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PubMed2007

Discrete states of a protein interaction network govern interphase and mitotic microtubule dynamics.

The cytoplasm of eukaryotic cells is thought to adopt discrete "states" corresponding to different steady states of protein networks that govern changes in subcellular organization. For example, in Xenopus eggs, the interphase to mitosis transition is induced solely by activation of cyclin-dependent kinase 1 (CDK1) that phosphorylates many proteins leading to a reorganization of the nucleus and assembly of the mitotic spindle. Among these changes, the large array of stable microtubules that exists in interphase is replaced by short, highly dynamic microtubules in metaphase. Using a new visual immunoprecipitation assay that quantifies pairwise protein interactions in a non-perturbing manner in Xenopus egg extracts, we reveal the existence of a network of interactions between a series of microtubule-associated proteins (MAPs). In interphase, tubulin interacts with XMAP215, which is itself interacting with XKCM1, which connects to APC, EB1, and CLIP170. In mitosis, tubulin interacts with XMAP215, which is connected to EB1. We show that in interphase, microtubules are stable because the catastrophe-promoting activity of XKCM1 is inhibited by its interactions with the other MAPs. In mitosis, microtubules are short and dynamic because XKCM1 is free and has a strong destabilizing activity. In this case, the interaction of XMAP215 with EB1 is required to counteract the strong activity of XKCM1. This provides the beginning of a biochemical description of the notion of "cytoplasmic states" regarding the microtubule system.

Animals↗
PubMed2002

Ab initio QM/MM dynamics simulation of the tetrahedral intermediate of serine proteases: insights into the active site hydrogen-bonding network.

Ab initio QM/MM dynamics simulation is employed to examine the stability of the tetrahedral intermediate during the deacylation step in elastase-catalyzed hydrolysis of a simple peptide. An extended quantum region includes the catalytic triad, the tetrahedral structure, and the oxyanion hole. The calculations indicate that the tetrahedral intermediate of serine proteases is a stable species on the picosecond time scale. On the basis of geometrical and dynamical properties, and in agreement with many experimental and theoretical studies, it is suggested that the crucial hydrogen bonds involved in stabilizing this intermediate are between Asp-102 and His-57 and between the charged oxygen of the intermediate and the backbone N-H group of Gly-193 in the oxyanion hole. The mobility of the imidazolium ring between O(w) and O(gamma), two of the oxygens of the tetrahedral structure, shows how the intermediate could proceed toward the product state without a "ring-flip mechanism", proposed earlier on the basis of NMR data. In addition to the proposed C(epsilon)(1)-H.O hydrogen bond between the imidazolium ring and the backbone carbonyl of Ser-214, we observe an alternative C(epsilon)(1)-H.O hydrogen bond with the backbone carbonyl of Thr-213, that can stabilize the intermediate during the imidazolium movement. Proton hopping occurs between Asp-102 and His-57 during the simulation. The proton is, however, largely localized on the nitrogen, and hence it does not participate in a low-barrier hydrogen bond. The study also suggests factors that may be implicated in product release: breaking the hydrogen bond of the charged oxygen with the backbone of Ser-195 in the oxyanion hole and a loop opening between residues 216-225 that enables the breaking of a hydrogen bond in subsite S(3).

Animals↗
PubMed2006

Response variability in balanced cortical networks.

We study the spike statistics of neurons in a network with dynamically balanced excitation and inhibition. Our model, intended to represent a generic cortical column, comprises randomly connected excitatory and inhibitory leaky integrate-and-fire neurons, driven by excitatory input from an external population. The high connectivity permits a mean field description in which synaptic currents can be treated as gaussian noise, the mean and autocorrelation function of which are calculated self-consistently from the firing statistics of single model neurons. Within this description, a wide range of Fano factors is possible. We find that the irregularity of spike trains is controlled mainly by the strength of the synapses relative to the difference between the firing threshold and the postfiring reset level of the membrane potential. For moderately strong synapses, we find spike statistics very similar to those observed in primary visual cortex.

Action Potentials↗
PubMed2002

Dynamic stability conditions for Lotka-Volterra recurrent neural networks with delays.

