SEARCH · PubMed Health

Results for “Pathway modelling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 523 records · Page 29Linked to original sources

PubMed2006

Receptor-mediated and intrinsic polarization and their interaction in chemotaxing cells.

Polarization--the clear and persistent localization of different signaling molecules to opposite ends of the cell-is critical for effective chemotaxis in eukaryotic systems. In many systems, polarization can also occur without an externally imposed chemical gradient. We build a modeling framework to study the relationship between the intrinsic capacity for polarization, and that induced by an external gradient. Working within this framework, we analyze different scenarios for the interaction of these pathways. The models are qualitatively simplified, motivated by known properties of the signaling pathways. We also examine the possible role of nonlinear transitions occurring in the polarization pathways. The modeling framework generates testable predictions regarding the relationship between intrinsic polarization and that induced during chemotaxis, and is the first step toward a systematic analysis of the interaction between these pathways.

Cell Membrane↗

PubMed2003

The tibial-1 pioneer pathway: an in vivo model for neuronal outgrowth and guidance.

As neurons extend axons to their targets during development, growth cones must reorient their direction of migration in response to extracellular guidance cues. A variety of model systems have been employed in order to dissect the cellular and molecular mechanisms that underlie this complex process. One preparation, the developing grasshopper limb bud, has proved to offer a number of advantages in which to examine mechanisms of growth cone guidance and motility in vivo. First, the relatively large size of the embryonic nervous system allows for straightforward imaging of both fixed and live neurons in vivo. Second, the peripheral nerves generated in the limb bud are highly stereotyped. Third, intact embryos can be cultured for a period of days, allowing for fairly easy perturbations at precise developmental stages. Fourth, due to the ease of dissection, numerous cell biological and molecular techniques can be utilized in the limb bud. Finally, axon guidance molecules and mechanisms are conserved between grasshoppers and other organism, including vertebrates.

Animals↗

PubMed2006

The importance of different timings of excitatory and inhibitory pathways in neural field models.

In this paper, we consider a neural field model comprised of two distinct populations of neurons, excitatory and inhibitory, for which both the velocities of action potential propagation and the time courses of synaptic processing are different. Using recently-developed techniques, we construct the Evans function characterising the stability of both stationary and travelling wave solutions, under the assumption that the firing rate function is the Heaviside step. We find that these differences in timing for the two populations can cause instabilities of these solutions, leading to, for example, stationary breathers. We also analyse "anti-pulses", a novel type of pattern for which all but a small interval of the domain (in moving coordinates) is active. These results extend previous work on neural fields with space-dependent delays, and demonstrate the importance of considering the effects of the different time-courses of excitatory and inhibitory neural activity.

Animals↗

PubMed2005

A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R: implication of this signaling pathway in pancreatic tumor models.

To date very few G protein-coupled receptors (GPCRs) have been shown to be connected to the Janus kinase (JAK)/STAT pathway. Thus our understanding of the mechanisms involved in the activation of this signaling pathway by GPCRs remains limited. In addition, little is known about the role of the JAK pathway in the physiological or pathophysiological functions of GPCRs. Here, we described a new mechanism of JAK activation that involves Galpha(q) proteins. Indeed, transfection of a constitutively activated mutant of Galpha(q) (Q209L) in COS-7 cells demonstrated that Galpha(q) is able to associate and activate JAK2. In addition, we showed that this mechanism is used to activate JAK2 by a GPCR principally coupled to G(q), the CCK2 receptor (CCK2R), and involves a highly conserved sequence in GPCRs, the NPXXY motif. In a pancreatic tumor cell line expressing the endogenous CCK2R, we demonstrated the activation of the JAK2/STAT3 pathway by this receptor and the involvement of this signaling pathway in the proliferative effects of the CCK2R. In addition, we showed in vivo that the targeted CCK2R expression in pancreas of Elas-CCK2 mice leads to the activation of JAK2 and STAT3. This process may contribute to the increase of pancreas growth as well as the formation of preneoplastic lesions leading to pancreatic tumor development observed in these transgenic animals.

