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Background and purpose: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. Methods: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat‐primed PCR and GC‐rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno‐associated virus (AAV)‐mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. Results: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p‐value = 0.29). Skin biopsy showed P62‐positive intranuclear NOTCH2NLC‐polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa‐NOTCH2NLC‐(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. Conclusions: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons. [ABSTRACT FROM AUTHOR]

Manipulating granular materials is a crucial function of robotic grippers. However, the existing approaches always suffer from low efficiency when dealing with large quantities of dispersed granules. To overcome this challenge, inspiration is drawn from an African elephant (Loxodonta Africana), which can employ both fingertip extensions on the trunk tip to efficiently grasp dispersed granular food all at once by mediating state transition of granules. Herein, this bio‐inspired intelligent strategy is integrated into a soft pneumatic gripper for transporting dispersed granules. To evaluate the critical actuation pressures while grasping granules, a library is constructed experimentally, and the effects of the initial relative height and relative lifting speed on the grasping success rate are examined. It is indicated in the experimental results that this trunk‐inspired robotic strategy leads to a success rate of over 90% and saves ≈50% duration of manipulation compared to the individual gripping fashion. Herein, new insights may be offered in this study into a novel manipulation strategy for efficiently transporting dispersed granular materials. [ABSTRACT FROM AUTHOR]

Reconfigurable continuum robots exhibit programmable interaction capability, enabling them to cope with challenges poorly addressed by conventional rigid robots. However, the regulation of the module type and/or sequence may result in time‐consuming and labor‐intensive problems. Therefore, in situ reconfiguration schemes are required to develop in a simple yet robust solution for continuum robot design. Herein, inspired by the structure characteristics of the seahorse tail, an original template based on a tensegrity building block (TBB) for creating an in situ reconfigurable continuum robotic paradigm is proposed. As the length of the stretchable struts in the TBB could be programmed, five typical homologous types from the template are derived. Then, ten TBBs into a continuum robot are assembled and the multi‐body dynamic framework is employed to develop a mechanical model for predicting the profile after deformation. Theoretical predictions demonstrate that the robotic shape can be customized in situ by switching the type of TBBs, without disassembling the robot. Furthermore, the tailored continuum robotic configurations are applied to conformally interact with the varying‐curvature objects. The experimental results suggest that the proposed programmable template offers a facile and rapid reconfiguration scheme for the continuum robots, which greatly improves the robotic interaction capability. [ABSTRACT FROM AUTHOR]

Background: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. Objectives: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross‐sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. Methods: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face‐to‐face interviews biennially. Results: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD‐MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early‐onset PD (EOPD, age at onset ≤50 years) and late‐onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa‐induced dyskinesias in women. Conclusions: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET‐associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET‐associated genes and PD, in a relatively large Chinese population cohort. Methods: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT‐O) to explore the variant burden of 33 ET‐associated genes, using whole‐exome sequencing (WES) data from 1494 early‐onset PD (EOPD) patients and 1357 control subjects from mainland China. Results: We report that rare loss‐of‐function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET‐related genes were significantly associated with EOPD. Interpretation: This is the first systematic analysis of ET‐associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD. [ABSTRACT FROM AUTHOR]

ABSTRACT We proposed an integrated bioanalytical method development and validation approach: (1) method screening based on analyte's physicochemical properties and metabolism information to determine the most appropriate extraction/analysis conditions; (2) preliminary stability evaluation using both quality control and incurred samples to establish sample collection, storage and processing conditions; (3) mock validation to examine method accuracy and precision and incurred sample reproducibility; and (4) method validation to confirm the results obtained during method development. This integrated approach was applied to the determination of compound I in rat plasma and compound II in rat and dog plasma. The effectiveness of the approach was demonstrated by the superior quality of three method validations: (1) a zero run failure rate; (2) >93% of quality control results within 10% of nominal values; and (3) 99% incurred sample within 9.2% of the original values. In addition, rat and dog plasma methods for compound II were successfully applied to analyze more than 900 plasma samples obtained from Investigational New Drug (IND) toxicology studies in rats and dogs with near perfect results: (1) a zero run failure rate; (2) excellent accuracy and precision for standards and quality controls; and (3) 98% incurred samples within 15% of the original values. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]