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At least 1,099 records · Page 61Linked to original sources

PubMed2005

Homology modeling of the DNA-binding domain of human Smad5: a molecular model for inhibitor design.

Members of the Smad protein family function as signal transducers of the transforming growth factor (TGF-beta) superfamily proteins. The human Smad5 protein, a signal transducer downstream of TGF-beta/BMP receptors, is composed of N-terminal DNA binding domain (MH1) and C-terminal protein-protein interaction domain (MH2) connected together by a linker motif. We used homology-modeling techniques to generate a reliable molecular model of the Smad5 MH1 domain based on the crystal structure of Smad3 MH1 domain. Our study presents the structural features of a BMP-regulated, R-Smad subfamily member (consisting of Smad1, Smad5 and Smad8) for the first time. This model provides a structural basis for explaining both functional similarities and differences between Smad3 and Smad5. Also, the structural model of this molecular target would be useful for structure-based inhibitor design because of its high accuracy. The results of our study provide important insights into understanding the structure-function relationship of the members of the Smad protein family and can serve to guide future genetic and biochemical experiments in this area.

Amino Acid Sequence↗

PubMed2006

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats.

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.

Acoustic Stimulation↗

PubMed2005

The canine model of human cognitive aging and dementia: pharmacological validity of the model for assessment of human cognitive-enhancing drugs.

For the past 15 years we have investigated the aged beagle dog as a model for human aging and dementia. We have shown that dogs develop cognitive deficits and neuropathology seen in human aging and dementia. These similarities increase the likelihood that the model will be able to accurately predict the efficacy of Alzheimer's disease (AD) treatments as well as detect therapeutics with limited or no efficacy. Better predictive validity of cognitive-enhancing therapeutics (CETs) could lead to enormous cost savings by reducing the number of failed human clinical trials and also may reduce the likelihood of negative outcomes such as those recently observed in the AN-1792 clinical trials. The current review assesses the pharmacological validity of the canine model of human aging and dementia. We tested the efficacy of (1) CP-118,954 and phenserine, two acetylcholinesterase inhibitors, (2) an ampakine, (3) selegiline hydrochloride, two drugs that have failed human AD trials, and (4) adrafinil, a putative CET. Our research demonstrates that dogs not only develop isomorphic changes in human cognition and brain pathology, but also accurately predict the efficacy of known AD treatments and the absence or limited efficacy of treatments that failed clinical trials. These findings collectively support the utilization of the dog model as a preclinical screen for identifying novel CETs for both age-associated memory disorder and dementia.

Aging↗

PubMed2004

An integrative model of binocular vision: a stereo model utilizing interocularly unpaired points produces both depth and binocular rivalry.

Half-occluded points (visible only in one eye) are perceived at a certain depth behind the occluding surface without binocular rivalry, even though no disparity is defined at such points. Here we propose a stereo model that reconstructs 3D structures not only from disparity information of interocularly paired points but also from unpaired points. Starting with an array of depth detection cells, we introduce cells that detect unpaired points visible only in the left eye or the right eye (left and right unpaired point detection cells). They interact cooperatively with each other based on optogeometrical constraints (such as uniqueness, cohesiveness, occlusion) to recover the depth and the border of 3D objects. Since it is contradictory for monocularly visible regions to be visible in both eyes, we introduce mutual inhibition between left and right unpaired point detection cells. When input images satisfy occlusion geometry, the model outputs the depth of unpaired points properly. An interesting finding is that when we input two unmatched images, the model shows an unstable output that alternates between interpretations of monocularly visible regions for the left and the right eyes, thereby reproducing binocular rivalry. The results suggest that binocular rivalry arises from the erroneous output of a stereo mechanism that estimates the depth of half-occluded unpaired points. In this sense, our model integrates stereopsis and binocular rivalry, which are usually treated separately, into a single framework of binocular vision. There are two general theories for what the "rivals" are during binocular rivalry: the two eyes, or representations of two stimulus patterns. We propose a new hypothesis that bridges these two conflicting hypotheses: interocular inhibition between representations of monocularly visible regions causes binocular rivalry. Unlike the traditional eye theory, the level of the interocular inhibition introduced here is after binocular convergence at the stage solving the correspondence problem, and thus open to pattern-specific mechanisms.