Amino Acid Motifs↗

PubMed2001

Effect of pH on skin permeation enhancement of acidic drugs by l-menthol-ethanol system.

The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.

Animals↗

PubMedDate not supplied

A neural model of predictive recognition in form pathway of visual cortex.

We present a functional model of form pathway in visual cortex based on predictive coding scheme, in which the prediction is compared with feedforward signals filtered by two kinds of spatial resolution maps, broad and fine resolution map. We propose here the functional role of the prediction and of the two kinds of resolution maps in perception of object form in visual system. The prediction is represented based on memory of dynamical attractors in temporal cortex, categorized by an elemental figure in posterior temporal cortex. The prediction is generated by the feedforward signals of main neurons in broad resolution maps of V(1) and V(4), and then is compared with the feedforward signals of main neurons in fine resolution map of V(1) and V(4).

Animals↗

PubMedDate not supplied

Quantitative prediction of biodegradability, metabolite distribution and toxicity of stable metabolites.

An evaluation of the capability of organic chemicals to mineralize is an important factor to consider when assessing their fate in the environment. Microbial degradation can convert a toxic chemical into an innocuous one, and vice versa, or alter the toxicity of a chemical. Moreover, primary biodegradation can convert chemicals into stable products that can be difficult to mineralize. In this paper, we present some new results obtained on the basis of a recently developed probabilistic approach to modeling biodegradation based on microbial transformation pathways. The metabolic transformations and their hierarchy were calibrated by making use of the ready biodegradability data from the MITI-I test and expert knowledge for the most probable transformation pathways. A model was developed and integrated into an expert software system named CATABOL that is able to predict the probability of biodegradation of organic chemicals directly from their structure. CATABOL simulates the effects of microbial enzyme systems, generates the most plausible transformation pathways, and quantitatively predicts the persistence and toxicity of the biodegradation products. A subset of 300 organic chemicals were selected from Canada's Domestic Substances List and subjected to CATABOL to compare predicted properties of the parent chemicals with their respective first stable metabolite. The results show that most of the stable metabolites have a lower acute toxicity to fish and a lower bioaccumulation potential compared to the parent chemicals. In contrast, the metabolites appear to be generally more estrogenic than the parent chemicals.

Animals↗

PubMed1999

Phospho-LAT-independent activation of the ras-mitogen-activated protein kinase pathway: a differential recruitment model of TCR partial agonist signaling.

Stimulation of mature T cells with agonist ligands of the Ag receptor (TCR) causes rapid phosphorylation of tyrosine-based activation motifs in the intracellular portion of TCR-zeta and CD3 and activation of several intracellular signaling cascades. Coordinate activation of these pathways is dependent on Lck- and ZAP-70-mediated tyrosine phosphorylation of a 36-kDa linker for activation of T cells and subsequent recruitment of phospholipase C-gamma1, Grb2-SOS, and SLP-76-vav. Here, we show that TCR partial agonist ligands can selectively activate one of these pathways, the Ras-mitogen-activated protein kinase pathway, by inducing recruitment of Grb2-SOS complexes to incompletely phosphorylated p21 phospho-TCR-zeta. This bypasses the need for activation of Lck and ZAP-70, and for phosphorylation of the linker for activation of T cells to activate Ras. We propose a general model in which differential recruitment of activating complexes away from transmembrane linker proteins may determine selective activation of a given signaling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Serengeti wildebeest migratory patterns modeled from rainfall and new vegetation growth.

