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PubMed2000

Influence of fibrin network conformation and fibrin fiber diameter on fibrinolysis speed: dynamic and structural approaches by confocal microscopy.

Abnormal fibrin architecture is thought to be a determinant factor of hypofibrinolysis. However, because of the lack of structural knowledge of the process of fibrin digestion, relationships between fibrin architecture and hypofibrinolysis remain controversial. To elucidate further structural and dynamic changes occurring during fibrinolysis, cross-linked plasma fibrin was labeled with colloidal gold particles, and fibrinolysis was followed by confocal microscopy. Morphological changes were characterized at fibrin network and fiber levels. The observation of a progressive disaggregation of the fibrin fibers emphasizes that fibrinolysis proceeds by transverse cutting rather than by progressive cleavage uniformly around the fiber. Plasma fibrin clots with a tight fibrin conformation made of thin fibers were dissolved at a slower rate than those with a loose fibrin conformation made of thicker (coarse) fibers, although the overall fibrin content remained constant. Unexpectedly, thin fibers were cleaved at a faster rate than thick ones. A dynamic study of FITC-recombinant tissue plasminogen activator distribution within the fibrin matrix during the course of fibrinolysis showed that the binding front was broader in coarse fibrin clots and moved more rapidly than that of fine plasma fibrin clots. These dynamic and structural approaches to fibrin digestion at the network and the fiber levels reveal aspects of the physical process of clot lysis. Furthermore, these results provide a clear explanation for the hypofibrinolysis related to a defective fibrin architecture as described in venous thromboembolism and in premature coronary artery disease.

Fibrin↗
PubMed2005

Mechanisms of 4-hydroxynonenal-induced neuronal microtubule dysfunction.

We have previously demonstrated that neuronal microtubules are exquisitely sensitive to the lipid peroxidation product 4-hydroxynonenal (HNE). The mechanism, however, by which HNE disrupts the microtubules, is not known. Sulfhydryl groups of protein-cysteines constitute main targets of HNE. Indeed, HNE is mainly detoxified by conjugation to glutathione (GSH), a reaction that leads to depletion of cellular GSH. GSH maintains protein sulfhydryl groups in the reduced form and has been implicated in the regulation of cytoskeletal function. Here, we assess what role depletion of cellular GSH plays in the HNE-induced microtubule disruption. We demonstrate that HNE and its intracellularly activated tri-ester analog, HNE(Ac)(3), cause substantial GSH depletion in Neuro2A cells. However, other compounds inducing GSH depletion had no effect on the microtubule network. Therefore, HNE-induced depletion of cellular GSH does not contribute to the HNE-induced microtubule disruption. We previously demonstrated that another main cellular target of HNE is tubulin, the core protein of microtubules containing abundant cysteines. The functional relevance of this adduction, however, had not been evaluated. Here, we demonstrate that exposure of Neuro 2A cells to HNE or HNE(Ac)(3) results in the inhibition of cytosolic taxol-induced tubulin polymerization. These and our previous observations strongly support the hypothesis that HNE-adduction to tubulin is the primary mechanism involved in the HNE-induced loss of the highly dynamic neuronal microtubule network.

Aldehydes↗
PubMed2001

Disintegration and reorganization of fibrin networks during tissue-type plasminogen activator-induced clot lysis.

