited by diffusion of nutrients. Attempts to incorporate autolysis into the model improved prediction of biomass concentration but were not based on sound biological assumptions and increased the complexity of the model. Further experimental work is required for accurate description of the effects of autolysis on pellet growth.

Models, Theoretical↗

Strategy for the treatment of acute myelogenous leukemia based on folate receptor beta-targeted liposomal doxorubicin combined with receptor induction using all-trans retinoic acid.

Up-regulation of folate receptor (FR) type-beta in acute myelogenous leukemia (AML) by all-trans retinoic acid (ATRA) and its restricted normal tissue distribution makes it a potential target for therapeutic intervention. The FR-beta in peripheral blood granulocytes was unable to bind folate and appeared to have a variant GPI membrane anchor, evident from its insensitivity to phosphatidylinositol-specific phospholipase C but not nitrous acid. Granulocyte FR-beta lacked mutations, and neither deglycosylation nor detergent solubilization restored folate binding. The posttranslational modification causing its nonfunctionality was evidently absent in FR-beta from AML cells from patient marrow, which bound folate. From flow cytometric analysis of 78 AML bone marrow specimens of different subtypes, 68% expressed FR-beta, most of which were also CD34+. In model cell lines that are FR - (KG-1a, L1210, and Chinese hamster ovary [CHO]) or FR + (KG-1, L1210 JF, and recombinant CHO-FR-beta), selective FR-mediated binding and cytotoxicity was obtained using folate-coated liposomes encapsulating fluorescent calcein (f-L-calcein) and doxorubicin (f-L-DOX), respectively, which could be blocked by 1 mM free folic acid. In the FR-beta-expressing KG-1 human AML cells, treatment with ATRA further increased this specificity. In mouse ascites leukemia models generated using L1210JF or KG-1 cells, increased median survival times were obtained with f-L-DOX treatment compared to nontargeted L-DOX. In the KG-1 model, ATRA treatment increased the cure rate with f-L-DOX from 10% to 60%. The above combined data from our 2 laboratories further support the feasibility and potential usefulness of selective ATRA-facilitated liposomal drug delivery in FR-beta + AMLs.

Animals↗

Effect of two different videotaped instructional models on motor and verbal behaviors of adults' lifting: a pilot study.

This study examined two different videotaped instructional models on subsequent motor and verbal behaviors of adults (N=9) learning how to lift properly. The correct model group viewed a narrated videotape of a skilled individual demonstrating lifting; the learning model group viewed a videotape of an unskilled individual being taught lifting by an instructor, and the controls received no intervention. Adults lifted from floor to waist a plastic crate during 15 acquisition and 3 retention trials and lowered the crate from waist to floor during 3 transfer trials. Learning and correct model motor performances were similar yet higher than those of controls during acquisition and transfer trials. Verbal reports indicated learning, and correct models generated more extensive and associated mechanical concepts than controls yet rarely monitored such concepts during performance. A single presentation of videotapes of proper lifting using either correct or learning models is effective in enhancing motor performance and proper lifting knowledge.

Adolescent↗

Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors.

The program Catalyst was used to build three-dimensional quantitative structure activity relationship (3D-QSAR) pharmacophore models of the structural features common to competitive-type inhibitors of cytochrome P-450 (CYP) 3A4. These were compared with 3D- and four-dimensional (4D)-QSAR partial least-squares (PLS) models built using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors for size and shape of the inhibitor. The Catalyst pharmacophore model generated from multiple conformers of competitive inhibitors of CYP3A4-mediated midazolam 1'-hydroxylation (n = 14) yielded a high correlation of observed and predicted Ki values of r = 0.91. Similarly, PLS MS-WHIM was used to produce 3D- and 4D-QSARs for this data set and produced models that were statistically predictable after cross-validation. Two additional Catalyst pharmacophores were constructed from literature Ki values (n = 32) derived from the inhibition of CYP3A-mediated cyclosporin A metabolism and IC50 data (n = 22) from the inhibition of CYP3A4-mediated quinine 3-hydroxylation. These Catalyst pharmacophores illustrated correlations of observed and predicted inhibition for CYP3A4 of r = 0.77 and 0.92, respectively. The corresponding 4D-QSARs generated by PLS MS-WHIM for these data sets were of comparable quality as judged by cross-validation. Both Ki pharmacophores generated with Catalyst were also validated by predicting the Ki(apparent) values of a test set of eight CYP3A4 inhibitors not included in either model. In seven of eight cases, the residuals of the predicted Ki(apparent) values were within 1 log unit of the observed values. The 3D- and 4D-QSAR models produced in this study suggest the utility of future in silico prediction of CYP3A4-mediated drug-drug interactions.

Catalysis↗