We used evolutionary programming to model innate migratory pathways of wildebeest in the Serengeti Mara Ecosystem, Tanzania and Kenya. Wildebeest annually move from the southern short-grass plains of the Serengeti to the northern woodlands of the Mara. We used satellite images to create 12 average monthly and 180 10-day surfaces from 1998 to 2003 of percentage rainfall and new vegetation. The surfaces were combined in five additive and three multiplicative models, with the weightings on rainfall and new vegetation from 0% to 100%. Modeled wildebeest were first assigned random migration pathways. In simulated generations, animals best able to access rainfall and vegetation were retained, and they produced offspring with similar migratory pathways. Modeling proceeded until the best pathway was stable. In a learning phase, modeling continued with the ten-day images in the objective function. The additive model, influenced 25% by rainfall and 75% by vegetation growth, yielded the best agreement, with a multi-resolution comparison to observed densities yielding 76.8% of blocks in agreement (kappa = 0.32). Agreement was best for dry season and early wet season (kappa = 0.22-0.57), and poorest for the late wet season (0.04). The model suggests that new forage growth is a dominant correlate of wildebeest migration.

Animal Migration↗

PubMed2006

Insights into muscle atrophy and recovery pathway based on genetic models.

PURPOSE OF REVIEW: Muscle atrophy is a pervasive problem that occurs with disuse, aging, and a myriad of disease conditions. The purposes of this review are to describe recent advances in studying muscle atrophy that have elucidated pathways involved at the molecular level; to compare different types of atrophy--primary (e.g. bed rest, immobilization) and secondary (when the atrophy is related to pathology as well as disuse, e.g. injury, sepsis etc.) and their multiple common features; to review progress in studying the recovery process and clinical status. RECENT FINDINGS: Major advances have been made at the molecular level. There are two phenotypes for muscle atrophy--primary, which is mainly related to disuse (e.g. bed), and secondary, when the atrophy is related to pathology as well as disuse. It appears that the two forms have multiple elements in common. Studies on the recovery process reveal a very complex sequence of events that are not the simple reverse of the muscle loss process. In contrast to the progress at the molecular level, progress in treating muscle atrophy or accelerating recovery has been disappointing. SUMMARY: Although nutritional supplementation and pharmacological agents continue to have the potential to minimize muscle atrophy, given its minimal risks, exercise sets a very high standard for treatment options when medically appropriate. Identification of pathways and control points offers the potential for new approaches.

Bed Rest↗

PubMed2005

Electroacupuncture regulates NMDA receptor NR1 subunit expression via PI3-K pathway in a rat model of cerebral ischemia-reperfusion.

Cell survival is regulated by the balance between death and survival signals. Previous studies have shown that the N-methyl-d-aspartate receptors (NMDARs) are responsible for the glutamate-induced excitotoxicity in the postischemic brain. Meanwhile, nerve growth factor (NGF) is critically involved in cell survival and neuroprotective effects via the extracellular signal-related kinase (ERK) pathway or the phosphatidylinositol 3-kinase (PI3-K) pathway mediated by the high affinity NGF receptor, tropomyosin-related kinase A (TrkA). Clinically, electroacupuncture (EA) has been shown to produce beneficial effects on stroke patients. However, the detailed mechanisms mediating the beneficial effects of EA on stroke are still unknown. In the present study, we found that EA treatment reversed the high expression of NR1 subunit and up-regulated the level of TrkA in a rat model of middle cerebral artery occlusion. Using protein kinase inhibitors of specific intracellular signaling pathways, we found that the neuroprotective effects of EA appear to be mediated by stimulation of the PI3-K pathway, but not ERK pathway. These findings may provide important experimental evidence for the clinical application of EA treatment for stroke patients.

Animals↗

PubMed2002

Age- and size-related trends in woody plant shoot development: regulatory pathways and evidence for genetic control.

Woody plants exhibit significant and predictable patterns of change in morphology and physiology as they become older and larger. Four models of potential pathways controlling these changes are presented: a stimulus-response model in which fully developed organs respond to changes in environment (defined here as everything external to the organ); an extrinsic model in which the attributes of developing organs are determined by environmental factors; an intrinsic model in which changes are a result of programmed changes in gene expression; and an extrinsic-intrinsic model in which changes in gene expression are induced by environmental factors. We review evidence that a genetic component is involved in controlling age- and size-related changes in foliar morphology and physiology and discuss the possibility of complex interactions among model pathways.

