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Results for “Pathway modelling”

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At least 181 records · Page 10Linked to original sources

PubMed2005

Slow folding of a three-helix protein via a compact intermediate.

The KIX domain of CREB binding protein (CBP) forms a small three-helix bundle which folds autonomously. Previous equilibrium unfolding experiments led to the suggestion that folding may not be strictly two-state. To investigate the folding mechanism in more detail, the folding kinetics of KIX have been studied by urea jump fluorescence-detected stopped-flow experiments. Clear evidence for an intermediate is obtained from the plot of the natural log of the observed rate constant versus denaturant concentration, the chevron plot, and from analysis of the initial fluorescence amplitudes of the stopped-flow experiments. The chevron plot exhibits a change in shape, rollover, at low denaturant concentrations, characteristic of the formation of an intermediate. The kinetic data can be fit to a three-state model involving a compact intermediate. An on-pathway model predicts that the position of the intermediate lies close to the native state. The folding rate in the absence of denaturant is 260 s(-)(1) at pH 7.5 and 25 degrees C. This is significantly slower than the rates of other helical proteins similar in size. The slow folding may be due to the necessity of forming a buried polar interaction in the native state. The potential functional significance of the folding intermediate is discussed.

CREB-Binding Protein↗

PubMed1998

Proposal of a multicompartmental model for use in the study of apolipoprotein E metabolism.

Apolipoprotein (apo) E is a 299-amino acid glycoprotein that serves a number of functions in lipoprotein metabolism. Apo E binds to the triglyceride-rich lipoproteins (TRL), very-low-density lipoprotein (VLDL), and chylomicrons, as they are lipolyzed, mediating their removal from plasma via lipoprotein receptors. Apo E is also found associated with high-density lipoprotein (HDL) and has been suggested to play a role in reverse cholesterol transport. Studies on the kinetic behavior of apo E from the TRL and HDL fractions provide insights into the metabolic relationships between TRL and HDL in vivo. We sought to develop a compartmental model that can be used for analysis of kinetic data in studies on the metabolism of TRL and HDL apo E. Using radioactive tracers, it has been previously observed that, in some instances, a portion of VLDL apo E that is removed from plasma subsequently reappears in VLDL. Four multicompartmental models were considered that could account for this type of behavior: model A, in which there is transfer of apo E from HDL to VLDL; model B, in which there is a bidirectional extravascular exchange; model C, in which there is removal and subsequent reintroduction of TRL apo E into plasma; and model D, in which there is secretion of TRL apo E into plasma directly and via an extravascular pathway. Models C and D provided the best fit to the experimental data. While no physiologically plausible analog to model C could be found, an extravascular delay, analogous to newly secreted apo E that enters the lymphatic system before appearing in plasma, was postulated for model D. It was this model that was used to analyze kinetic data from metabolic studies of apo E. The model was able to provide a satisfactory fit to kinetic data in studies in which subjects were given a primed-constant infusion of 2H3-leucine. It was determined that TRL apo E from the six subjects studied had a mean residence time of 0.11 +/- 0.05 days and a mean production rate of 10.6 +/- 7.2 mg/kg/d, while HDL apo E had a mean residence time of 2.96 +/- 0.99 days and a mean production rate of 0.07 +/- 0.07 mg/kg/d. We conclude that this model describes a potential pathway for the metabolism of a portion of apo E in plasma and can be used to calculate the residence time and production rate of TRL and HDL apo E under a variety of conditions.

Adult↗

PubMed1983

Computer simulation of metabolism in palmitate-perfused rat heart. II. Behavior of complete model.

Intermediary metabolism in rat hearts perfused with 11 mM glucose plus 1 mM palmitate was simulated by a computer model. Several enzyme submodels in a previous version of the isolated rat heart computer model were improved, and a new fatty acid oxidation pathway model was added. Compartmentation of metabolites in a pseudo-stationary state was calculated, and its implications are discussed, e.g., citrate level may not regulate glycolysis because it is mostly mitochondrial. Citrate synthetase, controlled largely by its inhibitors, is of key importance in regulating fatty acid metabolism. The response of aconitase to the mitochondrial Mg2+ level is of major importance in setting both the mitochondrial citrate and isocitrate levels. Pyruvate dehydrogenase is about 96% in the inactive phosphorylated form, and the active form is also 15% inhibited by products, severely limiting pyruvate oxidation and causing preferential utilization of palmitate as the metabolic fuel. The simulation is consistent with a creatine phosphate shuttle which delivers high energy phosphate to the site of its utilization for mechanical work.

