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PubMed2000

Visual search: bottom-up or top-down?

The aim of the experiments in this paper was to explore the relationship between top-down and bottom-up processes in visual search. Employing behavioral techniques, we first consider the possible role of the magnocellular visual pathway in visual search, and find that visual search does not necessarily depend on processing by this visual sub-system. We next use functional imaging (positron emission tomography) to explore the effect of varying top-down strategy during visual search. Our findings indicate that the neural processes underlying visual search are distributed over an extensive network of brain regions, with varying roles for different parts of the network as the dynamics of top-down vs. bottom-up influences shift. The conjunction of bottom-up processing with top-down attentional suppression of an irrelevant singleton could account for activity found in right primary visual cortex (V1). The conjunction of bottom-up processing with top-down attentional set could explain activity noted in the right superior temporal gyrus/insular cortex. The left lateral cerebellum appears to play a role in attention, either in signaling popout or in switching attention repeatedly between multiple visual attributes. Loci in left parietal cortex (parietal operculum/superior temporal gyrus, parieto-occipital fissure and precuneus) are implicated in attention-demanding search for a target shape. Returning to behavioral experiments, we find that, when multiple feature singletons compete for attention, interference between them is strongest for features closely related to the distinguishing target feature. This competition appears to be feature-level rather than object-level, and is characterized by a varying degree of specificity for different features. Task complexity modulates interference effects, even for abrupt visual onsets, which are often considered to capture attention involuntarily. Overall, our observations converge on the conclusion that visual search is extremely flexible and subject to considerable specificity of top-down control, although such specificity is clearly not absolute.

Adult↗

PubMed2002

Stimulation-induced within-representation and across-representation plasticity in human motor cortex.

The human motor cortex contains a dynamic and distributed network of motor representations. Formation, maintenance, and modification of these representations is an activity-driven process. Repeated stimulation of one representation results in increased motor output from this representation, a process referred to as "within-representation plasticity." We showed previously that within-representation plasticity of the upper arm representation occurs when repetitive transcranial magnetic stimulation (rTMS) is delivered to that representation during transient ischemic nerve block (INB) of the contralateral hand. INB reduces inhibition in the motor cortex and thus lowers the threshold for stimulation-induced plasticity. Here we studied the effects of rTMS delivered to nearby body part representations on the motor output from the upper arm representation. Six healthy subjects underwent INB-alone (control), or INB plus 30 min of focal 0.1 Hz rTMS of either the face, hand, arm, leg, or overlap arm/hand representations in motor cortex. INB-alone and rTMS of the leg representation resulted in only a short-lasting (< 20 min) increase in motor output from the arm representation, as measured by motor evoked potentials in the biceps. rTMS of arm and arm/hand representations induced a prolonged (> 60 min) within-representation increase. In contrast, rTMS of face or hand representations canceled the short-lasting increase and even led to a long-lasting decrease of motor output from the arm representation. Therefore, rTMS of the experimentally disinhibited motor cortex induces within-representation increase, and across-representation decrease of motor cortical output. This bidirectional plasticity might be used for purposeful modulation of human cortical function.

Adult↗

PubMed2001

Evidence for the involvement of Tiam1 in axon formation.

In cultured neurons, axon formation is preceded by the appearance in one of the multiple neurites of a large growth cone containing a labile actin network and abundant dynamic microtubules. The invasion-inducing T-lymphoma and metastasis 1 (Tiam1) protein that functions as a guanosine nucleotide exchange factor for Rac1 localizes to this neurite and its growth cone, where it associates with microtubules. Neurons overexpressing Tiam1 extend several axon-like neurites, whereas suppression of Tiam1 prevents axon formation, with most of the cells failing to undergo changes in growth cone size and in cytoskeletal organization typical of prospective axons. Cytochalasin D reverts this effect leading to multiple axon formation and penetration of microtubules within neuritic tips devoid of actin filaments. Taken together, these results suggest that by regulating growth cone actin organization and allowing microtubule invasion within selected growth cones, Tiam1 promotes axon formation and hence participates in neuronal polarization.

Actin Cytoskeleton↗

PubMed1992

An actin-associated protein present in the microtubule organizing center and the growth cones of PC-12 cells.

