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PubMed2003

Metabolic engineering: advances in modeling and intervention in health and disease.

The field of metabolic engineering encompasses a powerful set of tools that can be divided into (a) methods to model complex metabolic pathways and (b) techniques to manipulate these pathways for a desired metabolic outcome. These tools have recently seen increased utility in the medical arena, and this paper aims to review significant accomplishments made using these approaches. The modeling of metabolic pathways has been applied to better understand disease-state physiology in a variety of cellar, subcellular, and organ systems, including the liver, heart, mitochondria, and cancerous cells. Metabolic pathway engineering has been used to generate cells with novel biochemical functions for therapeutic use, and specific examples are provided in the areas of glycosylation engineering and dopamine-replacement therapy. In order to document the potential of applying both metabolic modeling and pathway manipulation, we describe pertinent advances in the field of diabetes research. Undoubtedly, as the field of metabolic engineering matures and is applied to a wider array of problems, new advances and therapeutic strategies will follow.

Computer Simulation↗

PubMed2002

Modeling the three-dimensional structure of H+-ATPase of Neurospora crassa.

Homology modeling in combination with transmembrane topology predictions are used to build the atomic model of Neurospora crassa plasma membrane H+-ATPase, using as template the 2.6 A crystal structure of rabbit sarcoplasmic reticulum Ca2+-ATPase [Toyoshima, C., Nakasako, M., Nomura, H. & Ogawa, H. (2000) Nature 405, 647-655]. Comparison of the two calcium-binding sites in the crystal structure of Ca2+-ATPase with the equivalent region in the H+-ATPase model shows that the latter is devoid of most of the negatively charged groups required to bind the cations, suggesting a different role for this region. Using the built model, a pathway for proton transport is then proposed from computed locations of internal polar cavities, large enough to contain at least one water molecule. As a control, the same approach is applied to the high-resolution crystal structure of halorhodopsin and the proton pump bacteriorhodopsin. This revealed a striking correspondence between the positions of internal polar cavities, those of crystallographic water molecules and, in the case of bacteriorhodopsin, the residues mediating proton translocation. In our H+-ATPase model, most of these cavities are in contact with residues previously shown to affect coupling of proton translocation to ATP hydrolysis. A string of six polar cavities identified in the cytoplasmic domain, the most accurate part of the model, suggests a proton entry path starting close to the phosphorylation site. Strikingly, members of the haloacid dehalogenase superfamily, which are close structural homologs of this domain but do not share the same function, display only one polar cavity in the vicinity of the conserved catalytic Asp residue.

Amino Acid Sequence↗

PubMed1997

Health services research on mental health in primary care.

OBJECTIVE: The article seeks to provide an international perspective on the facilitating role of health services research in the treatment of psychiatric disorders in primary care. It builds on Goldberg and Huxley's model describing pathways to mental care for the psychiatrically ill in the community. METHOD: Seventy studies were selected for review by Medline search, sixteen studies by contacting prominent researchers in the field. All studies are discussed more or less extensively. RESULTS: Case identification strategies including screening tools and diagnostic modules have been developed. Other strategies include educational training programs and psychiatric consultation services designed to facilitate psychopharmacological and other types of treatment of psychiatric disorders in primary care. Several models for the linkage of primary care and specialty mental health providers are discussed, and a primary care psychiatry programme is examined. CONCLUSION: Better psychiatric training of general practitioners (GPs), on-site consultation, and better communication between mental health professionals and GPs can improve the recognition, management, and referral of psychiatrically ill primary care patients. The further development of guidelines focusing on anxiety disorders, somatization, subthreshold disorders, and effectiveness in primary care is recommended.

Forecasting↗

PubMed2002

ERK regulation in chronic ethanol exposure and withdrawal.

The extracellular signal regulated protein kinases (ERKs), also known as mitogen-activated protein kinases (MAPK) of 42 and 44 kd, play a crucial role in the induction of various forms of neural plasticity. Ethanol induces long-lasting functional changes that are more severe following repeated exposure and may involve intracellular signal transduction mechanisms. Therefore, we investigated the regulation of the ERK signal transduction pathway in models of continuous and intermittent ethanol exposure and withdrawal. Moderate blood alcohol levels (BALs) reduced ERK activation in most of the brain regions studied. Conversely, during withdrawal, activation of ERK was increased in most areas with some regional variations in the levels and kinetics of induction. The most dramatic effects were observed in the amygdala, the cerebellum, the striatum and the hippocampus. In the amygdala and the cerebellum, the activation of ERK observed during withdrawal was significantly higher after intermittent ethanol exposure than after continuous exposure, suggesting the establishment of a form of sensitization to the effects of withdrawal on ERK regulation. Thus the dysregulation of the ERK pathway could contribute to escalation of withdrawal symptoms induced by repeated withdrawal and possibly to the neuroadaptative changes believed to underlie progression towards addiction.

