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PubMed2002

A unified model of NMDA receptor-dependent bidirectional synaptic plasticity.

Synapses in the brain are bidirectionally modifiable, but the routes of induction are diverse. In various experimental paradigms, N-methyl-d-aspartate receptor-dependent long-term depression and long-term potentiation have been induced selectively by varying the membrane potential of the postsynaptic neurons during presynaptic stimulation of a constant frequency, the rate of presynaptic stimulation, and the timing of pre- and postsynaptic action potentials. In this paper, we present a mathematical embodiment of bidirectional synaptic plasticity that is able to explain diverse induction protocols with a fixed set of parameters. The key assumptions and consequences of the model can be tested experimentally; further, the model provides the foundation for a unified theory of N-methyl-d-aspartate receptor-dependent synaptic plasticity.

Action Potentials↗
PubMed2006

Mesoscale modeling of complex binary fluid mixtures: towards an atomistic foundation of effective potentials.

This paper is devoted to equilibrium molecular-dynamics (MD) simulations of a fully atomistic model of binary mixtures of water (component 1) and ethanol (component 2). We investigate ways to extract from these simulations effective, pairwise additive potentials suitable to describe the interactions between coarse-grained molecules (i.e., beads) in corresponding mesoscale dissipative particle-dynamics simulations. The fully atomistic model employed in MD simulations is mapped onto an implicit water model, where the internal degrees of freedom of ethanol and all the degrees of freedom of water are integrated out. This gives us an effective one-component system consisting only of ethanol beads. The effective interaction potential between a pair of ethanol beads, Phi(R), is approximated at three levels of sophistication. At the lowest one, we approximate Phi(R) by the potential of mean force between the centers of mass of two ethanol beads calculated in the fully atomistic MD simulations; at the second level, we take Phi(R) to be the potential linked to total and direct correlation functions in the hypernetted-chain closure of the Ornstein-Zernike equation. At the third level we approximate Phi(R) numerically by improving it iteratively through the Boltzmann inversion scheme. Our results indicate that the level-one approach works only at the lowest (8 wt %) concentration; the level-two approach works only up to intermediate ethanol concentrations (ca. 50 wt %). Only the Boltzmann inversion scheme works for all, up to the highest concentration considered (70 wt %).

Journal Article↗
PubMed1990

The electrophysiological basis of epileptiform magnetic fields in neocortex.

Electrical measurements of epileptiform cellular currents in a penicillin model of focal epilepsy were directly compared to the extracranial magnetic fields these currents produce. Our data support the hypothesis that epileptiform magnetic fields result from intradendritic currents oriented perpendicular to the cortical surface. Furthermore, magnetic fields could be detected from epileptic foci smaller than 3 mm2. This work provides an empirical foundation for physical models with which to interpret noninvasive neuromagnetic recordings of epileptic discharge in human focal seizure disorders.

Animals↗
PubMed1999

Transitions, part 1: beyond pharmaceutical care.

A systems view of the amalgamation of existing pharmacy practice models is proposed. Pharmacy's evolution is traceable as a series of stages. The stages in pharmacy's evolution have been manufacturing pharmacy, compounding, distribution, clinical pharmacy, and pharmaceutical care. Good pharmacy practice (GPP) represents an international attempt to unite various conceptualizations of practice, including pharmaceutical care. GPP in turn provides a foundation for a model to explain current and changing practice, the total pharmacy care (TPC) model. TPC combines five existing practice models: drug information, self-care, clinical pharmacy, pharmaceutical care, and distribution. TPC, as the sum of these models, asserts that there will be an ongoing need for all five existing models of practice, that the proportion of pharmacists employing each model will reflect the needs of a given health care environment at a given time, and that if changes in health care provide more opportunities for pharmaceutical care, pharmacists will shift increasingly toward that type of practice. Total pharmacy care is the delivery of a comprehensive range of services that result in the maximum possible contribution to the health of a nation's population within the limits of the health care delivery structure.

Forecasting↗
PubMed2004

The hydrophobic-subtraction model of reversed-phase column selectivity.