In this study, we investigated tissue-type plasminogen activator (tPA)-induced lysis of glutamic acid (glu)-plasminogen-containing or lysine (lys)-plasminogen-containing thrombin-induced fibrin clots. We measured clot development and plasmin-mediated clot disintegration by thromboelastography, and used scanning electron microscopy (SEM) to document the structural changes taking place during clot formation and lysis. These events occurred in three overlapping stages, which were initiated by the addition of thrombin, resulting first in fibrin polymerization and clot network organization (Stage I). Autolytic plasmin cleavage of glu-plasminogen at lys-77 generates lys-plasminogen, exposing lysine binding sites in its kringle domains. The presence of lys-plasminogen within the thrombin-induced fibrin clot enhanced network reorganization to form thicker fibers as well as globular complexes containing fibrin and lys-plasminogen having a greater level of turbidity and a higher elastic modulus (G) than occurred with thrombin alone. Lys-plasminogen or glu-plasminogen that had been incorporated into the fibrin clot was activated to plasmin by tPA admixed with the thrombin, and led directly to clot disintegration (Stage II) concomitant with fibrin network reorganization. The onset of Stage III (clot dissolution) was signaled by a sustained secondary rise in turbidity that was due to the combined effects of lys-plasminogen presence or its conversion from glu-plasminogen, plus clot network reorganization. SEM images documented dynamic structural changes in the lysing fibrin network and showed that the secondary turbidity rise was due to extensive reorganization of severed fibrils and fibers to form wide, occasionally branched fibers. These degraded structures contributed little, if anything, to the structural integrity of the residual clot, and eventually collapsed completely during the course of progressive clot dissolution. These results provide new perspectives on the major structural events that occur in the fibrin clot matrix during fibrinolysis.

Fibrin↗
PubMed2004

Modeling infection transmission.

Understanding what determines patterns of infection spread in populations is important for controlling infection transmission. The science that advances this understanding uses mathematical and computer models that vary from deterministic models of continuous populations to models of dynamically evolving contact networks between individuals. These provide insight, serve as scientific theories, help design studies, and help analyze data. The key to their use lies in assessing the robustness of inferences made using them to violation of their simplifying assumptions. This involves changing model forms from deterministic to stochastic and from compartmental to network, as well as adding realistic detail and changing parameter values. Currently inferences about infection transmission are often made using stratified rate or risk comparisons, logistic regression models, or proportionate hazards models that assume an absence of transmission. Robustness assessment will show many of these inferences to be wrong. A community of epidemiologist modelers is needed for effective robustness assessment.

Data Interpretation, Statistical↗
PubMed1994

Modulation of associative memory function in a biophysical simulation of rat piriform cortex.

1. Associative memory function was analyzed in a realistic biophysical simulation of rat piriform (olfactory) cortex containing 240 pyramidal cells and 58 each of two types of inhibitory interneurons. Pyramidal cell simulations incorporated six different intrinsic currents and three different synaptic currents. We investigated the hypothesis that acetylcholine sets the appropriate dynamics for learning within the network, whereas removal of cholinergic modulation sets the appropriate dynamics for recall. The associative memory function of the network was tested during recall after simulation of the cholinergic suppression of intrinsic fiber synaptic transmission and the cholinergic suppression of neuronal adaptation during learning. 2. Hebbian modification of excitatory synaptic connections between pyramidal cells during learning of patterns of afferent activity allowed the model to show the basic associative memory property of completion during recall in response to degraded versions of those patterns, as evaluated by a performance measure based on normalized dot products. 3. During learning of multiple overlapping patterns of afferent activity, recall of previously learned patterns interfered with the learning of new patterns. As more patterns were stored this interference could lead to the exponential growth of a large number of excitatory synaptic connections within the network. This runaway synaptic modification during learning led to excessive excitatory activity during recall, preventing the accurate recall of individual patterns. 4. Runaway synaptic modification of excitatory intrinsic connections could be prevented by selective suppression of synaptic transmission at these synapses during learning. This allowed effective recall of single learned afferent patterns in response to degraded versions of those patterns, without interference from other learned patterns. 5. During learning, cholinergic suppression of neuronal adaptation enhanced the activity of cortical pyramidal cells in response to afferent input, compensating for decreased activity due to suppression of intrinsic fiber synaptic transmission. This modulation of adaptation led to more rapid learning of afferent input patterns, as demonstrated by higher values of the performance measure. 6. During recall, when suppression of excitatory intrinsic synaptic transmission was removed, continued cholinergic suppression of neuronal adaptation led to the spread of excessive activity. More stable activity patterns during recall could be obtained when the cholinergic suppression of neuronal adaptation was removed at the same time as the cholinergic suppression of synaptic transmission. 7. A realistic biophysical simulation of the effects of acetylcholine on synaptic transmission and neuronal adaptation in the piriform cortex shows that these effects act together to set the appropriate dynamics for learning, whereas removal of both effects sets the appropriate dynamics for recall.

