L-Type Amino Acid Transporter 1 (LAT1) Promotes PMA-Induced Cell Migration through mTORC2 Activation at the Lysosome.

The mTOR signaling pathway integrates signaling inputs from nutrients, including glucose and amino acids, which are precisely regulated by transporters depending on nutrient levels. The L-type amino acid transporter 1 (LAT1) affects the activity of mTORC1 through upstream regulators that sense intracellular amino acid levels. While mTORC1 activation by LAT1 has been thoroughly investigated in cultured cells, the effects of LAT1 expression on the activity of mTORC2 has scarcely been studied. Here, we provide evidence that LAT1 recruits and activates mTORC2 on the lysosome for PMA-induced cell migration. LAT1 is translocated to the lysosomes in cells treated with PMA in a dose- and time-dependent manner. Lysosomal LAT1 interacted with mTORC2 through a direct interaction with Rictor, leading to the lysosomal localization of mTORC2. Furthermore, the depletion of LAT1 reduced PMA-induced cell migration in a wound-healing assay. Consistent with these results, the LAT1 N3KR mutant, which is defective in PMA-induced endocytosis and lysosomal localization, did not induce mTORC2 recruitment to the lysosome, with the activation of mTORC2 determined via Akt phosphorylation or the LAT1-mediated promotion of cell migration. Taken together, lysosomal LAT1 recruits and activates the mTORC2 complex and downstream Akt for PMA-mediated cell migration. These results provide insights into the development of therapeutic drugs targeting the LAT1 amino acid transporter to block metastasis, as well as disease progression in various types of cancer.

Ankle stiffness asymmetry is associated with balance function in individuals with chronic stroke.

Ankle joint is one of important contributors on balance in stroke survivors. This study aimed to investigate the relationships of ankle stiffness symmetry ratios along the talocrural and subtalar axes with clinical balance measures and weight distribution during quiet standing in ambulatory chronic post-stroke survivors. The clinical trials involved 15 ambulatory elderly with chronic post-stroke hemiparesis and 15 healthy controls. Ankle stiffness was evaluated during non-weight-bearing isokinetic passive biaxial ankle movements, and ankle stiffness symmetry ratios between paretic and non-paretic ankle stiffness (SR: Inversion/Eversion SRIE & Dorsi-/Plantarflexion SRDP) were measured. A certified physiotherapist evaluated the Berg Balance Scale (BBS) and weight-distribution ratio (WDR) on bilateral force plates during quiet standing. Correlation coefficients, the factor analysis, and Pearson linear multiple regression were assessed with measured parameters. Correlation coefficients showed significances in-betweens; BBS and SRDP (r = -0.543, p = 0.022), WDR and SRIE (r = -0.667, p = 0.004), SRIE and SRDP (r = -0.604, p = 0.011). The exploratory factor analysis suggested four extracted factors; (1) Balance & Gait, (2) Stroke, (3) Symmetry and (4) Dimension. The first and second factors include general and pathological characteristics in stoke participants respectively. The third factor is associated with symmetrical characteristics explaining up to 99.9% of the variance. Multiple regression analysis showed ankle stiffness ratios predict BBS up to 60% of variance. The biaxial ankle stiffness ratio is a useful clinical variable that assesses balance function, in ambulatory chronic stroke survivors.

Learnability of Thyroid Nodule Assessment on Ultrasonography: Using a Big Data Set.

OBJECTIVE: The aims of the work described here were to evaluate the learnability of thyroid nodule assessment on ultrasonography (US) using a big data set of US images and to evaluate the diagnostic utilities of artificial intelligence computer-aided diagnosis (AI-CAD) used by readers with varying experience to differentiate benign and malignant thyroid nodules. METHODS: Six college freshmen independently studied the "learning set" composed of images of 13,560 thyroid nodules, and their diagnostic performance was evaluated after their daily learning sessions using the "test set" composed of images of 282 thyroid nodules. The diagnostic performance of two residents and an experienced radiologist was evaluated using the same "test set." After an initial diagnosis, all readers once again evaluated the "test set" with the assistance of AI-CAD. RESULTS: Diagnostic performance of almost all students increased after the learning program. Although the mean areas under the receiver operating characteristic curves (AUROCs) of residents and the experienced radiologist were significantly higher than those of students, the AUROCs of five of the six students did not differ significantly compared with that of the one resident. With the assistance of AI-CAD, sensitivity significantly increased in three students, specificity in one student, accuracy in four students and AUROC in four students. Diagnostic performance of the two residents and the experienced radiologist was better with the assistance of AI-CAD. CONCLUSION: A self-learning method using a big data set of US images has potential as an ancillary tool alongside traditional training methods. With the assistance of AI-CAD, the diagnostic performance of readers with varying experience in thyroid imaging could be further improved.