A recently developed treatment of reversed-phase column selectivity (the hydrophobic-subtraction model) is reviewed and extended, including its characterization of the selectivity of different column types (e.g., C1-C30, cyano, phenyl, etc.). The application of this model to retention data for various solutes and columns has provided new insights into the nature of different solute-column interactions and their relative importance in affecting sample retention and separation. Reversed-phase columns can be characterized by five selectivity parameters (H, S*, A, B and C), values of which are summarized here for more than 300 different columns. The selection of columns of either equivalent or different selectivity is readily achievable on the basis of their values of H, S*, etc. The development of the hydrophobic-subtraction model, its use in characterizing the selectivity of different reversed-phase liquid chromatography (RP-LC) columns, and its application to various practical problems as described here began in 1998. The original inspiration for this project owes much to Jack Kirkland, who also contributed actively to the initial studies that laid the foundation of this model; he has since provided other important support to this project. Jack and one of the authors (LRS) have enjoyed a strong professional relationship and personal friendship for the past 35 years, and it is the privilege of the authors to dedicate this paper and the work that it represents to Jack. His contributions to HPLC column technology have extended from the mid-1960s into the present century, and it is impossible to conceive of present day HPLC practice without Jack's contributions over the years. In this and other ways, his position as a pioneer and key implementer of HPLC is widely recognized. We wish Jack well in the years to come.

Chromatography, Liquid↗
PubMed2004

Foundations of chaotic mixing.

The simplest mixing problem corresponds to the mixing of a fluid with itself; this case provides a foundation on which the subject rests. The objective here is to study mixing independently of the mechanisms used to create the motion and review elements of theory focusing mostly on mathematical foundations and minimal models. The flows under consideration will be of two types: two-dimensional (2D) 'blinking flows', or three-dimensional (3D) duct flows. Given that mixing in continuous 3D duct flows depends critically on cross-sectional mixing, and that many microfluidic applications involve continuous flows, we focus on the essential aspects of mixing in 2D flows, as they provide a foundation from which to base our understanding of more complex cases. The baker's transformation is taken as the centrepiece for describing the dynamical systems framework. In particular, a hierarchy of characterizations of mixing exist, Bernoulli --> mixing --> ergodic, ordered according to the quality of mixing (the strongest first). Most importantly for the design process, we show how the so-called linked twist maps function as a minimal picture of mixing, provide a mathematical structure for understanding the type of 2D flows that arise in many micromixers already built, and give conditions guaranteeing the best quality mixing. Extensions of these concepts lead to first-principle-based designs without resorting to lengthy computations.

Complex Mixtures↗
PubMed2005

Extracellular domain nicotinic acetylcholine receptors formed by alpha4 and beta2 subunits.

Models of the extracellular ligand-binding domain of nicotinic acetylcholine receptors (nAChRs), which are pentameric integral membrane proteins, are attractive for structural studies because they potentially are water-soluble and better candidates for x-ray crystallography and because their smaller size is more amenable for NMR spectroscopy. The complete N-terminal extracellular domain is a promising foundation for such models, based on previous studies of alpha7 and muscle-type subunits. Specific design requirements leading to high structural fidelity between extracellular domain nAChRs and full-length nAChRs, however, are not well understood. To study these requirements in heteromeric nAChRs, the extracellular domains of alpha4 and beta2 subunits with or without the first transmembrane domain (M1) were expressed in Xenopus oocytes and compared with alpha4beta2 nAChRs based on ligand binding and subunit assembly properties. Ligand affinities of detergent-solubilized, extracellular domain alpha4beta2 nAChRs formed from subunits with M1 were nearly identical to affinities of alpha4beta2 nAChRs when measured with [3H]epibatidine, cytisine, nicotine, and acetylcholine. Velocity sedimentation suggested that these extracellular domain nAChRs predominantly formed pentamers. The yield of these extracellular domain nAChRs was about half the yield of alpha4beta2 nAChRs. In contrast, [3H]epibatidine binding was not detected from the extracellular domain alpha4 and beta2 subunits without M1, implying no detectable expression of extracellular domain nAChRs from these subunits. These results suggest that M1 domains on both alpha4 and beta2 play an important role for efficient expression of extracellular domain alpha4beta2 nAChRs that are high fidelity structural models of full-length alpha4beta2 nAChRs.

Animals↗
PubMed1996

Patient satisfaction report paves way to improved care.

In this article, the second in a two-part series, we show how a data-driven clinical model was implemented to improve care using patient satisfaction reports. Last month, we outlined the essential components of a data-driven clinical model and summarized two research paradigms that provide the theoretical foundation for such a model.

Data Collection↗
PubMed2006

An updated physiologically based pharmacokinetic model for hexachlorobenzene: incorporation of pathophysiological states following partial hepatectomy and hexachlorobenzene treatment.

