Biomedical subjects

Masato Okada

Publications and source records attributed to Masato Okada.

At least 37 records · Page 2Linked to original sources

PubMed2005

Potentiation of the ligand-binding activity of integrin alpha3beta1 via association with tetraspanin CD151.

CD151, one of the tetraspanins, forms a stable complex with integrin alpha3beta1, the major laminin receptor on the cell surface. We found that 8C3, an anti-CD151 mAb obtained by screening for reactivity with integrin alpha3beta1-CD151 complexes, was capable of dissociating CD151 from integrin alpha3beta1, thereby allowing us to deplete CD151 from purified integrin alpha3beta1-CD151 complexes. The CD151-free integrin alpha3beta1 thus obtained showed a significant reduction in its ability to bind to laminin-10/11, a high-affinity ligand for integrin alpha3beta1, with a concomitant reduction in its reactivity with mAb AG89, which recognizes activated beta1-containing integrins. These results raised the possibility that the association of integrin alpha3beta1 with CD151 potentiates the ligand-binding activity of the integrin through sustaining its activated conformation. In support of this possibility, the ligand-binding activity was restored when CD151-free integrin alpha3beta1 was reassociated with purified CD151. 8C3-induced dissociation of CD151 from integrin alpha3beta1 was also demonstrated on the surface of living cells by fluorescent resonance energy transfer imaging, accompanied by a concomitant reduction in the cell adhesion to laminin-10/11-coated substrates. CD151 knock-down by RNA interference also resulted in a reduction in the adhesive activity of the cells. Taken together, these results indicate that CD151 association modulates the ligand-binding activity of integrin alpha3beta1 through stabilizing its activated conformation not only with purified proteins but also in a physiological context.

Animals↗

PubMed2005

Role of Src family tyrosine kinases in the down-regulation of epidermal growth factor signaling in PC12 cells.

Src family tyrosine kinases (SFKs) play pivotal roles as molecular switches for various intracellular signaling pathways. SFKs have been implicated in epidermal growth factor (EGF) signaling, although their precise mechanisms of action in this pathway remain elusive. To address this issue, we focused on a membrane microdomain, lipid rafts, where SFKs are enriched. In PC12 cells, the EGF receptor (EGFR) is constitutively concentrated in lipid rafts, and further accumulation takes place upon EGF stimulation, followed by activation of SFKs, especially Src and Yes. Inhibition of SFK or disruption of lipid raft function causes EGF-induced neurite extension of PC12 cells. These effects are accompanied by an extended duration of Erk1/2 activation and are suppressed by a MEK inhibitor. In Csk(-/-) fibroblasts, suppression of SFK results in prolonged EGF-induced activation of Erk1/2, with concomitant suppression of EGFR degradation. Furthermore, analysis of the behavior of labeled EGF in PC12 cells reveals that suppression of SFK activity attenuates the rate of clustering of activated EGFR on the membrane. These results suggest that SFK activity in lipid rafts is required to facilitate the down-regulation of EGF signaling, by regulating the clustering of activated EGFR on the membrane in PC12 cells.

Animals↗

PubMed2005

The ubiquitously expressed Csk adaptor protein Cbp is dispensable for embryogenesis and T-cell development and function.

Regulation of Src family kinase (SFK) activity is indispensable for a functional immune system and embryogenesis. The activity of SFKs is inhibited by the presence of the carboxy-terminal Src kinase (Csk) at the cell membrane. Thus, recruitment of cytosolic Csk to the membrane-associated SFKs is crucial for its regulatory function. Previous studies utilizing in vitro and transgenic models suggested that the Csk-binding protein (Cbp), also known as phosphoprotein associated with glycosphingolipid microdomains (PAG), is the membrane adaptor for Csk. However, loss-of-function genetic evidence to support this notion was lacking. Herein, we demonstrate that the targeted disruption of the cbp gene in mice has no effect on embryogenesis, thymic development, or T-cell functions in vivo. Moreover, recruitment of Csk to the specialized membrane compartment of "lipid rafts" is not impaired by Cbp deficiency. Our results indicate that Cbp is dispensable for the recruitment of Csk to the membrane and that another Csk adaptor, yet to be discovered, compensates for the loss of Cbp.

Adaptor Protein Complex Subunits↗

PubMed2005

Correlated firing in a feedforward network with Mexican-hat-type connectivity.