Acetylcholine↗
PubMed2006

Neocortical network activity in vivo is generated through a dynamic balance of excitation and inhibition.

The recurrent excitatory and inhibitory connections between and within layers of the cerebral cortex are fundamental to the operation of local cortical circuits. Models of cortical function often assume that recurrent excitation and inhibition are balanced, and we recently demonstrated that spontaneous network activity in vitro contains a precise balance of excitation and inhibition; however, the existence of a balance between excitation and inhibition in the intact and spontaneously active cerebral cortex has not been directly tested. We examined this hypothesis in the prefrontal cortex in vivo, during the slow (<1 Hz) oscillation in ketamine-xylazine-anesthetized ferrets. We measured persistent network activity (Up states) with extracellular multiple unit and local field potential recording, while simultaneously recording synaptic currents in nearby cells. We determined the reversal potential and conductance change over time during Up states and found that the body of Up state activity exhibited a steady reversal potential (-37 mV on average) for hundreds of milliseconds, even during substantial (21 nS on average) changes in membrane conductance. Furthermore, we found that both the initial and final segments of the Up state were characterized by significantly more depolarized reversal potentials and concomitant increases in excitatory conductance, compared with the stable middle portions of Up states. This ongoing temporal evolution between excitation and inhibition, which exhibits remarkable proportionality within and across neurons in active local networks, may allow for rapid transitions between relatively stable network states, permitting the modulation of neuronal responsiveness in a behaviorally relevant manner.

Action Potentials↗
PubMed2006

Models for the study of whole systems.

This article summarizes a network and complex systems science model for research on whole systems of complementary and alternative medicine (CAM) such as homeopathy and traditional Chinese medicine. The holistic concepts of networks and nonlinear dynamical complex systems are well matched to the global and interactive perspectives of whole systems of CAM, whereas the reductionistic science model is well matched to the isolated local organ, cell, and molecular mechanistic perspectives of pharmaceutically based biomedicine. Whole systems of CAM are not drugs with specific actions. The diagnostic and therapeutic approaches of whole systems of CAM produce effects that involve global and patterned shifts across multiple subsystems of the person as a whole. For homeopathy, several characteristics of complex systems, including the probabilistic nature of attractor patterns, variable sensitivity of complex systems to initial conditions, and emergent behaviors in the evolution of a system in its full environmental context over time, could help account for the mixed basic science and controlled clinical trial research findings, in contrast with the consistently positive outcomes of observational studies in the literature. Application of theories and methods from complex systems and network science can open a new era of advances in understanding factors that lead to good versus poor individual global outcome patterns and to rational triage of patients to one type of care over another. The growing reliance on complex systems thinking and systems biology for cancer research affords a unique opportunity to bridge between the CAM and conventional medical worlds with some common language and conceptual models.

Acupuncture Therapy↗
PubMed1998

A structured, minimal parameter model of the central nitrogen metabolism in Saccharomyces cerevisiae: the prediction of the behavior of mutants.