Animals↗

PubMed2004

Cystinuria-specific rBAT(R365W) mutation reveals two translocation pathways in the amino acid transporter rBAT-b0,+AT.

Apical reabsorption of dibasic amino acids and cystine in kidney is mediated by the heteromeric amino acid antiporter rBAT/b(0,+)AT (system b(0,+)). Mutations in rBAT cause cystinuria type A, whereas mutations in b(0,+)AT cause cystinuria type B. b(0,+)AT is the catalytic subunit, whereas it is believed that rBAT helps the routing of the rBAT/b(0,+)AT heterodimeric complex to the plasma membrane. In the present study, we have functionally characterized the cystinuria-specific R365W (Arg(365)-->Trp) mutation of human rBAT, which in addition to a trafficking defect, alters functional properties of the b(0,+) transporter. In oocytes, where human rBAT interacts with the endogenous b(0,+)AT subunit to form an active transporter, the rBAT(R365W) mutation caused a defect of arginine efflux without altering arginine influx or apparent affinities for intracellular or extracellular arginine. Transport of lysine or leucine remained unaffected. In HeLa cells, functional expression of rBAT(R365W)/b(0,+)AT was observed only at the permissive temperature of 33 degrees C. Under these conditions, the mutated transporter showed 50% reduction of arginine influx and a similar decreased accumulation of dibasic amino acids. Efflux of arginine through the rBAT(R365W)/b(0,+)AT holotransporter was completely abolished. This supports a two-translocation-pathway model for antiporter b(0,+), in which the efflux pathway in the rBAT(R365W)/b(0,+)AT holotransporter is defective for arginine translocation or dissociation. This is the first direct evidence that mutations in rBAT may modify transport properties of system b(0,+).

Amino Acid Substitution↗

PubMed1986

Water and nonelectrolyte permeability of isolated rat hepatocytes.

We have measured the diffusive permeability coefficients of isolated rat hepatocytes to 3H2O, [14C]urea, [14C]erythritol, [14C]mannitol, [3H]sucrose, and [3H]inulin, employing a technique previously developed for erythrocytes (Redwood et al., J. Gen. Physiol 64:706-729, 1974). Diffusion coefficients for the tracer molecules were measured in packed hepatocytes, supernatant fluid, and intracellular medium (lysed hepatocytes) and were calculated assuming one-dimensional semi-infinite diffusion through a homogeneous medium. By applying the series-parallel pathway model, the following permeability coefficients (10(-5) cm/sec) for the hepatocyte plasma membrane were obtained. 3H2O, 98.6 +/- 18.4; [14C]urea, 18.2 +/- 5.3; [14C]erythritol, 4.8 +/- 1.6; [14C]mannitol, 3.1 +/- 1.4; [3H]sucrose, 0; [3H]inulin, 0. These results indicate that isolated rat hepatocytes are highly permeable to water and polar nonelectrolytes, when compared with other transporting epithelia. This relatively high cellular permeability is consistent with a model in which nonelectrolyte permeation is via an aqueous pathway of equivalent pore diameter of 8-12 A. The finding that [14C]erythritol and [14C]mannitol cross the hepatocyte plasma membrane indicates that these molecules enter the bile canaliculus through the transcellular route. Conversely, the failure of [3H]sucrose and [3H]inulin to permeate the hepatocyte in the isolated condition supports the concept that biliary entry of these large carbohydrates, at least that fraction which cannot be accounted for by a vesicular mechanism, must occur via the transjunctional shunt pathway.

Animals↗

PubMed2006

Adhesive dynamics simulation of neutrophil arrest with deterministic activation.

The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and beta2 -integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade. To study the possible mechanism by which neutrophil arrest could occur, we created an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the timescale of neutrophil activation, adhesion, and diapedesis.