A Novel Biosensor and Algorithm to Predict Vitamin D Status by Measuring Skin Impedance.

The deficiency and excess of vitamin D cause various diseases, necessitating continuous management; but it is not easy to accurately measure the serum vitamin D level in the body using a non-invasive method. The aim of this study is to investigate the correlation between vitamin D levels, body information obtained by an InBody scan, and blood parameters obtained during health checkups, to determine the optimum frequency of vitamin D quantification in the skin and to propose a vitamin D measurement method based on impedance. We assessed body composition, arm impedance, and blood vitamin D concentrations to determine the correlation between each element using multiple machine learning analyses and an algorithm which predicted the concentration of vitamin D in the body using the impedance value developed. Body fat percentage obtained from the InBody device and blood parameters albumin and lactate dehydrogenase correlated with vitamin D level. An impedance measurement frequency of 21.1 Hz was reflected in the blood vitamin D concentration at optimum levels, and a confidence level of about 75% for vitamin D in the body was confirmed. These data demonstrate that the concentration of vitamin D in the body can be predicted using impedance measurement values. This method can be used for predicting and monitoring vitamin D-related diseases and may be incorporated in wearable health measurement devices.

Reliability of Bi-Axial Ankle Stiffness Measurement in Older Adults.

This study involves measurements of bi-axial ankle stiffness in older adults, where the ankle joint is passively moved along the talocrural and subtalar joints using a custom ankle movement trainer. A total of 15 elderly individuals participated in test-retest reliability measurements of bi-axial ankle stiffness at exactly one-week intervals for validation of the angular displacement in the device. The ankle's range of motion was also compared, along with its stiffness. The kinematic measurements significantly corresponded to results from a marker-based motion capture system (dorsi-/plantar flexion: r = 0.996; inversion/eversion: r = 0.985). Bi-axial ankle stiffness measurements showed significant intra-class correlations (ICCs) between the two visits for all ankle movements at slower (2.14°/s, ICC = 0.712) and faster (9.77°/s, ICC = 0.879) speeds. Stiffness measurements along the talocrural joint were thus shown to have significant negative correlation with active ankle range of motion (r = -0.631, p = 0.012). The ankle movement trainer, based on anatomical characteristics, was thus used to demonstrate valid and reliable bi-axial ankle stiffness measurements for movements along the talocrural and subtalar joint axes. Reliable measurements of ankle stiffness may help clinicians and researchers when designing and fabricating ankle-foot orthosis for people with upper-motor neuron disorders, such as stroke.

Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria.

Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.

Ten catalytic snapshots of rhomboid intramembrane proteolysis from gate opening to peptide release.

Protein cleavage inside the cell membrane triggers various pathophysiological signaling pathways, but the mechanism of catalysis is poorly understood. We solved ten structures of the Escherichia coli rhomboid protease in a bicelle membrane undergoing time-resolved steps that encompass the entire proteolytic reaction on a transmembrane substrate and an aldehyde inhibitor. Extensive gate opening accompanied substrate, but not inhibitor, binding, revealing that substrates and inhibitors take different paths to the active site. Catalysis unexpectedly commenced with, and was guided through subsequent catalytic steps by, motions of an extracellular loop, with local contributions from active site residues. We even captured the elusive tetrahedral intermediate that is uncleaved but covalently attached to the catalytic serine, about which the substrate was forced to bend dramatically. This unexpectedly stable intermediate indicates rhomboid catalysis uses an unprecedented reaction coordinate that may involve mechanically stressing the peptide bond, and could be selectively targeted by inhibitors.

Effects of passive Bi-axial ankle stretching while walking on uneven terrains in older adults with chronic stroke.