The Lotka-Volterra model of neural networks, derived from the membrane dynamics of competing neurons, have found successful applications in many "winner-take-all" types of problems. This paper studies the dynamic stability properties of general Lotka-Volterra recurrent neural networks with delays. Conditions for nondivergence of the neural networks are derived. These conditions are based on local inhibition of networks, thereby allowing these networks to possess a multistability property. Multistability is a necessary property of a network that will enable important neural computations such as those governing the decision making process. Under these nondivergence conditions, a compact set that globally attracts all the trajectories of a network can be computed explicitly. If the connection weight matrix of a network is symmetric in some sense, and the delays of the network are in L2 space, we can prove that the network will have the property of complete stability.

Journal Article↗
PubMed2006

Construction of genetic oscillators with interlocked feedback networks.

To understand how a gene regulatory network functioning as an oscillator is built, a precise mathematical description of the network and its dynamical properties are developed in this paper. Our approach is based on analyzing the effect of interactions between smaller subnetworks with simple dynamics. We relate an oscillatory behavior of the network to the destabilization phenomenon of a steady state caused by the interactions in a simple discrete map. When source of the instability of the steady state rather than the oscillatory behavior itself is considered, linear stability analysis and feedback control theory can be employed. Moreover, the amplitudes robust against change in delay can also be obtained from the discrete map. The main ideas are illustrated by constructing a genetic oscillator termed a "repressilator" and analyzing the occurrence of cellular rhythms, although the theoretical results hold for a general class of biological systems. The method can be directly applied to design, construct genetic oscillators, and further control their dynamics, even for large-scale networks.

Animals↗
PubMed1996

Dynamics of a Winner-Take-All Neural Network.

This paper describes a neural network with lateral inhibition, which exhibits dynamic winner-take-all (WTA) behavior. The equations of this network model a current input MOSFET WTA circuit, which motivates the discussion. A very general sufficient condition for the network to have a WTA equilibrium point is obtained and sufficient conditions for the network to converge to the WTA point are presented. This gives explicit expressions for the resolution and lower bound of the input currents. We also show that whenever the network gets into the WTA region, it will stay in that region and settle down exponentially fast to the WTA point. This provides a speed up procedure for the decision making: as soon as it gets into the region, the winner can be picked up. Finally, we show that this WTA neural network has a self-resetting property. Copyright 1996 Elsevier Science Ltd

Journal Article↗
PubMed1992

A unique structural feature of a phospholipase A2 is probed by molecular dynamics.

The unusual catalytic network, revealed by the crystal structure of one of the two phospholipases A2 (PLA2) from the venom of the crotalid A.p.piscivorus has been probed using molecular dynamics. The catalytic network has been remodeled to a conformation similar to that found in all other PLA2, and the modeled structure has been submitted to energy minimization and molecular dynamics simulation, to explore the conformational space of the network. The calculations have yielded a large reorganization of the catalytic network, which gets a conformation close to that of the crystal structure. These results suggest that the unusual catalytic network observed in the studied PLA2 is a structural feature of the protein and not a crystal artifact.

Amino Acid Sequence↗
PubMed2003

Molecular architecture of intermediate filaments.

Together with microtubules and actin microfilaments, approximately 11 nm wide intermediate filaments (IFs) constitute the integrated, dynamic filament network present in the cytoplasm of metazoan cells. This network is critically involved in division, motility and other cellular processes. While the structures of microtubules and microfilaments are known in atomic detail, IF architecture is presently much less understood. The elementary 'building block' of IFs is a highly elongated, rod-like dimer based on an alpha-helical coiled-coil structure. Assembly of cytoplasmic IF proteins, such as vimentin, begins with a lateral association of dimers into tetramers and gradually into the so-called unit-length filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately yielding mature IFs after a compaction step. For nuclear lamins, however, assembly starts with a head-to-tail association of dimers. Recently, X-ray crystallographic data were obtained for several fragments of the vimentin dimer. Based on the dimer structure, molecular models of the tetramer and the entire filament are now a possibility.

Amino Acid Sequence↗
PubMed2004

Transient response of aerobic and anoxic activated sludge activities to sudden substrate concentration changes.