In order to enable future pathway engineering of a complex system, such as the nitrogen metabolism in yeast, mathematical modelling tools have to be developed. The stoichiometric and biochemical characteristics of the glutamate and glutamine nodes (the Central Nitrogen Metabolism, CNM) are qualitatively known. Quantitative knowledge about the dynamics of the network lacks and needs to be developed for metabolic reprogramming. A model-based-experiment approach is proposed in which the development of a model initiates new experiments of which the results then improve the model. As a first step in this iterative system identification cycle, recent experimental data, both qualitative and quantitative, obtained from defined studies on the CNM of the yeast Saccharomyces cerevisiae have been translated into an initial mathematical model. The model approach is based on a combination of Flux Analysis and simple enzyme kinetics. The model is constructed using nonlinear Ordinary Differential Equations and regulation of the synthesis and activity of key enzymes of the CNM is included. The parameters of the model are estimated with a constrained Least Squares algorithm using the steady-state and dynamic pulse data of a glutamine limited continuous culture. The resulting model describes a continuous culture of a wild-type strain correctly and in general the trends of the dynamic behaviour after both glutamine and ammonia pulses to this culture are good. Inclusion of countercurrent reactions and compartmentation in the model is essential for the descriptive quality of the model under dynamic conditions. It is clear that more experimental work is needed. The model indicates that the GOGAT/Glutamine Synthetase (GS) pathway plays a more important physiological stabilizing role in yeast than is generally assumed. New, model-based, experiments have to investigate the function of GOGAT, especially under dynamic conditions. Also redox cofactors and ATP have to be measured. The resulting model is validated with data of similar experiments with a GS-mutant. The quality of the prediction of the behaviour of the mutant is comparable to the descriptive property, which is a very promising result, taking into account the limited dataset compared to the system complexity.

Ammonia↗
PubMed2004

Constrained spin-dynamics description of random walks on hierarchical scale-free networks.

We study a random walk problem on the hierarchical network which is a scale-free network grown deterministically. The random walk problem is mapped onto a dynamical Ising spin chain system in one dimension with a nonlocal spin update rule, which allows an analytic approach. We show analytically that the characteristic relaxation time scale grows algebraically with the total number of nodes N as T--N(z). From a scaling argument, we also show the power-law decay of the autocorrelation function C(sigma)(t)--t(-alpha), which is the probability to find the Ising spins in the initial state sigma after t time steps, with the state-dependent nonuniversal exponent alpha. It turns out that the power-law scaling behavior has its origin in a quasiultrametric structure of the configuration space.

Journal Article↗
PubMed2004

Amplification of noise in a cascade chemical reaction.

Networks of chemical reactions have been given much attention recently. However, dynamical aspects of such networks remain to be elucidated. In this paper, we study a cascade chemical reaction, consisting of a series of downstream-coupled Brusselators. Along the cascade of reaction, small fluctuations naturally existing in the concentration of chemical species are amplified. Such amplification of small noise leads to the formation of chemical oscillations in the downstream chemical species. The amplification rate of small noise in the concentration along the cascade is studied and the method to calculate the amplification rate analytically is developed. It is also shown that the nonlinear evolution of the chemical oscillation in the downstream reaction strongly depends on the frequency of the initial inlet chemical concentration.

Journal Article↗
PubMed2003

Hepatic gene expression profiling reveals perturbed calcium signaling in a mouse model lacking both LDL receptor and Apobec1 genes.

Atherosclerosis is a complex disease that gene and environment interaction influences the progression of atherosclerotic lesion development. Our laboratory used mice lacking both the low density lipoprotein (LDL) receptor and Apobec1 genes (LDLR-/-Apobec1-/-, designated LDb) to investigate gene-gene interaction and the influence of an environmental factor (high-fat diet) on gene networks. LDb mice (males and females) at 5 months of age were fed a chow or high fat diet for 3-month. The mice on a chow diet had elevated plasma cholesterol and triglyceride levels and developed atherosclerosis. Feeding a high-fat diet accelerated the development of lesions >1.5-fold. We performed microarray analysis of the expression of 12442 murine genes in the livers of these animals, which identified 54 genes in males and 77 genes in females were significantly perturbed by the high-fat diet. Moreover, most of these genes (>70%) were upregulated. The results suggested that glycolysis, fat transport, and steroid hormone biosynthesis pathways were upregulated, probably to compensate for the high fat intake. Furthermore, a batch of stress-responsive genes was upregulated. The study also shows a dynamic cellular communication network including T cells, neutrophils, and monocytes/macrophages, which related to inflammatory and immune/complement responses. Importantly, this study discovered that many genes involved in calcium signaling and bone formation were up regulated. Alizarin Red S staining was used to detect calcium deposits in the region of atherosclerotic lesions. Real-time quantitative RT-PCR and Western blot analyses provided verification of the gene expression levels. In conclusion, this study demonstrated the global differential gene expression profiles, which are influenced by feeding a high fat diet to LDb mice. The results of the study provide new insights into the significance of calcification in atherogenesis.