Animals↗

PubMed2006

Assessing semantic similarity measures for the characterization of human regulatory pathways.

MOTIVATION: Pathway modeling requires the integration of multiple data including prior knowledge. In this study, we quantitatively assess the application of Gene Ontology (GO)-derived similarity measures for the characterization of direct and indirect interactions within human regulatory pathways. The characterization would help the integration of prior pathway knowledge for the modeling. RESULTS: Our analysis indicates information content-based measures outperform graph structure-based measures for stratifying protein interactions. Measures in terms of GO biological process and molecular function annotations can be used alone or together for the validation of protein interactions involved in the pathways. However, GO cellular component-derived measures may not have the ability to separate true positives from noise. Furthermore, we demonstrate that the functional similarity of proteins within known regulatory pathways decays rapidly as the path length between two proteins increases. Several logistic regression models are built to estimate the confidence of both direct and indirect interactions within a pathway, which may be used to score putative pathways inferred from a scaffold of molecular interactions.

Databases, Protein↗

PubMed2001

Irreversibility in unbranched pathways: preferred positions based on regulatory considerations.

It has been observed experimentally that most unbranched biosynthetic pathways have irreversible reactions near their beginning, many times at the first step. If there were no functional reasons for this fact, then one would expect irreversible reactions to be equally distributed among all positions in such pathways. Since this is not the case, we have attempted to identify functional consequences of having an irreversible reaction early in the pathway. We systematically varied the position of the irreversible reaction in model pathways and compared the resulting systemic behavior according to several criteria for functional effectiveness, using the method of mathematically controlled comparisons. This technique minimizes extraneous differences in systemic behavior and identifies those that are fundamental. Our results show that a pathway with an irreversible reaction located at the first step, and with all other reactions reversible, is on average better than an otherwise equivalent pathway with all reactions reversible, which in turn is on average better than an otherwise equivalent pathway with an irreversible reaction located at any step other than the first. Pathways with an irreversible first reaction and low concentrations of intermediates (one of the primary criteria for functional effectiveness) exhibit the following profile when compared to fully reversible pathways: changes in the concentration of intermediates in response to changes in the level of initial substrate are equally low, the robustness of the intermediate concentrations and of the flux is similar, the margins of stability are similar, flux is more responsive to changes in demand for end product, intermediate concentrations are less responsive to changes in demand for end product, and transient times are shorter. These results provide a functional rationale for the positioning of irreversible reactions at the beginning of unbranched biosynthetic pathways.

Homeostasis↗

PubMed2006

Transformation of vestibular signals into motor commands in the vestibuloocular reflex pathways of monkeys.

Parallel pathways mediate the rotatory vestibuloocular reflex (VOR). If the VOR undergoes adaptive modification with spectacles that change the magnification of the visual scene, signals in one neural pathway are modified, whereas those in another are not. By recording the responses of vestibular afferents and abducens neurons for vestibular oscillations at frequencies from 0.5 to 50 Hz, we have elucidated how vestibular signals are processed in the modified versus unmodified VOR pathways. For the small stimuli we used (+/- 15 degrees/s), the afferents with the most regular spontaneous discharge fired throughout the cycle of oscillation even at 50 Hz, whereas afferents with more irregular discharge showed phase locking. For all afferents, the firing rate was in phase with stimulus head velocity at low frequencies and showed progressive phase lead as frequency increased. Sensitivity to head velocity increased steadily as a function of frequency. Abducens neurons showed highly regular spontaneous discharge and very little evidence of phase locking. Their sensitivity to head velocity during the VOR was relatively flat across frequencies; firing rate lagged head velocity at low frequencies and shifted to large phase leads as stimulus frequency increased. When afferent responses were provided as inputs to a two-pathway model of the VOR, the output of the model reproduced the responses of abducens neurons if the unmodified and modified VOR pathways had frequency-dependent internal gains and included fixed time delays of 1.5 and 9 ms. The phase shifts predicted by the model provide fingerprints for identifying brain stem neurons that participate in the modified versus unmodified VOR pathways.

Acoustic Stimulation↗

PubMed2006

Conformationally averaged score functions for electronic propagation in proteins.