The state-of-the-art understanding of activated sludge processes as summarized in activated sludge models (ASMs) predicts an instantaneous increase in the biomass activity (which is measured, e.g., by the corresponding respiration rate OUR, NUR, etc.) under sudden substrate concentration changes. Experimental data (e.g., short-term batch respiration experiments under aerobic or anoxic conditions) collected for the calibration of the dynamic models (ASMs) often exhibit a transient phenomenon while attaining maximum activity, which cannot be explained by the current understanding of the activated sludge process. That transient phenomenon exhibits itself immediately upon addition of a substrate source to an endogenously respiring activated sludge sample and it usually takes a few minutes until the activated sludge reaches its maximum possible rate under given environmental conditions. This discrepancy between the state-of-the-art model and the experimental data is addressed in detail in this investigation. It is shown that the discrepancy is not caused by an error in the experimental set-up/data but it is rather due to model inadequacy. Among the hypotheses proposed, it appears that this transient response of the activated sludge most likely results from the sequence of intracellular reactions involved in substrate degradation by the activated sludge. Results from studies performed elsewhere with pure cultures (S. cerevisae and E. coli) support the hypothesis. The transient phenomenon can be described by a dynamic metabolic network model or by a simple first-order model, as adopted in this study. The transient phenomenon occurring in short-term batch respiration experiments is shown to interfere severely with parameter estimation if not modeled properly (2.8%, 11.5%, and 16.8% relative errors [average of three experiments] on Y(H), micro(maxH), and K(S), respectively). Proper modeling of this transient phenomenon whose time constant is on the order of minutes (1 to 3 min) is expected to contribute fundamentally to a better understanding and modeling of Orbal, carousel, and SBR-type treatment plants with fast-alternating process conditions, although such studies are beyond the scope of this report.

Aerobiosis↗
PubMed2005

High-affinity chelator thiols for switchable and oriented immobilization of histidine-tagged proteins: a generic platform for protein chip technologies.

Protein micro-/nanoarrays are becoming increasingly important in systematic approaches for the exploration of protein-protein interactions and dynamic protein networks, so there is a high demand for specific, generic, stable, uniform, and locally addressable protein immobilization on solid supports. Here we present multivalent metal-chelating thiols that are suitable for stable binding of histidine-tagged proteins on biocompatible self-assembled monolayers (SAMs). The architectures and physicochemical properties of these SAMs have been probed by various surface-sensitive techniques such as contact angle goniometry, ellipsometry, and infrared reflection-absorption spectroscopy. The specific molecular organization of proteins and protein complexes was demonstrated by surface plasmon resonance, confocal laser scanning, and atomic force microscopy. In contrast to the mono-NTA/His6 tag interaction, which has major drawbacks because of its low affinity and fast dissociation, drastically improved stability of protein binding by these multivalent chelator surfaces was observed. The immobilized histidine-tagged proteins are uniformly oriented and retain their function. At the same time, proteins can be removed from the chip surface under mild conditions (switchability). This new platform for switchable and oriented immobilization should assist proteome-wide wide analyses of protein-protein interactions as well as structural and single-molecule studies.

Biosensing Techniques↗
PubMed2005

Superficial and deep changes of cellular mechanical properties following cytoskeleton disassembly.

The cytoskeleton, composed of actin filaments, intermediate filaments, and microtubules, is a highly dynamic supramolecular network actively involved in many essential biological mechanisms such as cellular structure, transport, movements, differentiation, and signaling. As a first step to characterize the biophysical changes associated with cytoskeleton functions, we have developed finite elements models of the organization of the cell that has allowed us to interpret atomic force microscopy (AFM) data at a higher resolution than that in previous work. Thus, by assuming that living cells behave mechanically as multilayered structures, we have been able to identify superficial and deep effects that could be related to actin and microtubule disassembly, respectively. In Cos-7 cells, actin destabilization with Cytochalasin D induced a decrease of the visco-elasticity close to the membrane surface, while destabilizing microtubules with Nocodazole produced a stiffness decrease only in deeper parts of the cell. In both cases, these effects were reversible. Cell softening was measurable with AFM at concentrations of the destabilizing agents that did not induce detectable effects on the cytoskeleton network when viewing the cells with fluorescent confocal microscopy. All experimental results could be simulated by our models. This technology opens the door to the study of the biophysical properties of signaling domains extending from the cell surface to deeper parts of the cell.

