Objective Oculopharyngodistal myopathy (OPDM) is an adult‐onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5′‐UTR of LRP12, GIPC1, and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families. Methods Parametric linkage analysis was performed. Long‐read sequencing followed by repeat‐primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples. Results The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type 4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE‐seq data indicated that alternative transcription start sites exist upstream of the RefSeq‐annotated RILPL1 transcription start site. Strand‐specific RNA‐seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co‐localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type 4 patients. Interpretation Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type 4 pathogenesis. ANN NEUROL 2022;92:512–526

This study aims to explore the effects of Notch1 gene on remyelination in multiple sclerosis (MS). A mouse model of acute demyelination was successfully established and the model mice were grouped as cuprizone (CPZ) group, CPZ + small interfering RNA (siRNA)-Notch1 (siNotch1) group, and CPZ + siRNA negative control (NC) group. Meanwhile, another 3 groups (control, control + siNotch1, and control + siRNA NC) were established in normal mice. The changes of weight and maintenance time in rotating drum of mice were observed. Western blot analysis for the protein expressions related to Notch signaling pathway and oligodendrocyte (OL) differentiation in the corpus callosum of the mice. After model establishment, the weight of CPZ-induced demyelinated mice was decreased. During the repair period, the balance ability and movement of the mice was recovered, especially for those injected with siNotch1 plasmid. After model establishment, the number of myelinated axons was decreased. In comparison with the CPZ and CPZ siRNA NC groups, the CPZ + siNotch1 group had a decrease in the number of premature OLs, but increase in mature OLs, and a decrease in oligodendrocyte precursor cells and astrocytes. The expressions of proteins related to Notch signaling pathway, such as HES, Jagged-1 were decreased in the CPZ + siNotch1 group in contrast to the CPZ and CPZ + siRNA groups, but the OL-related transcription factor Sox10 was increased in the CPZ + siNotch1 group than in the CPZ + siRNA NC and CPZ groups, and Id2 was decreased. Our study provided evidence that the inhibition of Notch1 gene could accelerate remyelination in MS.

For patients with upper limb dysfunction after stroke, robot-assisted rehabilitation training plays an important role in functional recovery. The existing upper limb rehabilitation robots have some problems, such as complex mechanisms, insufficient compliance, and can only realize the rehabilitation training of shoulder and elbow joints in the horizontal plane. This research proposes a novel end-effector upper limb rehabilitation robot with three degrees of freedom. Two horizontal rotation freedoms are driven by motors and one vertical translation freedom is driven by a pneumatic cylinder. So it can realize the spatial rehabilitation training of shoulder and elbow joints. The rotation and translation transformation of the robot can be represented by a dual quaternion, which is concise in form and clear in the physical meaning. Therefore, this article adopts dual quaternions to complete the robot’s kinematics modeling, inverse kinematics calculation, and terminal spiral motion trajectory planning. To improve the low-speed moving performance of the spiral motion, a sliding mode control strategy plus feedforward compensation is employed to control the displacement of the cylinder. Experiments show that the robot can realize proximal joints training and has good position tracking accuracy (tracking error is within 2 mm) with smoothness under the proposed control strategy, which can guarantee the accuracy and comfort of passive rehabilitation training, contributing to restoring the function of the impairment upper limbs.

This paper presents the development of an upper limb end-effector based rehabilitation device for stroke patients, offering assistance or resistance along any 2-dimensional trajectory during physical therapy. It employs a non-backdrivable ball-screw-driven mechanism for enhanced control accuracy. The control system features three novel algorithms: First, the Implicit Euler velocity control algorithm (IEVC) highlighted for its stateof-the-art accuracy, stability, efficiency and generalizability in motion restriction control. Second, an Admittance Virtual Dynamics simulation algorithm that achieves a smooth and natural human interaction with the non-backdrivable end-effector. Third, a generalized impedance force calculation algorithm allowing efficient impedance control on any trajectory or area boundary. Experimental validation demonstrated the system's effectiveness in accurate end-effector position control across various trajectories and configurations. The proposed upper limb endeffector-based rehabilitation device, with its high performance and adaptability, holds significant promise for extensive clinical application, potentially improving rehabilitation outcomes for stroke patients.