Depth Perception↗

PubMed1998

Histopathological characterization of magnetic resonance imaging-detectable brain white matter lesions in a primate model of multiple sclerosis: a correlative study in the experimental autoimmune encephalomyelitis model in common marmosets (Callithrix jacchus).

Experimental autoimmune encephalomyelitis in the common marmoset, a nonhuman primate species (Callithrix jacchus), is a new model for multiple sclerosis. Given the close immunological relationship between marmosets and humans, it is an attractive model for investigating immunopathological pathways relevant to multiple sclerosis and to evaluate new treatments for the disease. Unlike in the originally documented model, experimental autoimmune encephalomyelitis induced without the use of Bordetella pertussis led to a chronic disease of moderate severity. The clinical course of experimental autoimmune encephalomyelitis in the present model was mainly chronic and progressive, but periods of incomplete remission did occur. At the chronic stage of the disease, actively demyelinating lesions were found together with inactive demyelinated and remyelinated (shadow) plaques. Before immunization and during clinically active experimental autoimmune encephalomyelitis, T1- and T2-weighted magnetic resonance brain images were obtained. Correlation of the data from the magnetic resonance images and the neuropathology analysis revealed that the hyperintense regions in T2-weighted images represented both active and inactive remyelinating lesions. Quantification showed that the number of lesions in T2-weighted magnetic resonance images equalled those found by pathological examination, and thus T2-weighted magnetic resonance imaging can be used to discern the total lesion load. Extravasation of gadolinium-diethylenetriamine-penta-acetic acid (triple dose) was found only in lesions, which by histopathology were shown to be engaged in the process of active demyelination.

Animals↗

PubMed1988

Quantum mechanical modeling of aspartic proteinase interactions: difference in binding of diastereomeric statine models.

Quantum mechanical calculations were carried out for the interaction of two diastereomeric model inhibitors of aspartic proteinases with a model for the active site, based on crystallographic coordinates of endothiapepsin. The model inhibitor is formamide N-(2-hydroxy 3-methyl propane) and the active site is represented by the full backbone and most of the side chains of the two partial sequences D32-T33-G34-S35 and D215-T216-G217-T218. Those calculations demonstrate that the best binding mode for this short inhibitor is consistent with the X-ray experiments and somewhat stronger with the inhibitor in a 2(S) configuration, compared to 2(R). Another binding mode is possible for this model inhibitor only in the 2(S)-configuration, and is weaker than the first.

Amino Acids↗

PubMed1981

A mean-field model of the alkane-saturated lipid bilayer above its phase transition. I. Development of the model.

A statistical mechanical model of a bilayer of dipalmitoyl-3-sn-phosphatidylcholine molecules in equilibrium with an aqueous phase saturated with an n-alkane is presented. A mean-field approach developed in previous work on a solventless bilayer (Gruen, Biochim. Biophys. Acta. 595:161--183, 1980) is extended to allow alkane chains to exist in the hydrophobic core of the membrane. As the alkane chains are chemically similar to the lipid chains, much of the analysis follows directly from the solventless model. Novel features of the present model are the inclusion of (a) a term which models the free energy cost of creating space for alkane conformations, (b) a term which constrains the chains to pack evenly in the hydrophobic region of the membrane, and (c) a term which estimates the free energy of mixing of the lipid and alkane molecules in the plane of the bilayer. On uptake of alkane, the dimensions of the bilayer increase. Allowance is made for an increase in thickness and/or an increase in area per lipid. A thermodynamic framework is established which allows evaluation of the free energy of a bilayer of arbitrary dimensions with a view to predicting the equilibrium structure.

