Three-Dimensional Position Presentation Via Head and Waist Vibrotactile Arrays.

This paper introduces a novel system designed to convey the three-dimensional positions surrounding the user. The system incorporates circumferential vibrotactile arrays strategically positioned on both the user's head and waist. Through the synergy of this two-dimensional arrangement and modulations in vibration amplitude, the system adeptly presents comprehensive three-dimensional positional information. Two prototypes, namely a spherical model and a cylindrical model, were employed as mappings between three-dimensional positions and vibration amplitudes. In Experiment 1, we evaluated the system's performance in indicating positions in depth, orientation, and height. Notably, discrimination rates for depth (Task 1) and orientation (Task 2) were 60% and 54%, respectively. Regarding height discrimination in the head-to-waist condition (Tasks 3 and 4), the cylindrical model outperformed the spherical model (54% and 52% vs. 32% and 36%). Conversely, in the head-above and waist-below condition (Task 5), the cylindrical model achieved a discrimination rate of 45%, while the spherical model did not. In Experiment 2, we explored the use of the cylindrical model to convey a moving three-dimensional position. The results showed an impressive 81% correct response rate, affirming the system's effectiveness in presenting three-dimensional motion stimuli.

Wearable High-Resolution Haptic Display Using Suction Stimuli to Represent Cutaneous Contact Information on Finger Pad.

A high-resolution haptic display that reproduces tactile distribution information on the contact surface between a finger and an object realizes the presentation of the softness of the object and the magnitude and direction of the applied force. In this article, we developed a 32-channel suction haptic display that can reproduce tactile distribution on fingertips with high resolution. The device is wearable, compact, and lightweight, thanks to the absence of actuators on the finger. A FE analysis of the skin deformation confirmed that the suction stimulus interfered less with adjacent stimuli in the skin than when pressing with positive pressure, thus allowing more precise control of local tactile stimuli. The optimal layout with the least error was selected from three configurations dividing 62 suction holes into 32 ports.The suction pressures were determined by calculating the pressure distribution by a real-time finite element simulation of the contact between the elastic object and the rigid finger. A discrimination experiment of softness with different Young's modulus and its JND investigation suggested that the higher resolution of the suction display improved the performance of the softness presentation compared to a 16-channel suction display previously developed by the authors.

TDS Similarity: Outlier Analysis Using a Similarity Index to Compare Time-Series Responses of Temporal Dominance of Sensations Tasks.

Temporal dominance of sensations (TDS) methods are used to record temporally developing sensations while eating food samples. Results of TDS tasks are typically discussed using averages across multiple trials and panels, and few methods have been developed to analyze differences between individual trials. We defined a similarity index between two time-series responses of TDS tasks. This index adopts a dynamic level to determine the importance of the timing of attribute selection. With a small dynamic level, the index focuses on the duration for attributes to be selected rather than on the timing of the attribute selection. With a large dynamic level, the index focuses on the temporal similarity between two TDS tasks. We performed an outlier analysis based on the developed similarity index using the results of TDS tasks performed in an earlier study. Certain samples were categorized as outliers irrespective of the dynamic level, whereas the categorization of a few samples depended on the level. The similarity index developed in this study achieved individual analyses of TDS tasks, including outlier detection, and adds new analysis techniques to TDS methods.

On the Analysis of Tactile Sensation Based on Time Measurement: An Experimental Case Study on the Interaction Between Skin and Lotion.

This paper presents a novel experimental case study in which tactile sensation is analyzed as 4-dimensional subjective data consisting of stimulus, participant, evaluation term, and temporal components, using a temporal measurement approach. Specifically, the skin and lotion interaction was evaluated using the Temporal Check-All-That-Apply (TCATA) method. Two practical analysis examples were conducted to experimentally demonstrate the potential use cases of time-series subjective tactile data. In the first example, stimulus classification accuracy was compared between different sampling periods, including the whole and late periods, with the latter being akin to the conventional Semantic Differential (SD) method condition. The results indicate that the whole and early periods exhibit higher accuracy compared to the latest period, implying that temporal measurements may capture more stimulus characteristics than the conventional approach. In the second example, cluster analysis based on the time-series subjective data was conducted. The results revealed that the participants were classified into two distinct clusters, with the trends of time-series changes being significantly different between the clusters.

Lactic acid induces HSPA1A expression through ERK1/2 activation.