We report on deterministic and stochastic evolutions of firing states through a feedforward neural network with Mexican-hat-type connectivity. The prevalence of columnar structures in a cortex implies spatially localized connectivity between neural pools. Although feedforward neural network models with homogeneous connectivity have been intensively studied within the context of the synfire chain, the effect of local connectivity has not yet been studied so thoroughly. When a neuron fires independently, the dynamics of macroscopic state variables (a firing rate and spatial eccentricity of a firing pattern) is deterministic from the law of large numbers. Possible stable firing states, which are derived from deterministic evolution equations, are uniform, localized, and nonfiring. The multistability of these three states is obtained where the excitatory and inhibitory interactions among neurons are balanced. When the presynapse-dependent variance in connection efficacies is incorporated into the network, the variance generates common noise. Then the evolution of the macroscopic state variables becomes stochastic, and neurons begin to fire in a correlated manner due to the common noise. The correlation structure that is generated by common noise exhibits a nontrivial bimodal distribution. The development of a firing state through neural layers does not converge to a certain fixed point but keeps on fluctuating.

Artifacts↗

PubMed2005

New device for endoscopic image display during microsurgical clipping of cerebral aneurysms--technical note--.

Endoscopy in microsurgery is most effective when a single surgeon can monitor both endoscopic and microscopic images simultaneously. However, monitoring systems of this kind, such as a contemporary microscope equipped with a picture-in-mode function, are expensive. The present display system is connected to the endoscope video camera and mounted on the surgeon's head. The liquid crystal display is positioned just under the microscope eyepieces, so reducing the need for the surgeon to refocus and redirect the gaze during surgery. This system allows nearly simultaneous endoscopic and microscopic monitoring. No changes to the surgical microscope are necessary.

Angioscopy↗

PubMed2004

Population dynamics of face-responsive neurons in the inferior temporal cortex.

Neurons in the inferior temporal (IT) cortex of monkeys respond selectively to complex visual stimuli, such as faces. Single neurons in the IT cortex encode different kinds of information about visual stimuli in their temporal firing patterns. To understand the temporal aspects of the information encoded at a population level in the IT cortex, we applied principal component analysis (PCA) to the responses of a population of neurons. The responses of each neuron were recorded while visual stimuli that consisted of geometric shapes and faces of humans and monkeys were presented. We found that global categorization, i.e. human faces versus monkey faces versus shapes, occurred in the earlier part of the population response, and that fine categorization occurred within each member of the global category in the later part of the population response. A cluster analysis, a mixture of Gaussians analysis, confirmed that the clusters in the earlier part of the responses represented the global category. Moreover, the clusters in the earlier part separated into sub-clusters corresponding to either human identity or monkey expression in the later part of the responses, and the global categorization was maintained even after the appearance of the sub-clusters. The results suggest that a hierarchical relationship of the test stimuli is represented temporally by the population response of IT neurons.

Animals↗

PubMed2004

Bifurcation analysis in an associative memory model.

We previously reported the chaos induced by the frustration of interaction in a nonmonotonic sequential associative memory model, and showed the chaotic behaviors at absolute zero. We have now analyzed bifurcation in a stochastic system, namely, a finite-temperature model of the nonmonotonic sequential associative memory model. We derived order-parameter equations from the stochastic microscopic equations. Two-parameter bifurcation diagrams obtained from those equations show the coexistence of attractors, which do not appear at absolute zero, and the disappearance of chaos due to the temperature effect.

Journal Article↗

PubMed2004

Pulse-coupled resonate-and-fire models.

We analyze two pulse-coupled resonate-and-fire neurons. Numerical simulation reveals that an antiphase state is an attractor of this model. We can analytically explain the stability of antiphase states by means of a return map of firing times, which we propose in this paper. The resultant stability condition turns out to be quite simple. The phase diagram based on our theory shows that there are two types of antiphase states. One of these cannot be seen in coupled integrate-and-fire models and is peculiar to resonate-and-fire models. The results of our theory coincide with those of numerical simulations.

Action Potentials↗

PubMed2004

Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG.

Nectins, Ca2+ -independent immunoglobulin-like cell-cell adhesion molecules, initiate cell-cell adhesion by their trans interactions and recruit cadherins to cooperatively form adherens junctions (AJs). In addition, the trans interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which increases the velocity of the formation of AJs. We examined here how nectins induce the activation of Cdc42 in MDCK epithelial cells and L fibroblasts. Nectins recruited and activated c-Src at the nectin-based cell-cell adhesion sites. FRG, a GDP/GTP exchange factor specific for Cdc42, was then recruited there, tyrosine phosphorylated by c-Src, and activated, causing an increase in the GTP-bound active form of Cdc42. Inhibition of the nectin-induced activation of c-Src suppressed the nectin-induced activation of FRG and Cdc42. Inhibition of the nectin-induced activation of FRG or depletion of FRG by RNA interference suppressed the nectin-induced activation of Cdc42. These results indicate that nectins induce the activation of Cdc42 through c-Src and FRG locally at the nectin-based cell-cell adhesion sites.