The pathfinding ability of the growth cone depends upon the integrity of a dynamic actin filament network. However, although a number of actin-binding proteins have been found in growth cones, it is not known how these proteins come to be concentrated there or how they might interact to produce these important actin filaments. In this report, an actin-associated protein recognized by the monoclonal antibody 2E4 is demonstrated to be present in PC-12 cells. In undifferentiated cells, this protein is present in an apparently inactive state in a perinuclear location that corresponds to that of the microtubule organizing center and not of the Golgi apparatus. Conversely, after NGF-induced differentiation, the antigen is found enriched in the neurite and growth cone and disappears from the perinuclear position. This disappearance is directly proportional to the length of the neurite. The antigen-antibody complex binds the ends of actin filaments in vitro in an ATP-sensitive manner, and the antibody stains the outermost edge of the actin filament ruffle in the leading edge of migrating fibroblasts. Hence, it is possibly involved in the membrane-associated polymerization of actin filaments such as that observed in growth cones.

Actins↗

PubMed2005

A genomic-scale search for regulatory binding sites in the integration host factor regulon of Escherichia coli K12.

We examined general aspects of the DNA-protein interaction between the integration host factor (IHF) global regulator and its regulatory binding sites in the Escherichia coli K12 genome. Two models were developed with distinct weight matrices for the regulatory binding sites recognized by IHF. Using these matrices we performed a genome scale scan and built a set of computationally predicted binding sites for each of the models. The sites found by the model associated with repetitive sequences had a higher score in the sequence to matrix alignment. They were also more rare than the other sites. The sites not associated with repeats rapidly tended to become undistinguishable from the background as statistical stringency was relaxed. We compared our results to the known sites documented in RegulonDB and found new members of the IHF Regulon. The two models exhibit clearly distinct affinity patterns (scores in the sequence to matrix alignments and in the number of regulatory sites), as we vary the stringency of the statistical confidence parameters. We suggest that these differences may play an important role in the dynamics of the network. We concluded that IHF may regulate two genes encoding ATP-dependent RNA helicases. This interaction is not described in RegulonDB, even as a computational prediction. IHF may also regulate RNA modification processes.

Binding Sites↗

PubMed1994

Development of anti-idiotypic antibodies to HLA antigens during pregnancy.

Thirty one pregnant women whose sera were initially positive for anti HLA antibodies were retested for lymphocytotoxicity 7-9 months after delivery. In the second testing 10 women were found to have lost the cytotoxic antibodies. These sera were tested for presence of anti-idiotypic antibodies by complement dependent cytotoxicity (CDC). In all ten sera tested, CDC blocking antibody was detected by inhibition technique at different dilutions. These antibodies directed specifically against the HLA antigen of the spouse. This CDC blocking factor could be the anti-idiotypic antibody (Ab2) directed against the cytotoxic anti-HLA antibody (Ab1). In one woman who conceived a second time, repeat sample obtained at the 7th month of the second pregnancy showed reappearance of the specific anti-HLA antibody. This may suggest that the Ab1-Ab2 network is under dynamic regulation.

Antibodies, Anti-Idiotypic↗

PubMed1998

Interactions of erythropoietin, granulocyte colony-stimulating factor, stem cell factor, and interleukin-11 on murine hematopoiesis during simultaneous administration.

We investigated how in vivo effects of single hematopoietic cytokines change if given in combination for a prolonged time. Mice were treated with every combination of recombinant human (rh) erythropoietin (EPO), rh granulocyte colony-stimulating factor (G-CSF), recombinant rat (rr) stem cell factor (SCF), and rh interleukin (IL)-11 by continuous infusion over 7 days (full factorial design with three dose levels for each cytokine). Burst-forming unit-erythroid (BFU-E), colony-forming unit-erythroid (CFU-E), and colony-forming unit-granulocyte-macrophage (CFU-GM) were determined in bone marrow and spleen, reticulocytes, hematocrit, granulocytes, and thrombocytes in the peripheral blood. An analysis of variance (ANOVA) and multiple comparison of means was used to evaluate the data. For several cell types, cytokine effects superimposed in an additive way if combined. However, in a large number of circumstances, nonadditive pairwise interactions were found. They differed in type and magnitude involving high-dose saturation, high-dose antagonistic effects, and even effect reversals (qualitative interactions). Hence, in general, it was not possible to foresee the combination effects on the basis of existing knowledge of single effects. On the other hand, the cytokine network was robust and no system hazards were observed under multiple cytokine combinations. The results illustrate that the cytokine network has nonlinear dynamic properties in vivo with dose-response characteristics of one cytokine being continuously modified by other cytokines.