Alkanes↗

PubMed2004

Biomimetic model of skeletal muscle isometric contraction: II. A phenomenological model of the skeletal muscle excitation-contraction coupling process.

This paper describes a new macroscopic, phenomenological model of the skeletal muscle excitation-contraction coupling process, as represented by four principal and consecutive compartments (biophysical, biochemical, and biomechanical phases) characteristic of isometric excitation-contraction coupling in mammalian skeletal muscle, and coupled by a system of simultaneous, first-order linear ordinary differential equations. The model is based upon biological compartmental transport kinetics and irreversible thermodynamic energy transformation, and represents a distinct improvement over other biomimetic models. The model was derived using physiological parameter data published in the literature, and validated using MATLAB R12.

Calcium↗

PubMed1997

Modeling medical trials in pharmacoeconomics using a temporal object model.

Time is an inherent feature of many medical applications. These applications can also benefit from the support of object database management systems which better capture the semantics of the complex objects that arise in the medical domain. In this paper, we present a uniform behavioral temporal object model which includes a rich and extensible set of types and behaviors to support the various features of a medical application. We concentrate here on the application of pharmacoeconomic medical trials. Pharmacoeconomics is a field of medical economics in which the costs and outcomes of alternative treatments are assessed and compared, in order to establish which is the most appropriate treatment for a particular illness in a particular setting. We describe in detail the histories and timelines features of our temporal model and show how they can effectively be used to model a pharmacoeconomic trial. We then give an instance of a pharmacoeconomic trial as it would appear in the temporal object model and show, using queries, how a series of different behaviors could be used to retrieve various components of the instance. These components could then be used to assess the alternative treatments involved in the trial and determine their cost-effectiveness.

Clinical Trials as Topic↗

PubMed2002

Grouped-neural network modeling for model predictive control.

A group of feed-forward neural networks (NNs), each providing the prediction of an individual process output at a future step, is used as the dynamic prediction model for the model-based predictive control (MPC) scheme in the proposed work. These NNs are parallel (independent) rather than cascaded--they are trained and implemented in parallel. Therefore, the complexity and effort in the training stage is decreased and compounded error propagation is eliminated from the prediction. A new strategy of compensating for the process-model mismatch under this grouped-NN model structure is also developed. Effectiveness of the scheme as a general nonlinear MPC is demonstrated by simulation results.

Algorithms↗

PubMed2000

Analysis of human abnormal walking using a multi-body model: joint models for abnormal walking and walking aids to reduce compensatory action.

This paper proposes new models of diseased joints and evaluates the effectiveness of walking aids such as a cane and a brace for compensating for lost functions due to joint disorders. The ZMJ concept described in the previous work (Yamashita and Tagawa, 1988. In: Radharaman (Ed.), Robotics and Factories of the Future'87. Springer, New York, pp. 670-677) is modified into three joint models as follows: a passive element joint (PEJ) which has a spring at the diseased joint; a constrained range joint (CRJ), the motion of which stays within some constrained relative angle; a partial moment joint (PMJ) which can produce a partial amount of the moment produced about the joint in normal walking. A cane can enlarge a supporting area and adjust the posture of the upper torso to be upright. An ischial weight-bearing brace is effective for conservative management of hip disorders by reducing a load to the joint (Shiba et al., 1998. Clinical Orthopaedics and Related Research 351, 149-157). Walking aids like a cane or brace have been conveniently used by the handicapped. Abnormal walking was simulated for each joint model. Dynamic effects of a cane and a brace on abnormal walking were examined by the multi-body walking model.

Ankle Joint↗

PubMed2002

Three-dimensional finite element modeling of skeletal muscle using a two-domain approach: linked fiber-matrix mesh model.