Alcohol Withdrawal Seizures↗

PubMed1988

Computer algorithm for modeling transmission over one or two conduction pathways through AV node.

The goal of this study was to develop and test models of conduction through the atrioventricular node, particularly to encompass possible transmission over multiple pathways. Output from the atrioventricular node was related to its input, the variable coupling interval of a single extrastimulus introduced to scan diastole during programmed atrial stimulation. Trials were performed three times in 15 patients after pacing for eight beats at 100 beats/min. Hyperbolic and exponential functions were used to model trial data. For conduction over a single pathway, the standard error of the estimate was less with the exponential than with the hyperbolic model. The preferred exponential model had the general form A2H2 = K1 + K2 exp(-A1A2/K3), with K1, K2, K3 being the parameters fitted. The algorithm describing transmission over two pathways minimized sums of squares of deviations from two such exponential functions, with potential "bifurcation" points between the functions being those farthest from the computed single curve of best fit. The model predicted (R2 greater than 0.90) that 43% of the trials showed single conduction pathways and the remaining 57% showed dual pathways. A cardiologist who independently examined the data discarded eight trials because of insufficient data or scatter and agreed with presence of two pathways and the point of discontinuity in plots in 81% of trials. The reasons for discordance were minor and thus the model was reasonably verified.

Adolescent↗

PubMed1999

A cerebellar model of timing and prediction in the control of reaching.

A simplified model of the cerebellum was developed to explore its potential for adaptive, predictive control based on delayed feedback information. An abstract representation of a single Purkinje cell with multistable properties was interfaced, using a formalized premotor network, with a simulated single degree-of-freedom limb. The limb actuator was a nonlinear spring-mass system based on the nonlinear velocity dependence of the stretch reflex. By including realistic mossy fiber signals, as well as realistic conduction delays in afferent and efferent pathways, the model allowed the investigation of timing and predictive processes relevant to cerebellar involvement in the control of movement. The model regulates movement by learning to react in an anticipatory fashion to sensory feedback. Learning depends on training information generated from corrective movements and uses a temporally asymmetric form of plasticity for the parallel fiber synapses on Purkinje cells.

Adaptation, Physiological↗

PubMed2006

An automated procedure for the extraction of metabolic network information from time series data.

Novel high-throughput measurement techniques in vivo are beginning to produce dense high-quality time series which can be used to investigate the structure and regulation of biochemical networks. We propose an automated information extraction procedure which takes advantage of the unique S-system structure and supports model building from time traces, curve fitting, model selection, and structure identification based on parameter estimation. The procedure comprises of three modules: model Generation, parameter estimation or model Fitting, and model Selection (GFS algorithm). The GFS algorithm has been implemented in MATLAB and returns a list of candidate S-systems which adequately explain the data and guides the search to the most plausible model for the time series under study. By combining two strategies (namely decoupling and limiting connectivity) with methods of data smoothing, the proposed algorithm is scalable up to realistic situations of moderate size. We illustrate the proposed methodology with a didactic example.

Algorithms↗

PubMed1997

Empirical parameterization of a model for predicting peptide helix/coil equilibrium populations.