Animals↗

PubMed1998

Natural organic compounds that affect to microtubule functions.

Microtubules (MT), composed of a protein tubulin (TN) alpha,beta-heterodimer with concomitant other proteins, microtubule associated proteins (MAPs and tau), are known to be the main component of spindles in a mitotic apparatus of eucaryotic cells, and are also involved in many other basic and essential cell functions. There are a number of natural and synthetic compounds that interfere with MT function to cause the mitotic arrest of eucaryotic cells. Such antimitotic agents show a broad biological activity, and can be used for medicinal and agrochemical purposes. On the other hand, they are also important as the biochemical tools for understanding the dynamics of MT network. Most of such antimitotic agents, with a few exceptions, bind to beta-TN. Among them, colchicine (CLC), vinblastine (VLB) and taxol have been of major importance in biochemical studies of MT and in studies of their intracellular functions. The former two both inhibit MT assembly but their binding sites on beta-TN are different; CLC-site and VLB-site, and many MT inhibitors bind to either sites. Taxol bind to TN at a site other than CLC-site and VLB-site, and promote MT assembly. We have worked on a variety of antimitotic agents that bind to CLC, VLB or taxol-site, in discoveries, structures, biological actions and/or interactions with TN. In this paper, I summarized the results of our studies on VLB-site ligands; (1) rhizoxin (RZX), isolated as a phytotoxin produced by a plant pathogenic fungus, and its related compounds, (2) derivatives of ansamitocin P-3 (ASMP3) (maytansinoid: MAY), isolated as a cytotoxic metabolite of an Actinomycete, (3) phomopsin A (PMSA), isolated as a mycotoxin produced by a plant parasitic fungus, (4) dolastatin 10 (DLS10), isolated as a cytotoxic metabolite of a see animal, (5) ustiloxins (USL) A-F, isolated as a mycotoxin produced by a plant pathogenic fungus, (6) arenastation A (ARSA), isolated as a cytotoxic metabolite of a sponge, and its synthetic analogs. From our studies on interactions of these VLB-site ligands with TN, we showed that the presence of a distinct RZX/MAY-binding site which only partially overlap with VLB-site, and that PMSA, DLS10, USLs and ARSA bind to the RZX/MAY site. RZX, ASMP3 and ARSA inhibit the growth of a variety of fungi, including Aspergillus nidulans. In order to obtain information as to the drug-TN interaction at the RZX/MAY site, RZX-resistant beta-TN gene mutants were isolated from RZX-sensitive wild-type A. nidulans. In all the beta-TN gene mutants, single amino acid (100th) alteration, asparagine-to-isoleucine, was observed. Sequence displacement experiments confirmed that this alteration conferred resistance to RZX and ASMP3, and also to ARSA. This resistance mechanism was further verified with yeasts Schizosaccharomyces pombe and Saccharomyces serevisiae. All the natural ligands mentioned above show potent cytotoxicity against human and murine tumor cells, but VLB, PMSA, DLS10 and USLA are inactive to both RZX-sensitive and -resistant fungal strains.

Animals↗

PubMed1999

Analytical description of the evolution of neural networks: learning rules and complexity.

We present the foundation of a physical formalism that allows us to characterize the dynamics of the evolution of neural networks both in regard to the network configuration and to network performance. Model runs were performed on a simple network consisting of six neurons, allowing complete analytical description of the network's behaviour. Order parameters are characterized that allow an analytical description of critical periods in network evolution. Thus, correlations of the local dynamics and the system's global behaviour could be computed. It is shown that local learning rules are sufficient to model complex dynamical aspects of the evolution of networks. It is demonstrated in how far novel statistical formalisms, e.g. neural complexity, can be employed to evaluate the system's dynamics. The introduction of order parameters allows an analytical characterization of transient phases in the network's behaviour, correlating network connectivity with neuronal firing patterns. The relevance of this approach for the interpretation of physiological data is discussed.