Models, Biological↗

PubMed2005

Plant metabolic diversity: a regulatory perspective.

Plants accumulate an amazing diversity of phytochemicals that play important roles in the interaction of plants with the environment. Mechanisms have been proposed to describe the evolution of phytochemicals from the perspective of the biosynthetic enzymes. However, it is not known how the transcription factors that regulate these pathways have evolved to ensure the coordinate expression of all the genes in a pathway. A model is provided here to explain how duplication and divergence of regulatory genes result in the control of new pathways. In this model, the purported ability of recently duplicated regulatory genes to activate new metabolic pathways is a consequence of mutations that partially impair function, resulting in the loss of activation of one or several steps in a metabolic pathway. Consequently, pathway intermediates accumulate and are then converted into new compounds by broad-specificity enzymes. In contrast to the resilience of developmental regulatory circuits, this model provides an explanation for the rapid evolution of new metabolic pathways from existing ones.

Enzymes↗

PubMed1992

Anticonvulsant role of nigrotectal projection in the maximal electroshock model of epilepsy--II. Pathways from substantia nigra pars lateralis and adjacent peripeduncular area to the dorsal midbrain.

Lesion evidence suggests that the superior colliculus is essential for mediating the anticonvulsant properties of nigral suppression in the electroshock model of epilepsy. However, our companion paper [Redgrave et al. (1991) Neuroscience 46, 379-390] established that the region of dorsal midbrain where bicuculline was most effective in suppressing tonic hindlimb extension did not correspond well with the known distribution of nigrotectal terminals. The purpose of the present anatomical study was, therefore, to investigate in more detail ventral midbrain connections to the dorsal midbrain anticonvulsant zone in rat. Small injections (10-20 nl) of a 1% solution of wheatgerm agglutinin conjugated with horseradish peroxidase were made specifically into the region of dorsal midbrain where bicuculline was maximally effective. Numerous retrogradely labelled cells were found in substantia nigra pars lateralis and adjacent peripeduncular area but not in substantia nigra pars reticulata. Retrogradely labelled cells were also located in ventral zona incerta. When wheatgerm agglutinin-horseradish peroxidase injections were made into lateral substantia nigra, a region of anterogradely transported reaction product characteristic of nerve terminals was observed in the caudolateral deep layers and underlying reticular tissue; this area corresponded well to the dorsal midbrain anticonvulsant zone. These data suggest that, in the electroshock model of epilepsy, direct connections between substantia nigra pars lateralis and adjacent peripeduncular area and the dorsal midbrain anticonvulsant zone could be critical for mediating the anticonvulsant properties previously attributed to substantia nigra pars reticulata. During the course of this study, anterograde projections from substantia nigra pars lateralis and adjacent peripeduncular area to both superficial and intermediate layers of the ipsilateral superior colliculus were noted. Additional experiments using retrograde transport of the fluorescent tracer Fast Blue confirmed these projections.

Amidines↗

PubMed2005

On the use of qualitative reasoning to simulate and identify metabolic pathways.

MOTIVATION: Perhaps the greatest challenge of modern biology is to develop accurate in silico models of cells. To do this we require computational formalisms for both simulation (how according to the model the state of the cell evolves over time) and identification (learning a model cell from observation of states). We propose the use of qualitative reasoning (QR) as a unified formalism for both tasks. The two most commonly used alternative methods of modelling biochemical pathways are ordinary differential equations (ODEs), and logical/graph-based (LG) models. RESULTS: The QR formalism we use is an abstraction of ODEs. It enables the behaviour of many ODEs, with different functional forms and parameters, to be captured in a single QR model. QR has the advantage over LG models of explicitly including dynamics. To simulate biochemical pathways we have developed 'enzyme' and 'metabolite' QR building blocks that fit together to form models. These models are finite, directly executable, easy to interpret and robust. To identify QR models we have developed heuristic chemoinformatics graph analysis and machine learning procedures. The graph analysis procedure is a series of constraints and heuristics that limit the number of ways metabolites can combine to form pathways. The machine learning procedure is generate-and-test inductive logic programming. We illustrate the use of QR for modelling and simulation using the example of glycolysis. AVAILABILITY: All data and programs used are available on request.