We explore the influence of conformational dynamics on protein-mediated electron donor-acceptor interactions. We introduce a thermally averaged score function to characterize electronic propagation from redox cofactors into the protein and solvent. The score function is explored for myoglobin at the extended-Hückel level, and the results are compared with those of simpler models. The conformationally averaged quantum results are consistent with the empirical analysis of the Pathways model. Notably, subtle effects of quantum interference among multiple coupling pathways that arise in static structures are largely averaged out when protein thermal motion is included. Propagation through bulk water near the single-protein interface decays rapidly with distance.

Algorithms↗

PubMed2002

Prediction of temporal gene expression. Metabolic opimization by re-distribution of enzyme activities.

A computational approach is used to analyse temporal gene expression in the context of metabolic regulation. It is based on the assumption that cells developed optimal adaptation strategies to changing environmental conditions. Time-dependent enzyme profiles are calculated which optimize the function of a metabolic pathway under the constraint of limited total enzyme amount. For linear model pathways it is shown that wave-like enzyme profiles are optimal for a rapid substrate turnover. For the central metabolism of yeast cells enzyme profiles are calculated which ensure long-term homeostasis of key metabolites under conditions of a diauxic shift. These enzyme profiles are in close correlation with observed gene expression data. Our results demonstrate that optimality principles help to rationalize observed gene expression profiles.

Databases as Topic↗

PubMed2006

Cortical inputs and GABA interneurons imbalance projection neurons in the striatum of parkinsonian rats.

The striatum receives massive cortical excitatory inputs and is densely innervated by dopamine. Striatal projection neurons form either the direct or indirect pathways. Models of Parkinson's disease propose that dopaminergic degeneration imbalances both pathways, although direct electrophysiological evidence is lacking. Here, striatal neurons were identified by electrophysiological criteria and Neurobiotin labeling combined with either immunohistochemistry or in situ hybridization. Their spontaneous discharge activity and spike response to cortical stimulation were recorded in vivo in anesthetized rats rendered hemi-parkinsonian by 6-hydroxydopamine. We showed that striatonigral neurons (direct pathway) were inhibited whereas striatopallidal neurons (indirect pathway) were activated by dopaminergic lesion. We also identified, with antidromic stimulations, corticostriatal neurons that preferentially innervate striatonigral or striatopallidal neurons and showed that dopaminergic depletion selectively decreased the spontaneous activity of the former. Therefore, dopamine degeneration induces a cascade of imbalances that spread out of the basal ganglia and affect the whole basal ganglia-thalamo-cortical circuits. Fast-spiking GABA interneurons provide potent feedforward inhibition of striatal projection neurons. We showed here that these interneurons narrowed the time window of the responses of projection neurons to cortical stimulation. In the dopamine-depleted striatum, because the intrinsic activity of these interneurons was not altered, their feedforward inhibition worsened the striatal imbalance. Indeed, the time window of the evoked responses was narrower for striatonigral neurons and wider for striatopallidal neurons. Therefore, after dopaminergic depletion, cortical inputs and GABA interneurons might imbalance striatal projection neurons and represent two novel nondopaminergic mechanisms that might secondarily contribute to the pathophysiology of Parkinson's disease.

Animals↗

PubMed2000

A model of pattern formation based on signaling pathways.

A model of pattern formation in the early embryo is presented. It is motivated by the necessary interaction of kinases and phosphatases, and in particular by the family of Wnt kinase and RPTP phosphatase signaling pathways. It is seen as complementary to the more short-range patterning of the Delta/Notch (or juxtacrine) signaling pathway.

Animals↗

PubMed2004

Consistent re-modeling of signaling pathways and its implementation in the TRANSPATH database.

The data model of the signaling pathways database TRANSPATH has been re-engineered to a three-layer model comprising experimental evidences and summarized pathway information, both in a mechanistically detailed manner, and a "semantic" projection for the abstract overview. Each molecule is described in the context of a certain reaction in the multidimensional space of posttranslational modification, molecular family relationships, and the biological species of its origin. The new model makes the data better suitable for reconstructing signaling pathways and networks and mapping expression data, for instance from microarray experiments, onto regulatory networks.