APOBEC-1 Deaminase↗
PubMed2005

Proton channel hydration and dynamics of a bacteriorhodopsin triple mutant with an M-state-like conformation.

The hydration and dynamics of purple membranes (PM) containing the bacteriorhodopsin (BR) triple mutant D96G/F171C/F219L were investigated by neutron diffraction coupled with H(2)O/D(2)O exchange and by energy-resolved neutron scattering. The mutant, which is active in proton transport (Tittor et al. in J. Mol. Biol. 319:555-565, 2002), has an "open" ground-state structure similar to that of the M intermediate in the photocycle of the wild type (wt) (Subramaniam and Henderson in Nature 406:653-657, 2000). The experiments demonstrated an increased proton channel hydration in the mutant PM compared with wt PM, in both high (86%) and low (57%) relative humidity. We suggest that this is due to the smaller side chains of the mutant residues liberating space for more water molecules in the proton channel, which would then be able to participate in the proton translocation network. PM thermal dynamics has been shown to be very sensitive to membrane hydration (Lehnert et al. in Biophys. J. 75:1945-1952, 1998). The global dynamical behaviour of the mutant PM on the 100-ps time scale, as a function of relative humidity, was found to be identical to that of the wt, showing that the "open" BR structure and additional water molecules in the proton channel do not provide a softer environment enabling increased flexibility.

Bacteriorhodopsins↗
PubMed2006

Adsorption and dynamics of long-range interacting fullerenes in a flexible, two-dimensional, nanoporous porphyrin network.

Herein, a detailed investigation of the adsorption and dynamics of C60 and C70 fullerenes hosted in a self-assembled, two-dimensional, nanoporous porphyrin network on a solid Ag surface is presented. Time-resolved scanning tunneling microscopy (STM) studies of these supramolecular systems at the molecular scale reveal distinct host-guest interactions giving rise to a pronounced dissimilar mobility of the two fullerenes within the porphyrin network. Furthermore, long-range coverage-dependent interactions between the all-carbon guests, which clearly affect their mobility and are likely mediated by a complex mechanism involving the Ag substrate and the flexible porphyrin host network, are observed. At increased fullerene coverage, this unprecedented interplay results in the formation of large fullerene chains and islands. By applying a lattice gas model with nearest-neighbor interactions and by evaluating the fullerene-pair distribution functions, the respective coverage-dependent guest-guest interaction energies are estimated.

Journal Article↗
PubMed1999

The molecular basis of the solution properties of hyaluronan investigated by confocal fluorescence recovery after photobleaching.

Hyaluronan (HA) is a highly hydrated polyanion, which is a network-forming and space-filling component in the extracellular matrix of animal tissues. Confocal fluorescence recovery after photobleaching (confocal-FRAP) was used to investigate intramolecular hydrogen bonding and electrostatic interactions in hyaluronan solutions. Self and tracer lateral diffusion coefficients within hyaluronan solutions were measured over a wide range of concentrations (c), with varying electrolyte and at neutral and alkaline pH. The free diffusion coefficient of fluoresceinamine-labeled HA of 500 kDa in PBS was 7.9 x 10(-8) cm(2) s(-1) and of 830 kDa HA was 5.6 x 10(-8) cm(2) s(-1). Reductions in self- and tracer-diffusion with c followed a stretched exponential model. Electrolyte-induced polyanion coil contraction and destiffening resulted in a 2.8-fold increase in self-diffusion between 0 and 100 mM NaCl. Disruption of hydrogen bonds by strong alkali (0.5 M NaOH) resulted in further larger increases in self- and tracer-diffusion coefficients, consistent with a more dynamic and permeable network. Concentrated hyaluronan solution properties were attributed to hydrodynamic and entanglement interactions between domains. There was no evidence of chain-chain associations. At physiological electrolyte concentration and pH, the greatest contribution to the intrinsic stiffness of hyaluronan appeared to be due to hydrogen bonds between adjacent saccharides.