Animals↗

PubMed2004

Dynamics of the adaptive natural gradient descent method for soft committee machines.

Adaptive natural gradient descent (ANGD) method realizes natural gradient descent (NGD) without needing to know the input distribution of learning data and reduces the calculation cost from a cubic order to a square order. However, no performance analysis of ANGD has been done. We have developed a statistical-mechanical theory of the simplified version of ANGD dynamics for soft committee machines in on-line learning; this method provides deterministic learning dynamics expressed through a few order parameters, even though ANGD intrinsically holds a large approximated Fisher information matrix. Numerical results obtained using this theory were consistent with those of a simulation, with respect not only to the learning curve but also to the learning failure. Utilizing this method, we numerically evaluated ANGD efficiency and found that ANGD generally performs as well as NGD. We also revealed the key condition affecting the learning plateau in ANGD.

Journal Article↗

PubMed2004

Coexistence of memory patterns and mixed states in a sparsely encoded associative memory model storing ultrametric patterns.

Analyzing the coexistence of memory patterns and mixed states gives important information for constructing a model for the face responsive neurons of the monkey inferior-temporal cortex. We analyzed whether the memory patterns coexist with mixed states when the sparse coding scheme is used for the associative memory model storing ultrametric patterns. For memory patterns and mixed states to coexist, there must be sufficient capacity for storing them and their threshold values must be the same. We determined that the storage capacities for all mixed states composed of correlated memory patterns diverge as 1/| f log f| (where f is the firing rate) even when the correlation of the memory patterns is infinitesimally small. We also determined that the memory patterns and the mixed states can become the equilibrium state of the model in the same threshold value. These results mean that they can coexist in this model. These findings should contribute to research on face responsive neurons in the monkey inferior-temporal cortex.

Action Potentials↗

PubMed2004

Csk defines the ability of integrin-mediated cell adhesion and migration in human colon cancer cells: implication for a potential role in cancer metastasis.

Progression of human colon cancer is often associated with elevated expression and activity of the Src family tyrosine kinase (SFK). SFK is ordinarily in equilibrium between inactive and primed states by a balance of negative regulatory kinase Csk and its counteracting tyrosine phosphatase(s), both of which act on the regulatory C-terminal tyrosine of SFK. To evaluate the contribution of the regulatory system of SFK in cancer progression, we here modulated the equilibrium status of SFK by introducing wild-type or dominant-negative Csk in human epithelial colon cancer cells, HCT15 and HT29. Overexpression of wild-type Csk induced decreased SFK activation, increased cell-cell contacts mediated by E-cadherin, decreased the number of focal contacts and decreased cell adhesion/migration and in vitro invasiveness. Conversely, expression of a dominant-negative Csk resulted in elevated SFK activation, enhanced phosphorylation of FAK and paxilllin, enhanced cell scattering, an increased number of focal contacts, dramatic rearrangement of actin cytoskeleton and increased cell adhesion/migration and in vitro invasiveness. In these scattered cells, however, localization, expression and phosphorylation of either E-cadherin or beta-catenin were not significantly affected, suggesting that the E-cadherin-mediated cell-cell contact is indirectly regulated by SFK. Furthermore, all these events occurred absolutely dependent on integrin-mediated cell adhesion. These findings demonstrate that Csk defines the ability of integrin-SFK-mediated cell adhesion signaling that influences the metastatic potential of cancer cells.

Actins↗

PubMed2004

On-line learning through simple perceptron learning with a margin.

We analyze a learning method that uses a margin kappa a la Gardner for simple perceptron learning. This method corresponds to the perceptron learning when kappa = 0 and to the Hebbian learning when kappa = infinity. Nevertheless, we found that the generalization ability of the method was superior to that of the perceptron and the Hebbian methods at an early stage of learning. We analyzed the asymptotic property of the learning curve of this method through computer simulation and found that it was the same as for perceptron learning. We also investigated an adaptive margin control method.

Learning↗

PubMed2004

Impact of deviation from precise balance of spike-timing-dependent plasticity.

Recent biological experimental findings have shown that synaptic plasticity depends on the relative timing of pre- and post-synaptic spikes and this is called spike-timing-dependent plasticity (STDP). Many authors have claimed that a precise balance between long-term potentiation (LTP) and long-term depression (LTD) of STDP is crucial in the storage of spatio-temporal patterns. Some authors have numerically investigated the impact of an imbalance between LTP and LTD on the network properties. However, the mathematical mechanism remains unknown. We analytically show that an associative memory network has the robust retrieval properties of spatio-temporal patterns, and these properties make the network less vulnerable to any deviation from a precise balance between LTP and LTD when the network contains a finite number of neurons.