Many people with stroke experience foot drop while walking. Further, walking on uneven surfaces is a common fall risk for these people that hinder with their daily life activities. In addition, a few years after a stroke, lower-limb exercises become less focused, especially the ankle joint movement. The objective of this study is to determine the gait performance of older adults with chronic stroke on an uneven surface in relation to ankle mobility after a four-week bi-axial ankle range of motion (ROM) exercise session. Fifteen older adults with chronic post-stroke hemiparesis (N = 15; mean age = 65 years) participated in a total of 12 bi-axial ankle ROM exercises that consisted of three 30-min training sessions per week for four weeks. Basic clinical tests and gait performance in even and uneven surfaces were evaluated before and after training. Participants with chronic post-stroke hemiparesis showed significantly improved ankle functions, decreased ankle stiffness (from 0.140 ±â€¯0.059 to 0.128 ±â€¯0.067 N·m/°; p = 0.025), and increased paretic ankle passive ROMs (dorsiflexion(DF)/plantarflexion(PF): from 27.3 ±â€¯14.7° to 50.6 ±â€¯10.3°, p < 0.001; inversion(INV)/eversion(EV): 21.7 ±â€¯9.7° to 28.6 ±â€¯9.9°; p = 0.033) after training. They exhibited significant improvements in the walking performance over an uneven surface, step kinematics (walking speed 0.257 ±â€¯0.17 to 0.320 ±â€¯0.178 m/s; p = 0.017; step length: 0.214 ±â€¯0.109 to 0.243 ±â€¯0.108 m; p = 0.009), and clinical balance and mobility (Berg balance scale: 47.2 ±â€¯4.7 to 50.1 ±â€¯3.9, p = 0.0001; timed-up and go test: 23.9 ±â€¯10.3 to 20.2 ±â€¯7.0 s, p = 0.0156). This study is the first research to investigate the walking performance on uneven surfaces in the elderly with chronic stroke in relation to the ankle biomechanical property changes.

Three-Dimensional Augmented Reality System for Balance and Mobility Rehabilitation in the Elderly: A Randomized Controlled Trial.

We attempted to evaluate the clinical efficiency of a novel three-dimensional interactive augmented reality system (3D-ARS) for balance and mobility rehabilitation. This system enables participant training with a realistic 3D interactive balance exercise and assessing movement parameters and joint angles by using a kinetic sensor system. We performed a randomized controlled trial in a general hospital. Thirty-six participants (age, 56-76 years) who could independently walk and stand on one leg were recruited. The participants were randomly assigned to either group. The control group (n = 18) underwent a conventional physical fitness program such as lower-extremity strengthening and balance training thrice per week for 1 month. The experimental group (n = 18) experienced 3D-ARS training thrice per week (1 session = 30 minutes) for 4 weeks. Training comprised a balloon game for hip exercise, cave game for knee exercise, and rhythm game for one-leg balance exercise. Lower-extremity clinical scale scores, fall index, and automatic balance score were measured by using Tetrax® posturography before, during, and after training. Significant group (3D-ARS vs. control) × time (before and after exercise) interaction effect was observed for Berg balance scale (BBS) scores (p = 0.04) and timed-up-and-go (TUG; p < 0.001). Overall improvements occurred in stability index, weight distribution index, fall risk index, and Fourier transformations index of posturography for both groups. However, score changes were significantly greater in the 3D-ARS group. Significant group × time interaction effect was observed for the fall risk index. This demonstrates that the 3D-ARS system can improve balance in the elderly more effectively.

Crystal Structures and Inhibition Kinetics Reveal a Two-Stage Catalytic Mechanism with Drug Design Implications for Rhomboid Proteolysis.

Intramembrane proteases signal by releasing proteins from the membrane, but despite their importance, their enzymatic mechanisms remain obscure. We probed rhomboid proteases with reversible, mechanism-based inhibitors that allow precise kinetic analysis and faithfully mimic the transition state structurally. Unexpectedly, inhibition by peptide aldehydes is non-competitive, revealing that in the Michaelis complex, substrate does not contact the catalytic center. Structural analysis in a membrane revealed that all extracellular loops of rhomboid make stabilizing interactions with substrate, but mainly through backbone interactions, explaining rhomboid's broad sequence selectivity. At the catalytic site, the tetrahedral intermediate lies covalently attached to the catalytic serine alone, with the oxyanion stabilized by unusual tripartite interactions with the side chains of H150, N154, and the backbone of S201. We also visualized unexpected substrate-enzyme interactions at the non-essential P2/P3 residues. These "extra" interactions foster potent rhomboid inhibition in living cells, thereby opening avenues for rational design of selective rhomboid inhibitors.