Animals↗
PubMed1991

Correlations between frequencies of kin.

Recent years have seen the development of formal and microsimulation models of the structure and dynamics of kin networks. These models generally assume uncorrelated fertility within and across generations. Several sets of real data, however, show positive correlations between the frequencies of various categories of kin. This paper uses formal models to calculate the correlations that will exist between certain categories of kin even if mothers and daughters have independent fertility. Mechanisms by which fertility might be transmitted from mothers to their daughters are considered and the implications for kin correlations are evaluated.

Adolescent↗
PubMed2005

Spatiotemporal patterns of dorsal root-evoked network activity in the neonatal rat spinal cord: optical and intracellular recordings.

Spatiotemporal patterns of dorsal root-evoked potentials were studied in transverse slices of the rat spinal cord by monitoring optical signals from a voltage-sensitive dye with multiple-photodiode optic camera. Typically, dorsal root stimulation generated two basic waveforms of voltage images: dual-component images consisting of fast, spike-like signal followed by a slow signal in the dorsal horn, and small, slow signals in the ventral horn. To qualitatively relate the optical signals to membrane potentials, whole cell recordings were combined with measurements of light absorption in the area around the soma. The slow optical signals correlated closely with subthreshold postsynaptic potentials in all regions of the cord. The spike-like component was not associated with postsynaptic action potentials, suggesting that the fast signal was generated by presynaptic action potentials. Firing in a single neuron could not be detected optically, implying that local voltage images originated from synchronously activated neuronal ensembles. Blocking glutamatergic synaptic transmission inhibited excitatory postsynaptic potentials (EPSPs) and significantly reduced the slow optical signals, indicating that they were mediated by glutamatergic synapses. Suppressing glycine-mediated inhibition increased the amplitude of both optical signals and EPSPs, while blocking GABA(A) receptor-mediated synapses, increased the amplitude and time course of EPSPs and prolonged the duration of voltage images in larger areas of the slice. The close correlation between evoked EPSPs and their respective local voltage images shows the advantage of the high temporal resolution optical system in measuring both the spatiotemporal dynamics of segmental network excitation and integrated potentials of neuronal ensembles at identified sites.

2-Amino-5-phosphonovalerate↗
PubMed2006

A mathematical model for adaptive transport network in path finding by true slime mold.

We describe here a mathematical model of the adaptive dynamics of a transport network of the true slime mold Physarum polycephalum, an amoeboid organism that exhibits path-finding behavior in a maze. This organism possesses a network of tubular elements, by means of which nutrients and signals circulate through the plasmodium. When the organism is put in a maze, the network changes its shape to connect two exits by the shortest path. This process of path-finding is attributed to an underlying physiological mechanism: a tube thickens as the flux through it increases. The experimental evidence for this is, however, only qualitative. We constructed a mathematical model of the general form of the tube dynamics. Our model contains a key parameter corresponding to the extent of the feedback regulation between the thickness of a tube and the flux through it. We demonstrate the dependence of the behavior of the model on this parameter.

Adaptation, Physiological↗
PubMed1989

Circuit analysis of the oscillatory state in glycolysis.

The oscillatory state of glycolysis in yeast extracts has been analysed by methods known from electronic circuit studies. The time course of the reactions are calculated by the method of least squares from experimentally determined sets of the concentrations of most of the metabolites. The dynamics of the glycolytic network of reactions can then be represented in terms of flow versus driving force (current versus voltage in the corresponding electronic circuit). The analysis of the dynamics leads to the conclusion that glycolysis is switched on and off in a pulsed manner during the oscillatory state. The resulting pulsed flow cannot only be measured with glycolytic end products, like carbon dioxide or ethanol, but can also readily be demonstrated by diagrams of reaction rates of single enzymic steps even in the initial stages of the glycolytic sequence. An analytic method widely applied to electronic circuits also proved to be useful in the study of the dynamics of a complex enzymic network.

Data Interpretation, Statistical↗