Objective:To develop a skeleton structure for the flexible manipulator of a robotic system used in natural orifice transluminal endoscopic surgery (NOTES), meeting the performance requirements of surgical actuators.Methods:A flexible manipulator structure and a control strategy for the corresponding structure were designed based on metal braiding technology. Geometric relationship formulas were derived according to the mechanical structure characteristics of the flexible manipulator. A theoretical model was established using the chained beam-constraint-model (CBCM) and mechanical spring theory. The finite element model of the mechanical structure was established, and simulation analysis was performed to verify the accuracy of the theoretical model. The bending stiffness of the metal-braided structure was tested to verify the load capacity of the flexible manipulator.Results:A flexible manipulator structure and a control strategy for the corresponding structure were designed based on metal braiding technology. With proper constraints, the maximum strain of the metal ring as a single stressed unit was about 1.49% when subjected to an axial force of 0.5 N. At this time, the material was in the linear elastic phase and the maximum deformation was about 0.308 9 mm, which was 3.26% higher than the theoretical value. The maximum strain of the manipulator skeleton was about 0.21% in the linear elastic phase. The maximum total deformation was about 7.135 5 mm, which was 6.30% higher than the theoretical value. The flexural stiffness of the manipulator skeleton was calculated to be 3.19 N·mm 2, which was comparable to a flexible manipulator made of shape memory polymers (SMPs) of the same magnitude and size. Conclusions:A skeleton structure for application to NOTES robotic flexible manipulators is developed that meets the support stiffness requirements for performing NOTES surgical tasks.

Genetic composition plays critical roles in the pathogenesis of autism spectrum disorder (ASD). Especially, inherited and de novo intronic variants are often seen in patients with ASD. However, the biological significance of intronic variants is difficult to address. Here, among a Chinese ASD cohort, we identified a recurrent inherited intronic variant in the CHD7 gene, which is specifically enriched in East Asian populations. CHD7 has been implicated in numerous developmental disorders including CHARGE syndrome and ASD. To investigate whether the ASD-associated CHD7 intronic variant affects neural development, we established human embryonic stem cells carrying this variant using CRISPR/Cas9 methods and found that the level of CHD7 mRNA significantly decreased compared to control. Upon differentiation towards the forebrain neuronal lineage, we found that neural cells carrying the CHD7 intronic variant exhibited developmental delay and maturity defects. Importantly, we found that TBR1, a gene also implicated in ASD, was significantly increased in neurons carrying the CHD7 intronic variant, suggesting the intrinsic relevance among ASD genes. Furthermore, the morphological defects found in neurons carrying CHD7 intronic mutations were rescued by knocking down TBR1, indicating that TBR1 may be responsible for the defects in CHD7-related disorders. Finally, the CHD7 intronic variant generated three abnormal forms of transcripts through alternative splicing, which all exhibited loss-of-function in functional assays. Our study provides crucial evidence supporting the notion that the intronic variant of CHD7 is potentially an autism susceptibility site, shedding new light on identifying the functions of intronic variants in genetic studies of autism.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
Humans ; Autism Spectrum Disorder/metabolism* ; Autistic Disorder ; Exome Sequencing ; DNA Copy Number Variations ; East Asian People ; Brain/metabolism* ; Mutation/genetics* ; Genetic Predisposition to Disease/genetics*

Animals ; Brain ; growth & development ; Child ; Eyelids ; abnormalities ; Female ; Humans ; Intellectual Disability ; genetics ; Limb Deformities, Congenital ; genetics ; Mice ; Microcephaly ; genetics ; Mutation, Missense ; N-Myc Proto-Oncogene Protein ; genetics ; Tracheoesophageal Fistula ; genetics

Animals ; SARS-CoV-2 ; Antibodies, Neutralizing ; Macaca mulatta ; COVID-19/prevention & control* ; Antibodies, Viral ; Vaccines