Utility of a Three-Dimensional Interactive Augmented Reality Program for Balance and Mobility Rehabilitation in the Elderly: A Feasibility Study.

OBJECTIVE: To improve lower extremity function and balance in elderly persons, we developed a novel, three-dimensional interactive augmented reality system (3D ARS). In this feasibility study, we assessed clinical and kinematic improvements, user participation, and the side effects of our system. METHODS: Eighteen participants (age, 56-76 years) capable of walking independently and standing on one leg were recruited. The participants received 3D ARS training during 10 sessions (30-minute duration each) for 4 weeks. Berg Balance Scale (BBS) and the Timed Up and Go (TUG) scores were obtained before and after the exercises. Outcome performance variables, including response time and success rate, and kinematic variables, such as hip and knee joint angle, were evaluated after each session. RESULTS: Participants exhibited significant clinical improvements in lower extremity balance and mobility following the intervention, as shown by improved BBS and TUG scores (p<0.001). Consistent kinematic improvements in the maximum joint angles of the hip and knee were observed across sessions. Outcome performance variables, such as success rate and response time, improved gradually across sessions, for each exercise. The level of participant interest also increased across sessions (p<0.001). All participants completed the program without experiencing any adverse effects. CONCLUSION: Substantial clinical and kinematic improvements were observed after applying a novel 3D ARS training program, suggesting that this system can enhance lower extremity function and facilitate assessments of lower extremity kinematic capacity.

Facilitation of corticospinal excitability by virtual reality exercise following anodal transcranial direct current stimulation in healthy volunteers and subacute stroke subjects.

BACKGROUND: There is growing evidence that the combination of non-invasive brain stimulation and motor skill training is an effective new treatment option in neurorehabilitation. We investigated the beneficial effects of the application of transcranial direct current stimulation (tDCS) combined with virtual reality (VR) motor training. METHODS: In total, 15 healthy, right-handed volunteers and 15 patients with stroke in the subacute stage participated. Four different conditions (A: active wrist exercise, B: VR wrist exercise, C: VR wrist exercise following anodal tDCS (1 mV, 20 min) on the left (healthy volunteer) or affected (stroke patient) primary motor cortex, and D: anodal tDCS without exercise) were provided in random order on separate days. We compared during and post-exercise corticospinal excitability under different conditions in healthy volunteers (A, B, C, D) and stroke patients (B, C, D) by measuring the changes in amplitudes of motor evoked potentials in the extensor carpi radialis muscle, elicited with single-pulse transcranial magnetic stimulation. For statistical analyses, a linear mixed model for a repeated-measures covariance pattern model with unstructured covariance within groups (healthy or stroke groups) was used. RESULTS: The VR wrist exercise (B) facilitated post-exercise corticospinal excitability more than the active wrist exercise (A) or anodal tDCS without exercise (D) in healthy volunteers. Moreover, the post-exercise corticospinal facilitation after tDCS and VR exercise (C) was greater and was sustained for 20 min after exercise versus the other conditions in healthy volunteers (A, B, D) and in subacute stroke patients (B, D). CONCLUSIONS: The combined effect of VR motor training following tDCS was synergistic and short-term corticospinal facilitation was superior to the application of VR training, active motor training, or tDCS without exercise condition. These results support the concept of combining brain stimulation with VR motor training to promote recovery after a stroke.

Development of virtual reality proprioceptive rehabilitation system for stroke patients.

In this study, the virtual reality (VR) proprioception rehabilitation system was developed for stroke patients to use proprioception feedback in upper limb rehabilitation by blocking visual feedback. To evaluate its therapeutic effect, 10 stroke patients (onset>3 month) trained proprioception feedback rehabilitation for one week and visual feedback rehabilitation for another week in random order. Proprioception functions were checked before, a week after, and at the end of training. The results show the click count, error distance and total error distance among proprioception evaluation factors were significantly reduced after proprioception feedback training compared to visual feedback training (respectively, p=0.005, p=0.001, and p=0.007). In addition, subjects were significantly improved in conventional behavioral tests after training. In conclusion, we showed the effectiveness and possible use of the VR to recover the proprioception of stroke patients.

Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity.

