Nobuhiko Asakura

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser⁸⁹⁷, whereas the EpCAM+ cells exhibited higher abundance of ERK, RSK and its phosphorylated form. This demonstrates that pro-oncogenic, ligand-independent EphA2 signaling plays a dominant role in CD90+ cells with higher motility and metastatic activity than EpCAM+ cells. We also showed that an AKT inhibitor reduced the proliferation and survival of CD90+ cells but did not affect those of EpCAM+ cells. Taken together, our results suggest that AKT activation may be a key pro-oncogenic regulator in HCC.

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Stuttering is a fluency disorder, partially alleviated during altered auditory feedback, suggesting abnormal sensorimotor integration in adults who stutter (AWS). As weighting of multiple integrating-information sources would be decided based on their reliabilities, the use of external (auditory feedback) and internal information (prediction of sensory consequences) could correlate with speech processing. We hypothesized that abnormal auditory-feedback processing in AWS could be related to decrease in internal processing precision. We used a perceptual-adaptation experiment of delayed auditory feedback (DAF) to verify the hypothesis. Seventeen AWS and 17 adults who do not stutter (ANS) were required to say “ah” and judge the simultaneity between their motor sensations and vocal sounds in each stimulus onset asynchrony (SOA) (0, 25, 50, 75, 100, 125, or 150 ms) after inducing adaptation of DAF (three conditions with 0-, 66-, or 133-ms delay). While no adaptation occurred during the 0 ms condition, perceptual change in simultaneity judgment (adaptation effect) occurred during the 66 and 133 ms conditions. The simultaneity judgments following exposure in each SOA were fitted to the psychometric function in each condition for the AWS and ANS groups. We calculated the μ (signifying the point of subjective simultaneity and adaptation-effect degree) and σ (signifying the detecting precision) of each function and analyzed them by parametric analyses. For the μ, participant groups and adaptation conditions showed a significant interaction; the adaptation effect was greater in the AWS than in the ANS group. Additionally, the μ and σ were only positively correlated in the AWS group. The point of subjective simultaneity for auditory delay by inducing DAF was higher in AWS than in ANS, indicating that perception of simultaneity in AWS was influenced by DAF to a greater extent. Moreover, the significant positive correlation between the μ and σ in AWS showed that the more imprecise the internal auditory processing, the more AWS relied on auditory feedback. It is suggested that the reliability of internal information differed within the AWS group, and AWS with reduced internal reliability appeared to compensate by relying to a great extent on auditory feedback information.

Active exploration of views of 3-D objects by manually controlling a device, such as a trackball, facilitates subsequent object recognition, suggesting that motor simulation contributes to object recognition. Further, biomechanical constraints, such as range of hand rotation, can affect mental rotation. Thus, the ease with which an object can be rotated by hand may modulate the facilitative effect active exploration through manual control has on object recognition. In our experiment, participants performed two sessions of a view-matching task, with a learning task administered between the two. In the learning task, one group of participants (active group) viewed and explored a novel 3-D object using their hand to rotate a handle attached to a cathode-ray tube monitor. The other group (passive group) observed on the monitor a replay of the movements of the 3-D object as manipulated by an active-group participant. Active-group participants were interviewed to determine the direction they found easiest to rotate their hand. The view-generalization performances were compared between the pre and post sessions. Although we observed a facilitative effect on the view-matching process in both groups, the active group exhibited view-dependent facilitation. The view-generalization range of the active group in the post-session was asymmetric in terms of the rotation direction. Most intriguingly, for most participants, this asymmetric change corresponded to the direction that afforded the easiest hand rotation (ulnar deviation). These findings suggest that the object-recognition process can be affected by ease of hand rotation, which is based on the biomechanical constraints of the wrist joint.

Two apparently contrasting theories have been proposed to account for the development of children’s theory of mind (ToM): theory-theory and simulation theory. We present a Bayesian framework that rationally integrates both theories for false belief reasoning. This framework exploits two internal models for predicting the belief states of others: one of self and one of others. These internal models are responsible for simulation-based and theory-based reasoning, respectively. The framework further takes into account empirical studies of a developmental ToM scale (e.g., Wellman & Liu, 2004): developmental progressions of various mental state understandings leading up to false belief understanding. By representing the internal models and their interactions as a causal Bayesian network, we formalize the model of children’s false belief reasoning as probabilistic computations on the Bayesian network. This model probabilistically weighs and combines the two internal models and predicts children’s false belief ability as a multiplicative effect of their early-developed abilities to understand the mental concepts of diverse beliefs and knowledge access. Specifically, the model predicts that children's proportion of correct responses on a false belief task can be closely approximated as the product of their proportions correct on the diverse belief and knowledge access tasks To validate this prediction, we illustrate that our model provides good fits to a variety of ToM scale data for preschool children. We discuss the implications and extensions of our model for a deeper understanding of developmental progressions of children’s ToM abilities.