Heat shock protein (HSP) A1A protects cells from various stressors. The concentrated liquid of the traditional Japanese rice black vinegar Kurozu increased HSPA1A expression in normal rat liver RLN-10 cells. Lactic acid, the primary component of concentrated Kurozu, induced HSPA1A expression in a concentration-dependent manner. Induction with 4 m m lactic acid increased HSPA1A expression by three times compared with that in the absence of lactic acid. The induction was inhibited by staurosporine or a selective MEK1/2 inhibitor (SL327). The phosphorylation of ERK1/2 was increased by lactic acid. These results suggest that lactic acid induces HSPA1A expression by activating ERK1/2. As well as lactate, 3,5-dihydroxybenzoic acid (DHBA), a ligand for G protein-coupled receptor 81 (GPR81), also induced HSPA1A at lower concentrations than lactate. The increased effect of DHBA on HSPA1A expression as compared with lactate may be related to the higher affinity of DHBA for GPR81 than of lactate.

Crystal structure of inhibitor-bound human MSPL that can activate high pathogenic avian influenza.

Infection of certain influenza viruses is triggered when its HA is cleaved by host cell proteases such as proprotein convertases and type II transmembrane serine proteases (TTSP). HA with a monobasic motif is cleaved by trypsin-like proteases, including TMPRSS2 and HAT, whereas the multibasic motif found in high pathogenicity avian influenza HA is cleaved by furin, PC5/6, or MSPL. MSPL belongs to the TMPRSS family and preferentially cleaves [R/K]-K-K-R↓ sequences. Here, we solved the crystal structure of the extracellular region of human MSPL in complex with an irreversible substrate-analog inhibitor. The structure revealed three domains clustered around the C-terminal α-helix of the SPD. The inhibitor structure and its putative model show that the P1-Arg inserts into the S1 pocket, whereas the P2-Lys and P4-Arg interacts with the Asp/Glu-rich 99-loop that is unique to MSPL. Based on the structure of MSPL, we also constructed a homology model of TMPRSS2, which is essential for the activation of the SARS-CoV-2 spike protein and infection. The model may provide the structural insight for the drug development for COVID-19.

Haptic Exploration During Fast Video Playback: Vibrotactile Support for Event Search in Robot Operation Videos.

Fast playback allows quick video exploration, but it also decreases the saliency of short events. We propose a haptic exploration for detection of short events during fast video playback, considering that event-related information in vibrotactile feedback can be preserved during fast playback using Time Scale Modification (TSM) methods developed for audio. We evaluate our proposal in two collision detection experiments using first-person view (FPV) videos. In the first experiment, viewers watched at a fixed playback speed, i.e., 1× or 2×, videos recorded with a camera mounted on a platform cart. In this experiment, event-related vibrations were measured at the back of the camera. In the second experiment, viewers used a media controller to adjust the playback speed in videos simulating an exploration with a mobile robot. In this experiment, event-related vibrations were generated from the measurements used in the first experiment. We show that a haptic exploration improves collision awareness under either constant or adjustable playback speed. In both experiments, the number of collisions reported without vibrotactile feedback deviated the greatest from the actual number of collisions in a video. Moreover, collision detection performance with vibrations time-scaled without Time Scale Modification (TSM) methods was not significantly different from performance without vibrations.

VEGFR-1 Regulates EGF-R to Promote Proliferation in Colon Cancer Cells.

The relationship between epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways in tumor growth is well established. EGF induces VEGF production in cancer cells, and the paracrine VEGF activates vascular endothelial cells to promote tumor angiogenesis and thus supports tumor cell growth in an angiogenesis-dependent manner. In this study, we found angiogenesis-independent novel crosstalk between the VEGF and the EGF pathways in the regulation of colon cancer cell proliferation. Stimulation of colon cancer cells with VEGF-A and placental growth factor (PlGF) activated VEGF receptor-1 (VEGFR-1) and increased proliferation activity in an autocrine EGF/EGF receptor (EGF-R)-dependent manner. Mechanistically, VEGFR-1 interacted with and stabilized EGF-R, leading to increased EGF-R protein levels and prolonged its expression on cell surface plasma membrane. In contrast, VEGFR-1 blockade by a neutralizing antibody and an antagonistic peptide of VEGFR-1 suppressed the complex formation of VEGFR-1 and EGF-R and decreased EGF-R expression via a lysosome-dependent pathway, resulting in the suppression of proliferation activity. Our results indicated that VEGFR-1 regulated EGF-R expression to promote proliferation activity in a cell-autonomous-dependent manner.