Actins↗
PubMed2004

Turning heads: development of vertebrate branchiomotor neurons.

The cranial motor neurons innervate muscles that control eye, jaw, and facial movements of the vertebrate head and parasympathetic neurons that innervate certain glands and organs. These efferent neurons develop at characteristic locations in the brainstem, and their axons exit the neural tube in well-defined trajectories to innervate target tissues. This review is focused on a subset of cranial motor neurons called the branchiomotor neurons, which innervate muscles derived from the branchial (pharyngeal) arches. First, the organization of the branchiomotor pathways in zebrafish, chick, and mouse embryos will be compared, and the underlying axon guidance mechanisms will be addressed. Next, the molecular mechanisms that generate branchiomotor neurons and specify their identities will be discussed. Finally, the caudally directed or tangential migration of facial branchiomotor neurons will be examined. Given the advances in the characterization and analysis of vertebrate genomes, we can expect rapid progress in elucidating the cellular and molecular mechanisms underlying the development of these vital neuronal networks. Developmental Dynamics 229:143-161, 2004.

Animals↗
PubMed2003

Modulation of neural connectivity during tongue movement and reading.

In a functional magnetic resonance imaging (fMRI) study, a novel connectivity analysis method termed within-condition interregional covariance analysis (WICA) was introduced for investigation into brain modulation during tongue movement and reading Chinese pinyins and logographic characters. We found that performing a horizontal tongue movement task generated a specific brain module with hierarchical orders of neural computation. Such functional modularity was further examined during both overt and silent Chinese reading tasks. Our results showed that overt pinyin reading was associated with the following distributed regions involved in tongue movement: the primary motor cortex (M1), the supplementary motor area (SMA), Broca's area, and Wernicke's area. Furthermore, we have used the WICA and demonstrated task-dependent covariance patterns that are strongly associated with the M1 mouth/tongue region, in which the Broca-Wernicke pathway is implicated in a meaning access procedure based on assembled phonology, while the SMA-Broca pathway is implicated in a meaning access procedure based on addressed phonology. Our functional connectivity analysis of the neural pathway involved in language processing may provide a basis for future studies of the dynamic neural network associated with language learning and reading in both developmental and disease conditions.

Adult↗
PubMed1993

Oscillatory binocular system and temporal segmentation of stereoscopic depth surfaces.

A dynamical neural network model of binocular stereopsis is proposed to solve the problem of segmentation which remains ambiguous even when the problem of binocular correspondence is solved. Being compatible with the recent neurophysiological findings (Engel et al. 1991), the model assumes that neural cells show oscillatory activities and that segmentation into a coherent depth surface is coded by synchronization of activities. Employing appropriate constraints for segmentation, the present model shows proper segmentation of depth surfaces and also solves segmentational ambiguity caused by a gap. It is newly shown that binocularly-unmatched monocular cells are discriminated in temporal segmentation of monocular cells caused by recurrent interactions between monocular and binocular cells. Integrative interactions with the other visual components through temporal segmentation are also discussed.

Computer Simulation↗
PubMed1993

Alterations in visual receptive fields in the superior colliculus induced by amphetamine.