Algorithms↗

PubMed2002

A model of the cerebellar pathways applied to the control of a single-joint robot arm actuated by McKibben artificial muscles.

This article describes an expanded version of a previously proposed motor control scheme, based on rules for combining sensory and motor signals within the central nervous system. Classical control elements of the previous cybernetic circuit were replaced by artificial neural network modules having an architecture based on the connectivity of the cerebellar cortex, and whose functioning is regulated by reinforcement learning. The resulting model was then applied to the motion control of a mechanical, single-joint robot arm actuated by two McKibben artificial muscles. Various biologically plausible learning schemes were studied using both simulations and experiments. After learning, the model was able to accurately pilot the movements of the robot arm, both in velocity and position.

Arm↗

PubMed1975

Verbal communications of community pharmacists.

Community pharmacists, by virtue of their location, are thought to be among the most accessible health care workers in the delivery system. To estimate the importance of this assertion it is necessary to understand the communication habits of pharmacists, especially their interactions with patients. Since verbal communication is the most frequent form of patient interaction, this study attempts to specify the type and amount of all pharmacist communication with emphasis on the pharmacist-patient process. Using a modified work sampling technique, communication data were collected on community pharmacists practicing in chain pharmacies. Data are presented in the context of a causal model. The strongest pathway in the model is found to be the inverse relationship of prescription department staffing to the percentage of time pharmacists devote to communication with patients. Prescription volume is seen to have a moderately positive effect on the level of communication. However, further analysis reveals staffing to be the limiting factor. The findings suggest that changes in the environment of the community pharmacists studied would do much to increase pharmacist-patient contact. An educational effort also is indicated to assure that patients receive quality communication.

Administrative Personnel↗

PubMed1996

Development of physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-344 rats.

Methyl tertiary-butyl ether (MTBE) and its metabolite tertiary-butanol (TBA) both cause renal tumors in chronically exposed male rats. Knowledge of the kinetic behavior of MTBE and TBA in rats and its comparison to the kinetics of these chemicals in humans will aid in assessing human risk. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for MTBE and TBA in rats that will form the basis for a human model. Physiological parameters such as blood flows, tissue volumes, and alveolar ventilation were obtained from the literature. Chemical-specific parameters such as the solubility of MTBE and TBA in blood and selected tissues and metabolic rate constants to describe whole-body metabolism of MTBE in rats were measured using vial equilibration and gas uptake techniques, respectively. MTBE metabolism was described in the model as occurring through two saturable pathways. The model was able to predict gas uptake data (100 to 2000 ppm starting concentrations) and levels of MTBE in blood of rats exposed to MTBE by inhalation (400 to 8000 ppm, 6 hr), i.v. (40 mg/kg), and oral (40 or 400 mg/kg) administration. Two different models to describe the dosimetry of TBA in a rat were tested for their ability to predict TBA blood levels after MTBE exposure. TBA blood levels were predicted best at low MTBE exposure concentrations using a two-compartment model. The pharmacokinetics of TBA appear to be far more complex than those of MTBE, and additional experimental data on TBA distribution and elimination will be necessary to refine the submodel. With a quantitative description of the important determinants of MTBE and TBA dosimetry understood, a better assessment of the potential toxic and cancer risk for humans exposed to MTBE can be made.

Administration, Inhalation↗