In previous applications of the finite element method in modeling mechanical behavior of skeletal muscle, the passive and active properties of muscle tissue were lumped in one finite element. Although this approach yields increased understanding of effects of force transmission, it does not support an assessment of the interaction between the intracellular structures and extracellular matrix. In the present study, skeletal muscle is considered in two domains: (1) the intracellular domain and (2) extracellular matrix domain. The two domains are represented by two separate meshes that are linked elastically to account for the trans-sarcolemmal attachments of the muscle fibers' cytoskeleton and extracellular matrix. With this approach a finite element skeletal muscle model is developed, which allows force transmission between these domains with the possibility of investigating their interaction as well as the role of the trans-sarcolemmal systems. The model is applied to show the significance of myofascial force transmission by investigating possible mechanical consequences due to any missing link within the trans-sarcolemmal connections such as found in muscular dystrophies. This is realized by making the links between the two meshes highly compliant at selected intramuscular locations. The results indicate the role of extracellular matrix for a muscle in sustaining its physiological condition. It is shown that if there is an inadequate linking to the extracellular matrix, the myofibers become deformed beyond physiological limits due to the lacking of mechanical support and impairment of a pathway of force transmission by the extracellular matrix. This leads to calculation of a drop of muscle force and if the impairment is located more towards the center of the muscle model, its effects are more pronounced. These results indicate the significance of non-myotendinous force transmission pathways.

Animals↗

PubMed1998

A comparative study of impact dynamics: wobbling mass model versus rigid body models.

We demonstrate that the results of inverse dynamics depend sensitively on the model used to simulate the human body. For this reason we produce "ideal" input data of the ground reaction force and the heel acceleration for a computer simulated drop jump with a wobbling mass model. Then we determine the internal torques and forces in the knee and hip joint via inverse dynamics by employing a rigid body model. It turns out that during the impact phase the analysis with the rigid body model yields completely incorrect internal torques and forces.

Acceleration↗

PubMed1999

Modeling and simulation of the dynamic behavior of monoliths. Effects of pore structure from pore network model analysis and comparison with columns packed with porous spherical particles.

A mathematical model is presented that could be used to describe the dynamic behavior, scale-up, and design of monoliths involving the adsorption of a solute of interest. The value of the pore diffusivity of the solute in the pores of the skeletons of the monolith is determined in an a priori manner by employing the pore network modeling theory of Meyers and Liapis [J. Chromatogr. A, 827 (1998) 197 and 852 (1999) 3]. The results clearly show that the pore diffusion coefficient, Dmp, of the solute depends on both the pore size distribution and the pore connectivity, nT, of the pores in the skeletons. It is shown that, for a given type of monolith, the film mass transfer coefficient, Kf, of the solute in the monolith could be determined from experiments based on Eq. (3) which was derived by Liapis [Math. Modelling Sci. Comput., 1 (1993) 397] from the fundamental physics. The mathematical model presented in this work is numerically solved in order to study the dynamic behavior of the adsorption of bovine serum albumin (BSA) in a monolith having skeletons of radius r(o) = 0.75x10(-6) m and through-pores having diameters of 1.5x10(-6)-1.8x10(-6) m [H. Minakuchi et al., J. Chromatogr. A, 762 (1997) 135]. The breakthrough curves of the BSA obtained from the monolith were steeper than those from columns packed with porous spherical particles whose radii ranged from 2.50x10(-6) m to 15.00x10(-6) m. Furthermore, and most importantly, the dynamic adsorptive capacity of the monolith was always greater than that of the packed beds for all values of the superficial fluid velocity, Vtp. The results of this work indicate that since in monoliths the size of through-pores could be controlled independently from the size of the skeletons, then if one could construct monolith structures having (a) relatively large through-pores with high through-pore connectivity that can provide high flow-rates at low pressure drops and (b) small-sized skeletons with mesopores having an appropriate pore size distribution (mesopores having diameters that are relatively large when compared with the diameter of the diffusing solute) and high pore connectivity, nT, the following positive results, which are necessary for obtaining efficient separations, could be realized: (i) the value of the pore diffusion coefficient, Dmp, of the solute would be large, (ii) the diffusion path length in the skeletons would be short, (iii) the diffusion velocity, vD, would be high, and (iv) the diffusional response time, t(drt), would be small. Monoliths with such pore structures could provide more efficient separations with respect to (a) dynamic adsorptive capacity and (b) required pressure drop for a given flow-rate, than columns packed with porous particles.

