Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development

Wearable Inertial Sensor-Based Hand-Guiding Gestures Recognition Method Robust to Significant Changes in the Body-Alignment of Subject

The accuracy of the wearable inertia-measurement-unit (IMU)-sensor-based gesture recognition may be significantly affected by undesired changes in the body-fixed frame and the sensor-fixed frame according to the change in the subject and the sensor attachment. In this study, we proposed a novel wearable IMU-sensor-based hand-guiding gesture recognition method robust to significant changes in the subject’s body alignment based on the floating body-fixed frame method and the bi-directional long short-term memory (bi-LSTM). Through comparative experimental studies with the other two methods, it was confirmed that aligning the sensor-fixed frame with the reference frame of the human body and updating the reference frame according to the change in the subject’s body-heading direction helped improve the generalization performance of the gesture recognition model. As a result, the proposed floating body-fixed frame method showed a 91.7% test accuracy, confirming that it was appropriate for gesture recognition under significant changes in the subject’s body alignment during gestures

Wearable Inertial Sensor-Based Hand-Guiding Gestures Recognition Method Robust to Significant Changes in the Body-Alignment of Subject

The accuracy of the wearable inertia-measurement-unit (IMU)-sensor-based gesture recognition may be significantly affected by undesired changes in the body-fixed frame and the sensor-fixed frame according to the change in the subject and the sensor attachment. In this study, we proposed a novel wearable IMU-sensor-based hand-guiding gesture recognition method robust to significant changes in the subject’s body alignment based on the floating body-fixed frame method and the bi-directional long short-term memory (bi-LSTM). Through comparative experimental studies with the other two methods, it was confirmed that aligning the sensor-fixed frame with the reference frame of the human body and updating the reference frame according to the change in the subject’s body-heading direction helped improve the generalization performance of the gesture recognition model. As a result, the proposed floating body-fixed frame method showed a 91.7% test accuracy, confirming that it was appropriate for gesture recognition under significant changes in the subject’s body alignment during gestures

Hand-Guiding Gesture-Based Telemanipulation with the Gesture Mode Classification and State Estimation Using Wearable IMU Sensors

This study proposes a telemanipulation framework with two wearable IMU sensors without human skeletal kinematics. First, the states (intensity and direction) of spatial hand-guiding gestures are separately estimated through the proposed state estimator, and the states are also combined with the gesture’s mode (linear, angular, and via) obtained with the bi-directional LSTM-based mode classifier. The spatial pose of the 6-DOF manipulator’s end-effector (EEF) can be controlled by combining the spatial linear and angular motions based on integrating the gesture’s mode and state. To validate the significance of the proposed method, the teleoperation of the EEF to the designated target poses was conducted in the motion-capture space. As a result, it was confirmed that the mode could be classified with 84.5% accuracy in real time, even during the operator’s dynamic movement; the direction could be estimated with an error of less than 1 degree; and the intensity could be successfully estimated with the gesture speed estimator and finely tuned with the scaling factor. Finally, it was confirmed that a subject could place the EEF within the average range of 83 mm and 2.56 degrees in the target pose with only less than ten consecutive hand-guiding gestures and visual inspection in the first trial

A Study on the Wear Characteristics of Al7075 with Changes in Surface Roughness and Ti Thin Film Deposition Time

Mechanical parts have a problem of wear when used in extreme environments. Aluminum, most used in the industrial field, is a representative material of light weight, but its wear resistance is not good. To resolve the wear problem of such materials, research and development of surface thin film deposition technology has been increasing. Wear resistance was investigated after the Ti thin film was deposited by sputtering, one of the main methods of this technique. The smaller the surface roughness value and the thicker the thin film, the better the wear resistance. However, when a thin film is deposited for a predetermined time or less, the bonding strength with the base metal is lowered and the wear resistance is confirmed as low

Migratory Cortical Interneuron-Specific Transcriptome Abnormalities in Schizophrenia

Cortical interneurons (cINs) are substantially affected in Schizophrenia (SCZ) and enriched for SCZ heritability during development. To understand SCZ-specific changes in these cells during development, we isolated migratory cINs from cIN spheres derived from 5 healthy control (HC) and 5 SCZ induced pluripotent stem cell lines (iPSCs). Transcriptome analyses show dysregulation in extracellular matrix pathways as the major disturbances in SCZ migratory cINs, whereas sphere cINs show dysregulation in immune pathways. This result suggests the importance of using homogeneous cell populations to identify stage-specific abnormalities and provides a platform to further study the biology of schizophrenia pathogenesis during early development

iPSC-Derived Homogeneous Populations of Developing Schizophrenia Cortical Interneurons Have Compromised Mitochondrial Function

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs

iPSC-Derived Homogeneous Populations of Developing Schizophrenia Cortical Interneurons Have Compromised Mitochondrial Function

Schizophrenia (SCZ) is a neurodevelopmental disorder. Thus, studying pathogenetic mechanisms underlying SCZ requires studying the development of brain cells. Cortical interneurons (cINs) are consistently observed to be abnormal in SCZ postmortem brains. These abnormalities may explain altered gamma oscillation and cognitive function in patients with SCZ. Of note, currently used antipsychotic drugs ameliorate psychosis, but they are not very effective in reversing cognitive deficits. Characterizing mechanisms of SCZ pathogenesis, especially related to cognitive deficits, may lead to improved treatments. We generated homogeneous populations of developing cINs from 15 healthy control (HC) iPSC lines and 15 SCZ iPSC lines. SCZ cINs, but not SCZ glutamatergic neurons, show dysregulated Oxidative Phosphorylation (OxPhos) related gene expression, accompanied by compromised mitochondrial function. The OxPhos deficit in cINs could be reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) but not by other chemicals previously identified as increasing mitochondrial function. The restoration of mitochondrial function by ALA/ALC was accompanied by a reversal of arborization deficits in SCZ cINs. OxPhos abnormality, even in the absence of any circuit environment with other neuronal subtypes, appears to be an intrinsic deficit in SCZ cINs

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in Pbmcs and Developing Cortical Interneurons in Schizophrenia

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