Modeling Semantically Multilayered Affective and Psychophysical Responses Toward Tactile Textures.

Subjective responses related to touch are described via perceptual and affective adjectives. Understanding relationships among such responses is useful for industrial surface design. We developed a method for investigating relationships among touch-related responses by constructing multilayered adjective models without assumptions regarding model structure such as adjective hierarchy or a definition of layers. The method consists of two processes through which a model structure and parameters are estimated. To acquire the model structure, subjectively evaluated causal relationships among adjective pairs are used. Free parameters, such as effects among adjectives, are then statistically estimated through sensory evaluation and structural equation modeling. To validate the method, two models with different levels of details were developed using 29 adjective pairs and 46 texture samples. For example, the model with three layers, which we categorized into psychophysical, affective, and hedonic layers, was constructed. Moreover, a detailed model with four layers was provided, which was more complex than previously reported models. The present method helps advance our understanding and design of connections among subjective surface ratings.

Introducing Whole Finger Effects in Surface Haptics: An Extended Stick-Slip Model Incorporating Finger Stiffness.

The kinematic serial chain configuration of a finger modulates the frictional properties during tactile exploration tasks. This paper analyzes and subsequently models the effects of the entire finger during sliding operations on a surface. Qualitative and quantitative study of finger movement patterns with postures, sliding directions, and contact angles first indicate the effect of finger stiffness on contact mechanics. A "stiffness ellipse" is subsequently modeled to incorporate finger pose effects, and then coupled with the lumped mass-spring-damper model of the finger pad to estimate resultant contact forces. The performance of the proposed model is verified by comparing with experimental results obtained from ten subjects. The proposed model could estimate the general tendencies of contact forces with change in postures (Extended and Flexed), sliding directions (proximal and distal), and contact angles (20°, 40° and 60°). The experimental results indicate that finger stiffness significantly modulates the contact forces, stick-slip frequency, preloading duration and initial spike during sliding. Introduction of finger posture effects could explain the change in finger normal force during tactile exploration tasks. The proposed haptic rendering model can be used to give a more natural user feedback in virtual fingertip-surface interactions.

VEGF pathway-targeting drugs induce evasive adaptation by activation of neuropilin-1/cMet in colon cancer cells.

Anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) are important treatments for a number of human malignancies, including colorectal cancers. However, there is increasing evidence that VEGF/VEGF-R inhibitors promote the adaptive and evasive resistance of tumor cells to the therapies. The mechanism by which the cancer cells become resistant remains unclear. One potential mechanism is that VEGF/VEGF-R blockers directly act on tumor cells independently of anti-angiogenic effects. In this study, the direct effects of an anti-VEGF antibody (bevacizumab) and a VEGF-R tyrosine kinase inhibitor (sunitinib) on the evasive adaptation of colon cancer cells were compared. HCT116 and RKO human colon cancer cell lines were chronically exposed (3 months) to bevacizumab or sunitinib in vitro to establish bevacizumab- and sunitinib-adapted cells, respectively. Transwell migration and invasion assays, western blotting, reverse transcription-quantitative polymerase chain reaction, co-immunoprecipitation analysis, cell survival assays and ELISAs were conducted to analyze the adapted cells. Compared with the control vehicle-treated cells, the two cell models exhibited increased migration and invasion activities to different degrees and through different mechanisms. The bevacizumab-adapted cells, but not in the sunitinib-adapted cells, exhibited redundantly increased expression levels of VEGF/VEGF-R family members, including VEGF-A, placental growth factor, VEGF-C, VEGF-R1 and VEGF-R3. In addition, the phosphorylation levels of VEGF-R1 and VEGF-R3 were increased in the bevacizumab-adapted cells compared with the control cells. Thus, the inhibition of VEGF-R1 and VEGF-R3 decreased the evasive activities of the cells, suggesting that they remained dependent on redundant VEGF/VEGF-R signaling. By contrast, the sunitinib-adapted cells exhibited increased neuropilin-1 (NRP1) expression levels compared with the control cells. In the sunitinib-adapted cells, NRP1 interacted with phosphorylated cMet, and the cMet activation was dependent on NRP1. Thus, NRP1 or cMet blockade suppressed the evasive activation of the sunitinib-adapted cells. These results suggest that the sunitinib-adapted cells switched from a VEGF-R-dependent pathway to an alternative NRP1/cMet-dependent one. The findings of the present study indicate that VEGF/VEGF-R inhibitors directly act on colon cancer cells and activate their evasive adaptation via different mechanisms.