A modification of the Lifson-Roig formulation of helix/coil transitions is presented; it (1) incorporates end-capping and coulombic (salt bridges, hydrogen bonding, and side-chain interactions with charged termini and the helix dipole) effects, (2) helix-stabilizing hydrophobic clustering, (3) allows for different inherent termination probabilities of individual residues, and (4) differentiates helix elongation in the first versus subsequent turns of a helix. Each residue is characterized by six parameters governing helix formation. The formulation of the conditional probability of helix initiation and termination that we developed is essentially the same as one presented previously (Shalongo W, Stellwagen, E. 1995. Protein Sci 4:1161-1166) and nearly the mathematical equivalent of the new capping formulation incorporated in the model presented by Rohl et al. (1996. Protein Sci 5:2623-2637). Side-chain/side-chain interactions are, in most cases, incorporated as context dependent modifications of propagation rather than nucleation parameters. An alternative procedure for converting [theta]221 values to experimental fractional helicities ( ) is presented. Tests of the program predictions suggest this method may have some advantages both for designed peptides and for the analysis of secondary structure preferences that could drive the formation of molten-globule intermediates on protein folding pathways. The model predicts the fractional helicity of 385 peptides with a root-mean-square deviation (RMSD) of 0.050 and locates (with precise definition of the termini in many cases) helices in proteins as well as competing methods. The propagation and nucleation parameters were derived from NMR data and from the CD data for a 79 peptide "learning set" for which an excellent fit resulted (RMSD = 0.0295). The current set of parameter corrections for capping boxes, helix dipole interactions, and side-chain/side-chain interactions (coulombic, hydrogen bonding and hydrophobic clustering), although still under development provide a significant improvement in both helix/coil equilibrium prediction for peptides and helix location in protein sequences. This is clearly evident in the rms deviations between CD measures and calculated values of fractional helicity for different classes of peptides before and after applying the corrections: for peptides lacking capping boxes and i/i + 3 and i/i + 4 side-chain/side-chain interactions RMSD = 0.044 (n = 164) versus RMSD = 0.054 (0.172 without the corrections, n = 221) for peptides that required context-dependent corrections of the parameters. If we restrict the analysis to N-acylated peptides with helix stabilizing side-chain/side-chain interactions (including N-capping boxes), the degree to which our corrections account for the stabilizing interaction can be judged from the change in helicity underestimation, ( calc- CD): -0.15 +/- 0.10, which is reduced to -0.018 +/- 0.048 (n = 191) upon applying the corrections.

Algorithms↗

PubMed1996

Traumatic memory characteristics: a cross-validated mediational model of response to rape among employed women.

In a cross-validated mediational model, the authors examined characteristics of memories formed in response to rape and other intense unpleasant and pleasant experiences. Data were responses to a mailed survey of women medical center and university employees. Measurement models of memory and symptom factors and a structural model with pathways among cognitive appraisal, emotional valence, memory characteristics, and health outcomes were developed in Sample 1 (N = 1,307) and confirmed in Sample 2 (N = 2,142). Rape had substantial direct effects on 2 memory factors (Clarity and Affect) and indirect effects through the construal of victimization. Rape was associated with memories described as more emotionally intense but less clear and coherent and less often thought of or talked about. Most effects on physical symptoms were nonsignificant. Implications of findings for neurohormonal and multiple representation models of emotional memory and to cognitive avoidance are discussed.

Adolescent↗

PubMed2003

The mitochondrial citrate transport protein: probing the secondary structure of transmembrane domain III, identification of residues that likely comprise a portion of the citrate transport pathway, and development of a model for the putative TMDIII-TMDIII' interface.

The mitochondrial citrate transport protein (CTP) has been investigated by mutating 28 consecutive residues within transmembrane domain III (TMDIII), one at a time, to cysteine. A cysteine-less CTP that retains wild-type functional properties, served as the starting template. The single Cys CTP mutants were abundantly expressed in Escherichia coli, isolated, and functionally reconstituted in a liposomal system. The accessibility of each single Cys mutant to two methanethiosulfonate reagents was evaluated by determining the rate constants for inhibition of CTP function. These rate constants varied by over five orders of magnitude. With two independent data sets we observed peaks and troughs in the rate constant data at identical amino acid positions and a periodicity of 4 was observed from residues 123-137. Based on the pattern of accessibility we conclude that residues 123-137 exist as an alpha-helix. Although less certain, a combination of the rate constant data and the specific activity data with the single Cys mutants suggests that the alpha-helical secondary structure may extend to residue 113. Furthermore, the rate constant data define water-accessible and water-inaccessible faces of the helix. We infer that the water-accessible face comprises a portion of the substrate translocation pathway through the CTP, whereas the water-inaccessible surface faces the lipid bilayer. Finally, based on a combination of the CTP inhibition rate constant data and the existence of significant sequence identity with a transmembrane segment within glycophorin A that forms a portion of its dimer interface, a model for a putative CTP TMDIII-TMDIII' dimer interface has been developed.

Amino Acid Sequence↗

PubMed2006

Use of the flux model of amino acid metabolism of Escherichia coli.