One of the essential cognitive abilities of the human brain is the ability to recognize 3D objects. However, the exact neural mechanism is still unclear. In this study, a model of the inferior temporal cortex for object recognition is proposed. The architecture of the model is based on the modular network SOM. The model has been trained to perform object recognition and classification tasks that have been reported to occur in the TE area in the brain of macaque monkeys. We show by simulation that the model is not only capable of classifying artificial 3D objects according to their structural similarity, but also capable of achieving view-invariant recognition of the objects by incorporating a mental-rotation type mechanism.

Previous research has shown that our ability to imagine object rotations is limited and associated with spatial reference frames; performance is poor unless the axis of rotation is aligned with the object-intrinsic frame or with the environmental frame. Here, we report an active effect of these reference frames on the process of mental rotation: they can disambiguate object rotations when the axis of rotation is ambiguous. Using novel mental rotation stimuli, in which the rotational axes between pairs of objects can be defined with respect to multiple frames of reference, we demonstrate that the vertical axis is preferentially used for imagined object rotations over the object-intrinsic axis for an efficient minimum rotation. In contrast, the object-intrinsic axis can play a decisive role when the vertical axis is absent as a way of resolving the ambiguity of rotational motion. When interpreted in conjunction with recent advances in the Bayesian framework for motion perception, our results suggest that these spatial frames of reference are incorporated into an internal model of object rotations, thereby shaping our ability to imagine the transformation of an object's spatial structure.

Harman et al (1999, Current Biology9 1315–1318) showed that active exploration of novel objects allows faster recognition of these objects than passive viewing. Here, we examined whether active exploration of particular objects can facilitate subsequent view matching of different objects within the same category. In the generalisation phase, participants performed a matching task between two serially presented views of novel paper-clip objects. When the two views were of the same object, these were related by rotation about the vertical or horizontal axis. Subsequently, in the observation phase, participants were presented with another 5 paper-clip objects. One group of participants (active group) actively explored each of the objects for 20 s using a trackball over a limited range (−45° to +45°) of the horizontal axis. The other participants observed a replay of the active exploration of each of these objects by a participant in the active group (passive group) or observed a static view of the objects (still group). Following this observation phase, the generalisation phase was repeated twice for all groups of participants. The active group showed a clear expansion of the generalisation range about the horizontal axis. However, this expansion disappeared when we replicated the experiment using a smaller range of active exploration (−30° to +30°) and the experiment in which the participants observed a rotating object within the range of −45° to +45°. Furthermore, we found a significant improvement in view generalisation about the vertical axis when participants actively explored objects using a turntable over a range in −45° to +45° of the vertical axis. Most importantly, since participants explored different objects from the ones that were used in the generalisation phase, these results cannot be explained by improvement of the encoding process. The present findings therefore suggest that: (i) active exploration facilitates the process of view matching, (ii) this effect depends on the exploration range and rotational axis, and (iii) interaction between motor and visual information is necessary to facilitate the process of view matching.

Many studies of on-line comprehension of semantic violations have shown that the human sentence processor rapidly constructs a higher-order semantic interpretation of the sentence. What remains unclear, however, is the amount of time required to detect semantic anomalies while concatenating two words to form a phrase with very rapid stimuli presentation. We aimed to examine the time course of semantic integration in concatenating two words in phrase structure building, using magnetoencephalography (MEG). In the MEG experiment, subjects decided whether two words (a classifier and its corresponding noun), presented each for 66 ms, form a semantically correct noun phrase. Half of the stimuli were matched pairs of classifiers and nouns. The other half were mismatched pairs of classifiers and nouns. In the analysis of MEG data, there were three primary peaks found at approximately 25 ms (M1), 170 ms (M2) and 250 ms (M3) after the presentation of the target words. As a result, only the M3 latencies were significantly affected by the stimulus conditions. Thus, the present results indicate that the semantic integration in concatenating two words starts from approximately 250 ms.