Hardness Perception Based on Dynamic Stiffness in Tapping.

A human can judge the hardness of an object based on the damped natural vibration caused by tapping the surface of the object using a fingertip. In this study, we investigated the influence of the dynamic characteristics of vibrations on the hardness perceived by tapping. Subjectively reported hardness values were related to the dynamic stiffness of several objects. The dynamic stiffness, which characterizes the impulsive response of an object, was acquired across the 40-1,000 Hz frequency range for cuboids of 14 types of materials by administering a hammering test. We performed two psychophysical experiments-a ranking task and a magnitude-estimation tasks-wherein participants rated the perceived hardness of each block by tapping it with a finger. We found that the perceptual effect of dynamic stiffness depends on the frequency. Its effect displayed a peak around 300 Hz and decreased or disappeared at higher frequencies, at which human perceptual capabilities are limited. The acquired results help design hardness experienced by products.

Antiangiogenic agent sunitinib induces epithelial to mesenchymal transition and accelerates motility of colorectal cancer cells.

Although vascular endothelial growth factor receptor (VEGF-R)-targeted antiangiogenic agents are important treatment for a number of human malignancies, there is accumulating evidence that the therapies may promote disease progression, such as invasion and metastasis. How tumors become to promote their evasiveness remains fully uncertain. One of possible mechanisms for the adaptation may be a direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. To elucidate a direct effect of VEGF-R-targeting drug (sunitinib), we established a human colorectal cancer cell model adapted to sunitinib. The sunitinib-conditioned cells showed a significant increase in cellular motility and migration activities, compared to the vehicle-treated control cells. Consistent with the phenotype, the sunitinib-conditioned cells decreased the expression levels of E-cadherin (an epithelial marker), while significantly increased the levels of Slug and Zeb1 (mesenchymal markers). Expression profiles of VEGF-R in the sunitinib-conditioned cells showed that only neuropilin-1 (NRP1) expression was significantly increased among all VEGF-R tested. Blockade of NRP1 using its antagonist clearly repressed the migration activation in sunitinib-conditioned cells, but not in the control cells. These results suggest that inhibition of VEGF-R on colorectal cancer cells can drive the epithelial-mesenchymal transition, leading to activation of cell motility in an NRP1-dependent manner. J. Med. Invest. 64: 250-254, August, 2017.

Regorafenib induces adaptive resistance of colorectal cancer cells via inhibition of vascular endothelial growth factor receptor.

Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells. In addition to endothelial cells, cancer cells express the three receptors, suggesting that the antiangiogenic inhibitors affect tumor cells. In fact, we previously demonstrated that regorafenib directly acted on human colorectal cancer cells and accelerated their apoptosis resistance and migration capability. Thus, we here elucidated how regorafenib induced the malignant phenotypes in colorectal cancer cells. To identify the responsible receptor among the regorafenib-targeting proangiogenic receptors, we examined the effects of a potent selective inhibitor for VEGF-R, FGF-R or PDGF-R on apoptosis resistance and migration capability. We clarified that blockade of VEGF-R, but not FGF-R and PDGF-R, induced the malignant phenotypes. We confirmed that blocking of VEGF ligands derived from colorectal cancer cells also induced the phenotypes. These results suggest that regorafenib progressed the malignancy via prevention of autocrine and paracrine VEGF signaling in colorectal cancer cells. J. Med. Invest. 64: 262-265, August, 2017.

The malignant progression effects of regorafenib in human colon cancer cells.

A number of anti-angiogenic drugs targeting vascular endothelial growth factor receptors (VEGF-R) have developed and enabled significant advances in cancer therapy including colorectal cancer. However, acquired resistance to the drugs occurs, leading to disease progression, such as invasion and metastasis. How tumors become the resistance and promote their malignancy remains fully uncertain. One of possible mechanisms for the resistance and the progression may be the direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. We investigated here the direct effect of a VEGF-R-targeting agent, regorafenib, which is the first small molecule inhibitor of VEGF-Rs for the treatment of patients with colorectal cancer, on phenotype changes in colon cancer HCT116 cells. Treatment of cells with regorafenib for only 2 days activated cell migration and invasion, while vehicle-treated control cells showed less activity. Intriguingly, chronic exposure to regorafenib for 90 days dramatically increased migration and invasion activities and induced a resistance to hypoxia-induced apoptosis. These results suggest that loss of VEGF signaling in cancer cells may induce the acquired resistance to VEGF/VEGF-R targeting therapy by gaining two major malignant phenotypes, apoptosis resistance and activation of migration/invasion.