Animals↗

PubMed2004

Phase transitions for rock-scissors-paper game on different networks.

Monte Carlo simulations and dynamical mean-field approximations are performed to study the phase transitions in the rock-scissors-paper game on different host networks. These graphs are originated from lattices by introducing quenched and annealed randomness simultaneously. In the resulting phase diagrams three different stationary states are identified for all structures. The comparison of results on different networks suggests that the value of the clustering coefficient plays an irrelevant role in the emergence of a global oscillating phase. The critical behavior of phase transitions seems to be universal and can be described by the same exponents.

Journal Article↗

PubMed2006

Manganese suppresses ATP-dependent intercellular calcium waves in astrocyte networks through alteration of mitochondrial and endoplasmic reticulum calcium dynamics.

The neurotoxicity of manganese [Mn] is due in part to glutamate excitotoxicity. Release of ATP by astrocytes is a critical modulator of glutamatergic neurotransmission, which is regulated by calcium (Ca(2+)) waves that propagate through astrocytic networks in response to synaptic activity. It was postulated that Mn alters ATP-dependent intracellular Ca(2+) dynamics in astrocytes, thereby suppressing Ca(2+) wave activity. Confluent primary cultures of cortical astrocytes were loaded with the Ca(2+)-sensitive dye fluo-4 and examined by fluorescence microscopy for Ca(2+) wave activity following micropipet mechanical stimulation of a single cell. Mitochondrial Ca(2+) was evaluated by fluorescence microscopy following addition of ATP using the mitochondrial-specific Ca(2+) dye rhod-2-AM. Imaging studies revealed that pretreatment of astrocytes with 1-10 microM Mn significantly reduced the rate, area, and amplitude of mechanically induced Ca(2+) waves. This attenuation was not a result of inhibited mitochondrial calcium uptake because robust calcium waves were still observed following pretreatment of astrocytes with Ru360, an inhibitor of mitochondrial Ca(2+) uptake, either in coupling or uncoupling conditions. However, determination of endoplasmic reticulum (ER) Ca(2+) levels in cells using the sarco/endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin indicated that Mn reduced the available pool of releasable ER Ca(2+) at concentrations as low as 1 muM. Examination of ATP-stimulated changes in mitochondrial Ca(2+) indicated that, in cells pretreated with Mn, mitochondria retained high levels of Ca(2+). It is concluded that exposure of astrocytes to low concentrations of Mn(2+) results in sequestration of Ca(2+) within the mitochondria that reduces the available pool of releasable Ca(2+) within the ER, thereby inhibiting calcium wave activity.

Adenosine Triphosphate↗

PubMed2002

Short-term dynamics of synaptic transmission within the excitatory neuronal network of rat layer 4 barrel cortex.

The short-term plasticity of synaptic transmission between excitatory neurons within a barrel of layer 4 rat somatosensory neocortex was investigated. Action potentials in presynaptic neurons at frequencies ranging from 1 to 100 Hz evoked depressing postsynaptic excitatory postsynaptic potentials (EPSPs). Recovery from synaptic depression followed an exponential time course with best-fit parameters that differed greatly between individual synaptic connections. The average maximal short-term depression was close to 0.5 with a recovery time constant of around 500 ms. Analysis of each individual sweep showed that there was a correlation between the amplitude of the response to the first and second action potentials such that large first EPSPs were followed by smaller than average second EPSPs and vice versa. Short-term depression between excitatory layer 4 neurons can thus be termed use dependent. A simple model describing use-dependent short-term plasticity was able to closely simulate the experimentally observed dynamic behavior of these synapses for regular spike trains. More complex irregular trains of 10 action potentials occurring within 500 ms were initially well described, but during the train errors increased. Thus for short periods of time the dynamic behavior of these synapses can be predicted accurately. In conjunction with data describing the connectivity, this forms a first step toward computational modeling of the excitatory neuronal network of layer 4 barrel cortex. Simulation of whisking-evoked activity suggests that short-term depression may provide a mechanism for enhancing the detection of objects within the whisker space.

Action Potentials↗

PubMed2003

[Predict SARS infection with the small world network model].