Adsorption↗

PubMed1999

A structural modeling analysis of anxiety and depression in patients undergoing coronary artery bypass graft surgery: a model generating approach.

The present study is a longitudinal study designed to explore structural relationships between anxiety, depression, personality, and background factors (e.g., gender, age, and complicated medical characteristics) in patients undergoing coronary artery bypass graft (CABG) surgery. At two timepoints before and two after CABG, 217 patients completed self-report questionnaires. To explore structural relationships, the structural equation modeling (SEM) method was applied. Using the model-generating approach, a model was developed, providing a good fit. The structural relationships revealed, in particular, the key position of neuroticism, which was related to both pre- and postoperative anxiety and depression. Relationships between anxiety and depression over time, both intra- and interrelationships, were relatively weak. Relationships between anxiety and depression at the same points in time were relatively strong, with preoperative depression leading to preoperative anxiety, and postoperative anxiety leading to postoperative depression. To provide a useful framework for development of intervention strategies, further research is needed to evaluate the plausibility of the final structural model.

Adult↗

PubMed1990

The theory of sliding filament models for muscle contraction. II. Biochemically-based models of the contraction cycle.

A seven-state sliding filament model is proposed which differs from the model of Eisenberg & Greene. It is based on a simplified version of the in-vitro contraction cycle of Stein et al., and also has some desirable dynamical features of the empirical three-state model of Nishiyama & Murase. Appropriate x-dependences for all reaction rates are derived from the transition-state theory. The seventh-state is assumed to be a high-tension intermediate of A.M.ATP, from which direct but x-dependent dissociation can occur. If the final A.M.ATP state has a sufficiently lower tension than that of A.M.ADP.Pi, then the dominant escape path from the intermediate state is shown to be direct dissociation of the actin-myosin bond. This leads to an approximate five-state model for active and relaxed muscle in which A.M and the final A.M.ATP state are omitted.

Actins↗

PubMed1987

The theory of sliding filament models for muscle contraction. I. The two-state model.

The mechanical and thermal properties of Huxley's 1957 sliding filament model for striated muscle contraction are reconsidered, with emphasis on general relationships between two-state models and muscle behaviour. New empirical forms for the rate functions f(x) and g(x) are proposed, which give an improved fit to experiments. A specific procedure, based on the shortening heat, for determining model parameters is described and applied to various choices of rate functions. The change in slope of the tension-velocity curve observed by Katz is shown to require at least one discontinuity in the binding rate f(x), and a general formula is given. The two-state model also gives a symmetric cusp in the ATP-rate vs velocity curve at v = 0. The theory is extended to time-varying situations and applied to transient responses following isometric activation by tetanus (including latency relaxation), and unloaded and after-loaded contractions. The early burst of heat production can also be fitted by assigning appropriate values to the heats of binding and dissociation.

Adenosine Triphosphate↗

PubMed2003

Epidemiological modeling in a branching population. Particular case of a general SIS model with two age classes.

This paper covers the elaboration of a general class of multitype branching processes for modeling in a branching population, the evolution of a disease with horizontal and vertical transmissions. When the size of the population may tend to infinity, normalization must be carried out. As the initial size tends to infinity, the normalized model converges a.s. to a dynamical system the solution of which is the probability law of the state of health for an individual ancestors line. The focal point of this study concerns the transient and asymptotical behaviors of a SIS model with two age classes in a branching population. We will compare the asymptotical probability of extinction on the scale of a finite population and on the scale of an individual in an infinite population: when the rates of transmission are small compared to the rate of renewing the population of susceptibles, the two models lead to a.s. extinction, giving consistent results, which no longer applies to the opposite situation of important transmissions. In that case the size of the population plays a crucial role in the spreading of the disease.

Age Factors↗