Physiologically based pharmacokinetic (PBPK) modeling is generally used for describing xenobiotic disposition in animals and humans with normal physiological conditions. We describe here an updated PBPK model for hexachlorobenzene (HCB) in male F344 rats with the incorporation of pathophysiological conditions. Two more features contribute to the distinctness of this model from the earlier published versions. This model took erythrocyte binding into account, and a particular elimination process of HCB, the plasma-to-gastrointestinal (GI) lumen passive diffusion (i.e., exsorption), was incorporated. Our PBPK model was developed using data mined from multiple pharmacokinetic studies in the literature, and then modified to simulate HCB disposition under the conditions of our integrated pharmacokinetics/liver foci bioassay. This model included plasma, erythrocytes, liver, fat, rapidly and slowly perfused compartments, and GI lumen. To account for the distinct characteristics of HCB absorption, the GI lumen was split into an upper and a lower part. HCB was eliminated through liver metabolism and the exsorption process. The pathophysiological changes after partial hepatectomy, such as alterations in the liver and body weights and fat volume, were incorporated in our model. With adjustment of the transluminal diffusion-related parameters, the model adequately described the data from the literature and our bioassay. Our PBPK model simulation suggests that HCB absorption and exsorption processes depend on exposure conditions; different exposure conditions dictate different absorption and exsorption rates. This model forms a foundation for our further exploration of the quantitative relationship between HCB exposure and development of preneoplastic liver foci.

Animals↗
PubMed2006

Gene networks as a tool to understand transcriptional regulation.

Gene regulatory networks, or simply gene networks (GNs), have shown to be a promising approach that the bioinformatics community has been developing for studying regulatory mechanisms in biological systems. GNs are built from the genome-wide high-throughput gene expression data that are often available from DNA microarray experiments. Conceptually, GNs are (un)directed graphs, where the nodes correspond to the genes and a link between a pair of genes denotes a regulatory interaction that occurs at transcriptional level. In the present study, we had two objectives: 1) to develop a framework for GN reconstruction based on a Bayesian network model that captures direct interactions between genes through nonparametric regression with B-splines, and 2) to demonstrate the potential of GNs in the analysis of expression data of a real biological system, the yeast pheromone response pathway. Our framework also included a number of search schemes to learn the network. We present an intuitive notion of GN theory as well as the detailed mathematical foundations of the model. A comprehensive analysis of the consistency of the model when tested with biological data was done through the analysis of the GNs inferred for the yeast pheromone pathway. Our results agree fairly well with what was expected based on the literature, and we developed some hypotheses about this system. Using this analysis, we intended to provide a guide on how GNs can be effectively used to study transcriptional regulation. We also discussed the limitations of GNs and the future direction of network analysis for genomic data. The software is available upon request.

Bayes Theorem↗
PubMed2006

[Effect of immunostimulatory sequence on the expression of EOTAXIN of experimental allergic rhinitis].

OBJECTIVE: To investigate the effect of CpG DNA applied intraperitoneally on the expression of EOTAXIN of allergic rhinitis model. METHOD: CpG DNA was injected intraperitoneally to rat at the same time of the basic intraperitoneal immunized. The symptoms, expression of eosinophil (EOS) in nasal cavity and expression of EOTAXIN in the nasal mucosa were measured. RESULT: After the CpG DNA was applied, the symptom scores, eosinophil (EOS) in nasal cavity and expression of EOTAXIN were weaken. CONCLUSION: There was great reverse effect of CpG DNA on the foundation of rat model of experimental allergic rhinitis, suppression of EOTAXIN may be one of the mechanisms.

Animals↗
PubMed1999

A community-based case management model for hypertension and diabetes.

Health research conducted over the past 15 years in the Mississippi Delta has continually documented a population experiencing poor health status (high rates of chronic diseases and excessive related mortalities). Both individual and health system resources are scarce in this region, posing barriers to effective chronic disease management. Two of the most significant chronic diseases that burden this population are hypertension and diabetes. To address this issue, the Delta Community Partners In Care project centering on chronic disease control was developed by a consortium of local health care institutions and supported by a national foundation. The intervention model centers on the utilization of a community-based case management approach in 13 clinical sites. Both compliance to pharmacological and individualized nonpharmacological therapy and continuity of care are stressed. A number of outcome measures showed significant improvement over the 24 month project period (N = 756).