Enzymatic cleavage of transmembrane anchors to release proteins from the membrane controls diverse signaling pathways and is implicated in more than a dozen diseases. How catalysis works within the viscous, water-excluding, two-dimensional membrane is unknown. We developed an inducible reconstitution system to interrogate rhomboid proteolysis quantitatively within the membrane in real time. Remarkably, rhomboid proteases displayed no physiological affinity for substrates (K(d) ~190 µM/0.1 mol%). Instead, ~10,000-fold differences in proteolytic efficiency with substrate mutants and diverse rhomboid proteases were reflected in k(cat) values alone. Analysis of gate-open mutant and solvent isotope effects revealed that substrate gating, not hydrolysis, is rate limiting. Ultimately, a single proteolytic event within the membrane normally takes minutes. Rhomboid intramembrane proteolysis is thus a slow, kinetically controlled reaction not driven by transmembrane protein-protein affinity. These properties are unlike those of other studied proteases or membrane proteins but are strikingly reminiscent of one subset of DNA-repair enzymes, raising important mechanistic and drug-design implications.

Proprioception rehabilitation training system for stroke patients using virtual reality technology.

We investigated a virtual reality (VR) proprioceptive rehabilitation system that could manipulate the visual feedback of upper-limb during training and could do training by relying on proprioception feedback only. Virtual environments were designed in order to switch visual feedback on/off during upper-limb training. Two types of VR training tasks were designed for evaluating the effect of the proprioception focused training compared to the training with visual feedback. In order to evaluate the developed proprioception feedback virtual environment system, we recruited ten stroke patients (age: 54.7± 7.83years, on set: 3.29± 3.83 years). All patients performed three times PFVE task in order to check the improvement of proprioception function just before training session, after one week training, and after all training. In a comparison between FMS score and PFVE, the FMS score had a significant relationship with the error distance(r = -.662, n=10, p = .037) and total movement distance(r = -.726, n=10, p = .018) in PFVE. Comparing the training effect between in virtual environment with visual feedback and with proprioception, the click count, error distance and total error distance was more reduced in PFVE than VFVE. (Click count: p = 0.005, error distance: p = 0.001, total error distance: p = 0.007). It suggested that the proprioception feedback rather than visual feedback could be effective means to enhancing motor control during rehabilitation training. The developed VR system for rehabilitation has been verified in that stroke patients improved motor control after VR proprioception feedback training.

Upper extremity rehabilitation of stroke: facilitation of corticospinal excitability using virtual mirror paradigm.

BACKGROUND: Several experimental studies in stroke patients suggest that mirror therapy and various virtual reality programs facilitate motor rehabilitation. However, the underlying mechanisms for these therapeutic effects have not been previously described. OBJECTIVES: We attempted to delineate the changes in corticospinal excitability when individuals were asked to exercise their upper extremity using a real mirror and virtual mirror. Moreover, we attempted to delineate the role of visual modulation within the virtual environment that affected corticospinal excitability in healthy subjects and stroke patients. METHODS: A total of 18 healthy subjects and 18 hemiplegic patients were enrolled into the study. Motor evoked potential (MEP)s from transcranial magnetic stimulation were recorded in the flexor carpi radialis of the non-dominant or affected upper extremity using three different conditions: (A) relaxation; (B) real mirror; and (C) virtual mirror. Moreover, we compared the MEPs from the virtual mirror paradigm using continuous visual feedback or intermittent visual feedback. RESULTS: The rates of amplitude increment and latency decrement of MEPs in both groups were higher during the virtual mirror task than during the real mirror. In healthy subjects and stroke patients, the virtual mirror task with intermittent visual feedback significantly facilitated corticospinal excitability of MEPs compared with continuous visual feedback. CONCLUSION: Corticospinal excitability was facilitated to a greater extent in the virtual mirror paradigm than in the real mirror and in intermittent visual feedback than in the continuous visual feedback, in both groups. This provides neurophysiological evidence supporting the application of the virtual mirror paradigm using various visual modulation technologies to upper extremity rehabilitation in stroke patients.

Crystal structure of staphylococcal enterotoxin G (SEG) in complex with a mouse T-cell receptor {beta} chain.