A novel myogenic function residing in the 5' non-coding region of Insulin receptor substrate-1 (Irs-1) transcript.

BACKGROUND: There is evidence that several messenger RNAs (mRNAs) are bifunctional RNAs, i.e. RNA transcript carrying both protein-coding capacity and activity as functional non-coding RNA via 5' and 3' untranslated regions (UTRs). RESULTS: In this study, we identified a novel bifunctional RNA that is transcribed from insulin receptor substrate-1 (Irs-1) gene with full-length 5'UTR sequence (FL-Irs-1 mRNA). FL-Irs-1 mRNA was highly expressed only in skeletal muscle tissue. In cultured skeletal muscle C2C12 cells, the FL-Irs-1 transcript functioned as a bifunctional mRNA. The FL-Irs-1 transcript produced IRS-1 protein during differentiation of myoblasts into myotubes; however, this transcript functioned as a regulatory RNA in proliferating myoblasts. The FL-Irs-1 5'UTR contains a partial complementary sequence to Rb mRNA, which is a critical factor for myogenic differentiation. The overexpression of the 5'UTR markedly reduced Rb mRNA expression, and this reduction was fully dependent on the complementary element and was not compensated by IRS-1 protein. Conversely, knockdown of FL-Irs-1 mRNA increased Rb mRNA expression and enhanced myoblast differentiation into myotubes. CONCLUSIONS: Our findings suggest that the FL-Irs-1 transcript regulates myogenic differentiation as a regulatory RNA in myoblasts.

Haptic invitation of textures: perceptually prominent properties of materials determine human touch motions.

In daily life, certain textures and materials invite our touch motions. To seek the nature of such haptic invitation, we conducted a series of experiments consisting of sensory evaluations and ranking tasks for 36 materials to ascertain their perceptual properties and their degrees of haptic invitation. In addition, we recorded the human touch motions elicited by these materials. The results showed high degrees of haptic invitation for materials with perceptually prominent textures, which indicates that such textures frequently invite human touch motions. We also developed a Bayesian network model that represented the probabilistic relationships between invited touch motions and the properties of textures. The model substantiated the observation that different types of textural prominence led to different types of invited touch motions. These results collectively suggest that materials with prominent textures frequently encourage humans to touch them, using appropriate or specified touch motions.

Psychophysical dimensions of tactile perception of textures.

This paper reviews studies on the tactile dimensionality of physical properties of materials in order to determine a common structure for these dimensions. Based on the commonality found in a number of studies and known mechanisms for the perception of physical properties of textures, we conclude that tactile textures are composed of three prominent psychophysical dimensions that are perceived as roughness/smoothness, hardness/softness, and coldness/warmness. The roughness dimension may be divided into two dimensions: macro and fine roughness. Furthermore, it is reasonable to consider that a friction dimension that is related to the perception of moistness/dryness and stickiness/slipperiness exists. Thus, the five potential dimensions of tactile perception are macro and fine roughness, warmness/coldness, hardness/softness, and friction (moistness/dryness, stickiness/slipperiness). We also summarize methods such as psychological experiments and mathematical approaches for structuring tactile dimensions and their limitations.

[Space flight/bedrest immobilization and bone. Development of inhibitors for atrophy caused by unloading stress].

Muscle atrophy caused by unloading stress is a serious problem in bed rest patients or astronauts. In our previous studies, we revealed that induction and activation of ubiquitin ligase Cbl-b played an important role in skeletal muscle atrophy caused by unloading stress. Under muscle atrophy conditions, Cbl-b interacted with and degraded IRS-1 (insulin receptor substrate 1) that is a central molecule in the IGF-1 signaling pathway. In addition, we developed a Cbl-b inhibitor (Cblin) that a pentapeptide mimetic of tyrosin608-phosphorylated IRS-1, DGpYMP. This Cblin peptide inhibited Cbl-b mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of MAFbx/atrogin-1. We are further developing Cbl-b inhibitors that are more effective than an original Cblin peptide.