Case Management↗
PubMed2006

Estimating the parameters of a model for protein-protein interaction graphs.

We find accurate approximations for the expected number of three-cycles and unchorded four-cycles under a stochastic distribution for graphs that has been proposed for modelling yeast two-hybrid protein-protein interaction networks. We show that unchorded four-cycles are characteristic motifs under this model and that the count of unchorded four-cycles in the graph is a reliable statistic on which to base parameter estimation. Finally, we test our model against a range of experimental data, obtain parameter estimates from these data and investigate possible improvements in the model. Characterization of this model lays the foundation for its use as a prior distribution in a Bayesian analysis of yeast two-hybrid networks that can potentially aid in identifying false-positive and false-negative results.

Algorithms↗
PubMedDate not supplied

The effects of inflammatory bowel disease on adolescents.

Adolescence is a time of profound change for individuals. It is a period that witnesses biologic, social, and psychological change in the individual as well as role changes within the family and peer groups. Compounding these difficult transitions with the onset of inflammatory bowel disease leads to additional problems with adolescence adjustment. In the limited studies that have addressed the adolescent and inflammatory bowel disease, several key concepts emerge that point to ways for successfully dealing with these adolescent adjustment problems. Roy's Adaptation Model provides a foundation for identifying and selecting interventions in working with adolescents and chronic illness. A review of the literature finds the need for further study of the difficulties encountered by the changes of adolescence coupled with the onset of inflammatory bowel disease.

Adaptation, Psychological↗
PubMed2004

Reverse methanogenesis: testing the hypothesis with environmental genomics.

Microbial methane consumption in anoxic sediments significantly impacts the global environment by reducing the flux of greenhouse gases from ocean to atmosphere. Despite its significance, the biological mechanisms controlling anaerobic methane oxidation are not well characterized. One current model suggests that relatives of methane-producing Archaea developed the capacity to reverse methanogenesis and thereby to consume methane to produce cellular carbon and energy. We report here a test of the "reverse-methanogenesis" hypothesis by genomic analyses of methane-oxidizing Archaea from deep-sea sediments. Our results show that nearly all genes typically associated with methane production are present in one specific group of archaeal methanotrophs. These genome-based observations support previous hypotheses and provide an informed foundation for metabolic modeling of anaerobic methane oxidation.

Anaerobiosis↗
PubMed2005

Multi-agent model for Indian rural health care.

PURPOSE: The objective of this paper is to present a model that uses multi-agent system (MAS) technology to assist doctors based at rural areas to receive timely expert opinions from specialist doctors working in medical institutions like the Postgraduate Institute of Medical Research, Chandigarh or the All India Institute of Medical Sciences, New Delhi. DESIGN/METHODOLOGY/APPROACH: A MAS is a software entity wherein agent metaphor is used to represent human-like intelligence and behavior. These agents are distributed over geographical areas and are part of software running at these sites. The foundation for this model lies in the fact that medical intelligence is distributed in nature and, if it is possible to bring this knowledge together, it could prove to be advantageous in providing improved health care to those people in rural areas. A few existing research works are included to demonstrate the usage of MAS in health care. FINDINGS: It has been observed that the health scenario in India is ranked poor world-wide by international organizations and, with the increasing population, this will worsen. RESEARCH LIMITATIONS/IMPLICATIONS: Initially, the aim is to concentrate on a few medical departments only. It can be extended into more detailed framework. PRACTICAL IMPLICATIONS: Physical computing and networking infrastructure are required for practical implementation along with training for the doctors. ORIGINALITY/VALUE: The primary beneficiaries of this system are likely to be those patients in the rural sector requiring expert medical opinion. The government health organizations will be able to provide quality medical facilities comparable with the medical facilities available in the developed nations. Currently this would seem to be a distant dream.

Delivery of Health Care↗
PubMed2005

Osteoporosis: Health beliefs and barriers to treatment in an assisted living facility.

The purpose of this study was to describe residents' perceptions of osteoporosis and barriers to treatment in an assisted living setting. An exploratory, qualitative design was used. Five residents and the Director of Nursing participated in semi-structured interviews. Common health behaviors themes related to osteoporosis emerged that provide insight for nursing education and practice. The themes are discussed in light of the Health Belief Model, providing a framework for understanding osteoporosis-related health beliefs. This model lays a foundation upon which future interventions can be tested for effectiveness in improving osteoporosis-related care in assisted living.

Aged↗
PubMed2026

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Animals↗