A program implementing a flux model of Escherichia coli metabolism was used to analyze the effects of the addition of amino acids (tryptophan, tyrosine, phenylalanine, leucine, isoleucine, valine, histidine, lysine, threonine, cysteine, methionine, arginine, proline) to minimal medium or media lacking nitrogen, carbon, or both. The overall response of the metabolic system to the addition of various amino acids to the minimal medium is similar. Glycolysis and the synthesis of pyruvate with its subsequent degradation to acetate via acetyl-CoA become more efficient, whereas the fluxes through the pentose phosphate pathway and the TCA cycle decrease. If amino acids are used as the sole source of carbon, nitrogen, or both, the changes in the flux distribution are determined mainly by the carbon limitation. The phosphoenolpyruvate to glucose-6-phosphate flux increases; the flux through the pentose phosphate path is directed towards ribulose-5-phosphate. Other changes are determined by the compounds that are the primary products of catabolism of the added amino acid.

Amino Acids↗

PubMed2002

Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.

Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf(Delta)(ARE) mouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon gamma and requires the function of CD8(+) T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell-derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor-deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow-derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase-deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

Animals↗

PubMedDate not supplied

A model for optokinetic eye movements in turtles that incorporates properties of retinal-slip neurons.

The turtle's optokinetic response is described by a simple model that incorporates visual-response properties of neurons in the pretectum and accessory optic system. Using data from neuronal and eye-movement recordings that have been previously published, the model was realized using algebraic-block simulation software. It was found that the optokinetic response, modelled as a simple negative feedback system, was similar to that measured from a behaving animal. Because the responses of retinal-slip detecting neurons corresponded to the nonlinear, closed-loop optokinetic response, it was concluded that the visual signals encoded in these neurons could provide sufficient sensory information to drive the optokinetic reflex. Furthermore, it appears that the low gain of optokinetic eye movements in turtles, which have a negligible velocity storage time constant, may allow stable oculomotor output in spite of neuronal delays in the reflex pathway. This model illustrates how visual neurons in the pretectum and accessory optic system can contribute to visually guided eye movements.

Animals↗

PubMed2004

Vaccinia virus recombinants as a model system to analyze interferon-induced pathways.

The interferons (IFNs) are a family of cytokines with broad antiviral activities that also control cell proliferation and modulate immune responses. IFNs exert their pleiotropic actions through the regulation of multiple pathways that have been subjected to extensive study using diverse approaches. The scope of this review is to show how we can take advantage of vaccinia virus (VV) to study IFN-related pathways. We summarize and present the different VV models available for studying IFN function and the possibilities that they offer to analyze IFN-induced pathways, IFN modulators, and the biologic effects at the molecular and cellular levels. Emphasis is given to studies of dsRNA-activated signaling with VV lacking E3L (VV DeltaE3L) and in RNA-activated protein kinase (PKR)-related pathways, through the use of VV recombinants (VVr) with inducible PKR (VV PKR). The latest system is versatile, as expression of PKR can be regulated and induced at different times; similarly, VVr can be generated expressing other PKR modulators. As an example of the utility of VVr, we describe how this model has been used to analyze the antiviral and proapoptotic functions of PKR, the impact of PKR on translation, and the PKR-induced activation of the nuclear factor-kappaB (NF-kappaB) pathway.

Animals↗

PubMed1991

DNA binding by the archaeal histone HMf results in positive supercoiling.

HMf, a histone from the hyperthermophilic archaeon Methanothermus fervidus binds double-stranded DNA molecules in vitro, forming compact structures that visibly resemble eukaryal nucleosomes. We show here that HMf binding increases the helical periodicity of DNA molecules to approximately 11 base pairs (bp) per turn and that DNA molecules in these nucleosome-like structures are constrained in positive toroidal supercoils. Based on the mass of HMf needed to cause a change in linking number (delta Lk), the maximum delta Lk introduced into circular DNA molecules of known sizes, and electron microscopy, we estimate that each HMf-DNA structure contains between 90 and 150 bp of DNA wrapped in 1.5 positive toroidal supercoils around a core of four HMf molecules. A model and pathway for the formation of these structures in vitro are presented and the possible role of positive toroidal wrapping of the M. fervidus genome in vivo is discussed.

Archaeal Proteins↗

PubMed2005

Cognitive flexibility and decision-making in a model of conditional visuomotor associations.