We report of our numerical simulation of SARS infection dynamics with the small world network model. The negative feedback mechanism and the effect of information flow are added in the model. The simulation fits well with the observed data. The main results of our simulation are that the feedback mechanism can effectively slow down the SARS infecting rate, but it may cause sustained oscillations in number of infection cases. Moreover, keeping the transparency of information is a key factor to resist SARS in the society.

Computer Simulation↗

PubMed2006

UMMS: constrained harmonic and anharmonic analyses of macromolecules based on elastic network models.

UMass Morph Server (UMMS) has been developed for the broad impact on the study of molecular dynamics (MD). The elastic network model (ENM) of a given macromolecule has been proven as a useful tool for analyzing thermal behaviors locally and predicting folding pathways globally. UMMS utilizes coarse-grained ENMs at various levels. These simplifications remarkably save computation time compared with all-atom MD simulations so that one can bring down massive computational problems from a supercomputer to a PC. To improve computational efficiency and physical reality of ENMs, the symmetry-constrained, rigid-cluster, hybrid and chemical-bond ENMs have been developed and implemented at UMMS. One can request both harmonic normal mode analysis of a single macromolecule and anharmonic pathway generation between two conformations of a same molecule using elastic network interpolation at http://biomechanics.ecs.umass.edu/umms.html.

Computational Biology↗

PubMed2026

Urban stormwater infrastructure as a microplastic superhighway: a critical review of transport dynamics, modelling, and mitigation across pavements and drainage networks.

This review examines the transport, fate, modelling, and mitigation of Microplastics (MPs) in urban stormwater infrastructure, with emphasis on pavements, runoff pathways, micro-drainage, and macro-drainage systems. Following a systematic review approach, more than 1000 records were screened and approximately 50 core studies were retained when they addressed urban stormwater or drainage-related MP transport with adequate methodological reporting; marine-only studies and biological-effect studies without direct relevance to transport processes were excluded. The evidence shows that stormwater systems function not merely as passive conduits but as dynamic reactive transport systems with temporary storage, where particle mobilisation, sedimentation, resuspension, and temporary retention regulate MP export. Road surfaces, especially high-traffic areas, are major reservoirs of tyre wear, road-marking, atmospheric, and litter-derived particles that are rapidly mobilised during rainfall. Conventional grab sampling may underestimate MP loads, which in some cases exceed treated wastewater effluent loads by up to six-fold. Drainage structures such as manholes can immobilise up to 17.3% of near-neutrally buoyant particles, while biofouling and aggregation may shift buoyant polymers from wash-load to bedload. Mitigation systems, including permeable pavements, bioretention, wetlands, and technical inserts, can achieve high removal of coarse MPs, but performance declines for fine particles below 100 µm. The review highlights the need for standardised flow-proportional sampling, physically informed modelling, and treatment-train strategies targeting both surface sources and in-network storage.

Microplastics↗

PubMed1996

Chaos and synchrony in a model of a hypercolumn in visual cortex.

Neurons in cortical slices emit spikes or bursts of spikes regularly in response to a suprathreshold current injection. This behavior is in marked contrast to the behavior of cortical neurons in vivo, whose response to electrical or sensory input displays a strong degree of irregularity. Correlation measurements show a significant degree of synchrony in the temporal fluctuations of neuronal activities in cortex. We explore the hypothesis that these phenomena are the result of the synchronized chaos generated by the deterministic dynamics of local cortical networks. A model of a "hypercolumn" in the visual cortex is studied. It consists of two populations of neurons, one inhibitory and one excitatory. The dynamics of the neurons is based on a Hodgkin-Huxley type model of excitable voltage-clamped cells with several cellular and synaptic conductances. A slow potassium current is included in the dynamics of the excitatory population to reproduce the observed adaptation of the spike trains emitted by these neurons. The pattern of connectivity has a spatial structure which is correlated with the internal organization of hypercolumns in orientation columns. Numerical simulations of the model show that in an appropriate parameter range, the network settles in a synchronous chaotic state, characterized by a strong temporal variability of the neural activity which is correlated across the hypercolumn. Strong inhibitory feedback is essential for the stabilization of this state. These results show that the cooperative dynamics of large neuronal networks are capable of generating variability and synchrony similar to those observed in cortex. Auto-correlation and cross-correlation functions of neuronal spike trains are computed, and their temporal and spatial features are analyzed. In other parameter regimes, the network exhibits two additional states: synchronized oscillations and an asynchronous state. We use our model to study cortical mechanisms for orientation selectivity. It is shown that in a suitable parameter regime, when the input is not oriented, the network has a continuum of states, each representing an inhomogeneous population activity which is peaked at one of the orientation columns. As a result, when a weakly oriented input stimulates the network, it yields a sharp orientation tuning. The properties of the network in this regime, including the appearance of virtual rotations and broad stimulus-dependent cross-correlations, are investigated. The results agree with the predictions of the mean field theory which was previously derived for a simplified model of stochastic, two-state neurons. The relation between the results of the model and experiments in visual cortex are discussed.