Algorithms↗

PubMed2006

Depicting combinatorial complexity with the molecular interaction map notation.

To help us understand how bioregulatory networks operate, we need a standard notation for diagrams analogous to electronic circuit diagrams. Such diagrams must surmount the difficulties posed by complex patterns of protein modifications and multiprotein complexes. To meet that challenge, we have designed the molecular interaction map (MIM) notation (http://discover.nci.nih.gov/mim/). Here we show the advantages of the MIM notation for three important types of diagrams: (1) explicit diagrams that define specific pathway models for computer simulation; (2) heuristic maps that organize the available information about molecular interactions and encompass the possible processes or pathways; and (3) diagrams of combinatorially complex models. We focus on signaling from the epidermal growth factor receptor family (EGFR, ErbB), a network that reflects the major challenges of representing in a compact manner the combinatorial complexity of multimolecular complexes. By comparing MIMs with other diagrams of this network that have recently been published, we show the utility of the MIM notation. These comparisons may help cell and systems biologists adopt a graphical language that is unambiguous and generally understood.

Combinatorial Chemistry Techniques↗

PubMed2005

The active role played by xenogeneic endothelial cells in the indirect presentation pathway is not lymphocyte trans-co-stimulation.

The human CD4+ T lymphocyte response to major histocompatibility complex (MHC) class II-negative porcine endothelial cells is dependent on the presence of human monocytes through a human leukocyte antigen (HLA) class II-restricted indirect presentation pathway. Because the role of porcine endothelial cells had been previously shown to do more than simply supply xenopeptides, co-stimulatory signals were analysed. Endothelial cells were shown to express the CD54, CD58, CD59 and CD86 transcripts; however, no membrane B7 molecule could be detected. Blocking experiments in a direct pathway model confirmed that porcine endothelial cells could provide co-stimulatory signals to human T cells through the CD2 and LFA-1 pathways. Nevertheless, the proliferation achieved in the indirect presentation model required co-stimulation by LFA-1, CD2 and CD28, engaged by co-stimulation molecules expressed in the cis-form by the human monocytes. These results clearly show that the active role played by the endothelial cells in the indirect pathway is not lymphocyte trans-co-stimulation and suggest that cis-co-stimulation dominates trans-co-stimulation when both are present.

Abatacept↗

PubMed2005

A new image representation algorithm inspired by image submodality models, redundancy reduction, and learning in biological vision.

We develop a new biologically motivated algorithm for representing natural images using successive projections into complementary subspaces. An image is first projected into an edge subspace spanned using an ICA basis adapted to natural images which captures the sharp features of an image like edges and curves. The residual image obtained after extraction of the sharp image features is approximated using a mixture of probabilistic principal component analyzers (MPPCA) model. The model is consistent with cellular, functional, information theoretic, and learning paradigms in visual pathway modeling. We demonstrate the efficiency of our model for representing different attributes of natural images like color and luminance. We compare the performance of our model in terms of quality of representation against commonly used basis, like the discrete cosine transform (DCT), independent component analysis (ICA), and principal components analysis (PCA), based on their entropies. Chrominance and luminance components of images are represented using codes having lower entropy than DCT, ICA, or PCA for similar visual quality. The model attains considerable simplification for learning from images by using a sparse independent code for representing edges and explicitly evaluating probabilities in the residual subspace.

Algorithms↗

PubMed2000

Levodopa-induced dyskinesias and dopamine-dependent stereotypies: a new hypothesis.

The basal ganglia are thought to modulate the release or inhibition of movements by way of direct and indirect pathways that act as a push-pull system of cortico-basal ganglia circuits. Here we suggest a three-pathway model of the basal ganglia that takes into consideration the fundamental division of the striatum into striosomes and extrastriosomal matrix. We suggest that, in addition to the balance between direct and indirect pathways on which normal release of individual movements depends, the balance of activity between these matrix-based pathways and the striosomal pathway regulates the frequency of release of given behavioral sequences and, thus, modulates behavioral focus. Differential plasticity in these compartmentally organized circuits might contribute to the development of L-dopa-induced dyskinesias under parkinsonian conditions and dopamine-receptor-agonist induced stereotypies under normal conditions.

Animals↗