Arbitrary visuomotor associations map a stimulus onto a particular response upon reinforcing rewards. Changes in the associations between stimuli and responses require the neural networks to discard the already learned mappings and build new ones. This is a key aspect of cognitive flexibility. In addition, learning within this experimental paradigm requires a trial-and-error exploration strategy of the available stimulus-response associations. A system performing this task must be able to both build up mappings for stimulus-response associations and at the same time perform non-deterministically to explore the behavioural space until it reaches certainty. We hypothesize an integrate-and-fire network model that accounts for the neurophysiological data of a conditional visuomotor association task and is able to show non-deterministic behaviour. We aim at identifying multistable attractor regimes in the network dynamics, which intrinsically enable the system to make errors and thereby to perform trial-and-error exploration. Our model combines cognitive flexibility with multistable attractors in neurodynamical systems, believed to be the basis of decision-making. If multistable attractors support the exploration of the behavioural space, then our model predicts that the brain should respond stochastically with correct or incorrect activity to visuomotor associations until it has reached certainty. This should be visible not only in the corresponding activity in the premotor area, but also in activity corresponding to other associations or even other stimuli in the prefrontal cortex.

Algorithms↗

PubMed1999

Beta(2)-adrenergic receptor down-regulation. Evidence for a pathway that does not require endocytosis.

Sustained activation of most G protein-coupled receptors causes a time-dependent reduction of receptor density in intact cells. This phenomenon, known as down-regulation, is believed to depend on a ligand-promoted change of receptor sorting from the default endosome-plasma membrane recycling pathway to the endosome-lysosome degradation pathway. This model is based on previous studies of epidermal growth factor (EGF) receptor degradation and implies that receptors need to be endocytosed to be down-regulated. In stable clones of L cells expressing beta(2)-adrenergic receptors (beta(2)ARs), sustained agonist treatment caused a time-dependant decrease in both beta(2)AR binding sites and immuno-detectable receptor. Blocking beta(2)AR endocytosis with chemical treatments or by expressing a dominant negative mutant of dynamin could not prevent this phenomenon. Specific blockers of the two main intracellular degradation pathways, lysosomal and proteasome-associated, were ineffective in preventing beta(2)AR down-regulation. Further evidence for an endocytosis-independent pathway of beta(2)AR down-regulation was provided by studies in A431 cells, a cell line expressing both endogenous beta(2)AR and EGF receptors. In these cells, inhibition of endocytosis and inactivation of the lysosomal degradation pathway did not block beta(2)AR down-regulation, whereas EGF degradation was inhibited. These data indicate that, contrary to what is currently postulated, receptor endocytosis is not a necessary prerequisite for beta(2)AR down-regulation and that the inactivation of beta(2)ARs, leading to a reduction in binding sites, may occur at the plasma membrane.

Adrenergic beta-2 Receptor Agonists↗

PubMed1997

Essential pathway of reentry in the canine model of atrial flutter. Analysis using radiofrequency ablation.

In humans, the isthmus in the low right atrium between the tricuspid annulus and the inferior vena cava or the coronary sinus ostium is a well-established target of catheter ablation of common atrial flutter. In the canine model of atrial flutter with a Y-shaped incision, the tricuspid annulus was thought to constitute the essential reentrant pathway. The present study was designed to determine whether the supravalvular tissue around the tricuspid annulus is essential to atrial flutter in the canine model with an intercaval obstacle on the basis of the results of radiofrequency ablation. Epicardial approach of radiofrequency ablation was tested in 4 groups of dogs. Group A (5 dogs): Single application of radiofrequency energy (20 W) for 5 sec to the mid right atrial free wall. Group B (9 dogs): One to two applications to the tricuspid annulus. A ligature was also placed encircling the tricuspid annulus from the supravalvular atrial tissue to the subvalvular ventricular tissue. Group C (9 dogs): Linear transverse applications to the mid right atrial free wall between the tricuspid annulus and the intercaval obstacle. Group D (10 dogs): The isthmus between the inferior vena cava and the tricuspid annulus was ablated. After the experiment, the heart was excised for anatomical and histological studies. Atrial flutter was never abolished in all dogs in Groups A and B. A ligature encircling the tricuspid annulus also failed to terminate atrial flutter in 2 dogs tested. In contrast, atrial flutter was successfully abolished in 6 dogs (67%) of Group C and in 7 dogs (70%) of Group D. Total energy delivered was significantly higher in Group C than in Group D (364 +/- 133 versus 139 +/- 65 joules, p < 0.003). The total energy required for successful ablation was related to the cross sectional area of the ablation site (r = 0.55, p < 0.05). These results indicate that the tricuspid annulus is not an essential part of the reentrant pathway in the canine model of atrial flutter with an intercaval obstacle. The entire atrial tissue between the anatomical barriers could be involved in the reentrant pathway, and should therefore be ablated transmurally for successful ablation.

Animals↗