Models, Neurological↗

PubMed2003

Visualization of TGN to endosome trafficking through fluorescently labeled MPR and AP-1 in living cells.

We have stably expressed in HeLa cells a chimeric protein made of the green fluorescent protein (GFP) fused to the transmembrane and cytoplasmic domains of the mannose 6-phosphate/insulin like growth factor II receptor in order to study its dynamics in living cells. At steady state, the bulk of this chimeric protein (GFP-CI-MPR) localizes to the trans-Golgi network (TGN), but significant amounts are also detected in peripheral, tubulo-vesicular structures and early endosomes as well as at the plasma membrane. Time-lapse videomicroscopy shows that the GFP-CI-MPR is ubiquitously detected in tubular elements that detach from the TGN and move toward the cell periphery, sometimes breaking into smaller tubular fragments. The formation of the TGN-derived tubules is temperature dependent, requires the presence of intact microtubule and actin networks, and is regulated by the ARF-1 GTPase. The TGN-derived tubules fuse with peripheral, tubulo-vesicular structures also containing the GFP-CI-MPR. These structures are highly dynamic, fusing with each other as well as with early endosomes. Time-lapse videomicroscopy performed on HeLa cells coexpressing the CFP-CI-MPR and the AP-1 complex whose gamma-subunit was fused to YFP shows that AP-1 is present not only on the TGN and peripheral CFP-CI-MPR containing structures but also on TGN-derived tubules containing the CFP-CI-MPR. The data support the notion that tubular elements can mediate MPR transport from the TGN to a peripheral, tubulo-vesicular network dynamically connected with the endocytic pathway and that the AP-1 coat may facilitate MPR sorting in the TGN and endosomes.

Adaptor Protein Complex 1↗

PubMed1997

Traveling waves and the processing of weakly tuned inputs in a cortical network module.

Recent studies have shown that local cortical feedback can have an important effect on the response of neurons in primary visual cortex to the orientation of visual stimuli. In this work, we study the role of the cortical feedback in shaping the spatiotemporal patterns of activity in cortex. Two questions are addressed: one, what are the limitations on the ability of cortical neurons to lock their activity to rotating oriented stimuli within a single receptive field? Two, can the local architecture of visual cortex lead to the generation of spontaneous traveling pulses of activity? We study these issues analytically by a population-dynamic model of a hypercolumn in visual cortex. The order parameter that describes the macroscopic behavior of the network is the time-dependent population vector of the network. We first study the network dynamics under the influence of a weakly tuned input that slowly rotates within the receptive field. We show that if the cortical interactions have strong spatial modulation, the network generates a sharply tuned activity profile that propagates across the hypercolumn in a path that is completely locked to the stimulus rotation. The resultant rotating population vector maintains a constant angular lag relative to the stimulus, the magnitude of which grows with the stimulus rotation frequency. Beyond a critical frequency the population vector does not lock to the stimulus but executes a queasi-periodic motion with an average frequency that is smaller than that of the stimulus. In the second part we consider the stable intrinsic state of the cortex under the influence of isotropic stimulation. We show that if the local inhibitory feedback is sufficiently strong, the network does not settle into a stationary state but develops spontaneous traveling pulses of activity. Unlike recent models of wave propagation in cortical networks, the connectivity pattern in our model is spatially symmetric, hence the direction of propagation of these waves is arbitrary. The interaction of these waves with an external-oriented stimulus is studied. It is shown that the system can lock to a weakly tuned rotating stimulus if the stimulus frequency is close to the frequency of the intrinsic wave.

Animals↗