Superantigens (SAgs) are bacterial or viral toxins that bind MHC class II (MHC-II) molecules and T-cell receptor (TCR) in a nonconventional manner, inducing T-cell activation that leads to inflammatory cytokine production, which may result in acute toxic shock. In addition, the emerging threat of purpura fulminans and community-associated meticillin-resistant Staphylococcus aureus emphasizes the importance of a better characterization of SAg binding to their natural ligands that may allow the development of reagents to neutralize their action. The three-dimensional structure of the complex between a mouse TCR ß chain (mVß8.2) and staphylococcal enterotoxin G (SEG) at 2.0 Å resolution revealed a binding site that does not conserve the "hot spots" present in mVß8.2-SEC2, mVß8.2-SEC3, mVß8.2-SEB, and mVß8.2-SPEA complexes. Analysis of the mVß8.2-SEG interface allowed us to explain the higher affinity of this complex compared with the others, which may account for the early activation of T-cells bearing mVß8.2 by SEG. This mode of interaction between SEG and mVß8.2 could be an adaptive advantage to bestow on the pathogen a faster rate of colonization of the host.

Assessing energetic contributions to binding from a disordered region in a protein-protein interaction .

Many functional proteins are at least partially disordered prior to binding. Although the structural transitions upon binding of disordered protein regions can influence the affinity and specificity of protein complexes, their precise energetic contributions to binding are unknown. Here, we use a model protein-protein interaction system in which a locally disordered region has been modified by directed evolution to quantitatively assess the thermodynamic and structural contributions to binding of disorder-to-order transitions. Through X-ray structure determination of the protein binding partners before and after complex formation and isothermal titration calorimetry of the interactions, we observe a correlation between protein ordering and binding affinity for complexes along this affinity maturation pathway. Additionally, we show that discrepancies between observed and calculated heat capacities based on buried surface area changes in the protein complexes can be explained largely by heat capacity changes that would result solely from folding the locally disordered region. Previously developed algorithms for predicting binding energies of protein-protein interactions, however, are unable to correctly model the energetic contributions of the structural transitions in our model system. While this highlights the shortcomings of current computational methods in modeling conformational flexibility, it suggests that the experimental methods used here could provide training sets of molecular interactions for improving these algorithms and further rationalizing molecular recognition in protein-protein interactions.

Distinct conformations of Ly49 natural killer cell receptors mediate MHC class I recognition in trans and cis.

Certain cell-surface receptors engage ligands expressed on juxtaposed cells and ligands on the same cell. The structural basis for trans versus cis binding is not known. Here, we showed that Ly49 natural killer (NK) cell receptors bound two MHC class I (MHC-I) molecules in trans when the two ligand-binding domains were backfolded onto the long stalk region. In contrast, dissociation of the ligand-binding domains from the stalk and their reorientation relative to the NK cell membrane allowed monovalent binding of MHC-I in cis. The distinct conformations (backfolded and extended) define the structural basis for cis-trans binding by Ly49 receptors and explain the divergent functional consequences of cis versus trans interactions. Further analyses identified specific stalk segments that were not required for MHC-I binding in trans but were essential for inhibitory receptor function. These data identify multiple distinct roles of stalk regions for receptor function.

Development and verification of an alcohol craving-induction tool using virtual reality: craving characteristics in social pressure situation.

Alcoholism is a disease that affects parts of the brain that control emotion, decisions, and behavior. Therapy for people with alcoholism must address coping skills for facing high-risk situations. Therefore, it is important to develop tools to mimic such conditions. Cue exposure therapy (CET) provides high-risk situations during treatment, which raises the individual's ability to recognize that alcohol craving is being induced. Using CET, it is hard to simulate situations that induce alcohol craving. By contrast, virtual reality (VR) approaches can present realistic situations that cannot be experienced directly in CET. Therefore, we hypothesized that is possible to model social pressure situations using VR. We developed a VR system for inducing alcohol craving under social pressure situations and measured both the induced alcohol craving and head gaze of participants. A 2 x 2 experimental model (alcohol-related locality vs. social pressure) was designed. In situations without an avatar (no social pressure), more alcohol craving was induced if alcohol was present than if it was not. And more alcohol craving was induced in situations with an avatar (social pressure) than in situations without an avatar (no social pressure). The difference of angle between the direction of head gazing and the direction of alcohol or avatar was smaller in situations with an avatar alone (social pressure) than in situations with alcohol alone. In situations with both alcohol and an avatar, the angle between the direction of head gaze and the direction of the avatar was smaller than between the direction of head gaze and the direction of the alcohol. Considering the results, this VR system induces alcohol craving using an avatar that can express various social pressure situations.