Visual response properties were examined in the superficial layers of the superior colliculus (SC) of anesthetized, paralyzed cats before and after i.v. administration of d-amphetamine. Receptive fields (RFs) of single SC units were plotted using small spots of light presented to the contralateral eye. Within the first hour following d-amphetamine injections, RF size gradually increased, reaching a maximum 86 min post-injection. On average, the area of the RF increased by 5.6 times and RF expansion was observed in all single units examined in the superficial layers. Over the subsequent 4-8 h following the injection, RF area gradually decreased and returned to control dimensions. Most RFs displayed asymmetrical patterns of expansion, showing relatively more horizontal than vertical growth. As RF expansion developed, responses to stimuli flashed "on" and "off" at various locations both inside and outside the borders of the control RF became progressively more vigorous. In contrast, no significant changes were noted in direction-selective responses at any time after d-amphetamine injections. Using an array of light bar stimuli of different lengths, the strength of surround suppression was found to be significantly diminished by d-amphetamine. The reduction in surround suppression was especially clear for bar lengths which exceeded the diameter of the control RF. No RF expansion was observed in the superficial layers of the SC when d-amphetamine was injected intravitreally. Furthermore, d-amphetamine had no discernable effect on the RF sizes of cells in the visual cortex. These results suggest that the RF changes in the SC were not of either retinal or cortical origin. We conclude that the mean retinal area which can potentially influence the activity of RFs in the superficial layers of the SC may be on average over 5 times greater than the RF area determined using conventional methods and criteria. These findings raise the interesting possibility that the relatively small size and sharp borders characteristic of RFs in the superficial layers arise from local inhibitory networks which delimit a broader field of excitatory activity supplied by retinal and cortical afferent terminals. Thus, in order to generate the RF changes observed here, either these local inhibitory circuits are amphetamine sensitive, or more likely, these inhibitory networks are dynamically modulated by an, as yet unidentified, amphetamine-sensitive input affecting visual RFs in the superficial layers.

Animals↗
PubMed1995

The stationary state of epithelia.

A tissue is a geometrical, space-filling, random cellular network; it remains in this steady state while individual cells divide. Cell division is a local, elementary topological transformation which establishes statistical equilibrium of the structure. We describe the physical conditions to maintain stationary the epidermis (of mammals or of the cucumber), in spite of the fact that cells constantly divide and die. Specifically, we study the statistical equilibrium of the basal layer, a corrugated surface filled with cells, constituting a two-dimensional topological froth. Cells divide and detach from the basal layer, and these two topological transformations are responsible for the stationary state of the epidermis. The topological froth is capable of responding rapidly and locally to external constraints, and is a good illustration of the plasticity of random cellular networks. Statistical equilibrium is controlled by entropy, both as a measure of disorder and as information, and is characterized by observable relations between average cell shapes and sizes. The technique can be applied to any random cellular network in dynamical equilibrium. Mitosis as the dominating topological transformation and the fact that the distribution of cell shapes is very narrow are the only inputs specific to biology.

Animals↗
PubMed1989

A neural network model for limb trajectory formation.

This paper deals with the problem of representing and generating unconstrained aiming movements of a limb by means of a neural network architecture. The network produced time trajectories of a limb from a starting posture toward targets specified by sensory stimuli. Thus the network performed a sensory-motor transformation. The experimenters trained the network using a bell-shaped velocity profile on the trajectories. This type of profile is characteristic of most movements performed by biological systems. We investigated the generalization capabilities of the network as well as its internal organization. Experiments performed during learning and on the trained network showed that: (i) the task could be learned by a three-layer sequential network; (ii) the network successfully generalized in trajectory space and adjusted the velocity profiles properly; (iii) the same task could not be learned by a linear network; (iv) after learning, the internal connections became organized into inhibitory and excitatory zones and encoded the main features of the training set; (v) the model was robust to noise on the input signals; (vi) the network exhibited attractor-dynamics properties; (vii) the network was able to solve the motor-equivalence problem. A key feature of this work is the fact that the neural network was coupled to a mechanical model of a limb in which muscles are represented as springs. With this representation the model solved the problem of motor redundancy.

Extremities↗
PubMed1995

Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state.

In the field of biological regulation, models dictated by experimental work are usually complex networks comprising intertwined feedback loops. In this paper the biological roles of individual positive loops (multistationarity, differentiation) and negative loops (homeostasis, with or without oscillations, buffering of gene dosage effect) are discussed. The relationship between feedback loops and steady states is then clarified, and the problem: "How can one conveniently disentangle complex networks?" is then considered. Initiated long ago, logical descriptions have been generalized from various viewpoints; these developments are briefly discussed. The recent concept of the loop-characteristic state, defined as the logical state located at the level of the thresholds involved in the loop, together with its application, are then presented. Biological applications are also discussed.

Arginine↗