Action Potentials↗

PubMed2004

Mixed states on neural network with structural learning.

We investigated the properties of mixed states in a sparsely encoded associative memory model with a structural learning method. When mixed states are made of s memory patterns, s types of mixed states, which become equilibrium states of the model, can be generated. To investigate the properties of s types of the mixed states, we analyzed them using the statistical mechanical method. We found that the storage capacity of the memory pattern and the storage capacity of only a particular mixed state diverge at the sparse limit. We also found that the threshold value needed to recall the memory pattern is nearly equal to the threshold value needed to recall the particular mixed state. This means that the memory pattern and the particular mixed state can be made to easily coexist at the sparse limit. The properties of the model obtained by the analysis are also useful for constructing a transform-invariant recognition model.

Algorithms↗

PubMed2004

Associative memory by recurrent neural networks with delay elements.

The synapses of real neural systems seem to have delays. Therefore, it is worthwhile to analyze associative memory models with delayed synapses. Thus, a sequential associative memory model with delayed synapses is discussed, where a discrete synchronous updating rule and a correlation learning rule are employed. Its dynamic properties are analyzed by the statistical neurodynamics. In this paper, we first re-derive the Yanai-Kim theory, which involves macrodynamical equations for the dynamics of the network with serial delay elements. Since their theory needs a computational complexity of O(L4t) to obtain the macroscopic state at time step t where L is the length of delay, it is intractable to discuss the macroscopic properties for a large L limit. Thus, we derive steady state equations using the discrete Fourier transformation, where the computational complexity does not formally depend on L. We show that the storage capacity alphaC is in proportion to the delay length L with a large L limit, and the proportion constant is 0.195, i.e. alphaC=0.195L. These results are supported by computer simulations.

Association Learning↗

PubMed2004

Storage capacity diverges with synaptic efficiency in an associative memory model with synaptic delay and pruning.

It is known that storage capacity per synapse increases by synaptic pruning in the case of a correlation-type associative memory model. However, the storage capacity of the entire network then decreases. To overcome this difficulty, we propose decreasing the connectivity while keeping the total number of synapses constant by introducing delayed synapses. In this paper, a discrete synchronous-type model with both delayed synapses and their prunings is discussed as a concrete example of the proposal. First, we explain the Yanai-Kim theory by employing statistical neurodynamics. This theory involves macrodynamical equations for the dynamics of a network with serial delay elements. Next, considering the translational symmetry of the explained equations, we rederive macroscopic steady-state equations of the model by using the discrete Fourier transformation. The storage capacities are analyzed quantitatively. Furthermore, two types of synaptic prunings are treated analytically: random pruning and systematic pruning. As a result, it becomes clear that in both prunings, the storage capacity increases as the length of delay increases and the connectivity of the synapses decreases when the total number of synapses is constant. Moreover, an interesting fact becomes clear: the storage capacity asymptotically approaches 2/pi due to random pruning. In contrast, the storage capacity diverges in proportion to the logarithm of the length of delay by systematic pruning and the proportion constant is 4/pi. These results theoretically support the significance of pruning following an overgrowth of synapses in the brain and may suggest that the brain prefers to store dynamic attractors such as sequences and limit cycles rather than equilibrium states.

Action Potentials↗

PubMed2004

DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites.

We have identified and characterized a novel member of the G protein-coupled receptor (GPCR) family, termed DREG. DREG belongs to the LNB-TM7 subfamily and possesses a long amino-terminus that contains a CUB domain, a PTX domain, a hormone binding domain and a GPCR proteolytic site (GPS) domain. RT-PCR experiments and whole mount in situ hybridization in mice showed that DREG is expressed at high levels in the heart and somite during embryogenesis and in the adult lung. When DREG was transiently expressed in mammalian cultured cells, a 35-kD fragment was generated by endogenous proteolytic processing at the conserved GPS domain. This short fragment was found associated with the cell membrane, typical of GPCRs. DREG was further cleaved in the middle of the extracellular domain, generating a soluble 70-kD fragment containing the CUB and PTX domains. This processing was inhibited by an inhibitor of the endoprotease furin but not of matrix metalloproteinases. These results raise the possibility that DREG plays a role in development, not only as a receptor or an adhesion molecule but also as a secreted ligand.

Alternative Splicing↗