Autosomal dominant non-syndromic hearing loss is highly heterogeneous, and eyes absent 4 (EYA4) is a disease-causing gene. Most EYA4 mutations founded in the Eya-homologous region, however, no ...deafness causative missense mutation in variable region of EYA4 have previously been found. In this study, we identified a pathogenic missense mutation located in the variable region of the EYA4 gene for the first time in a four-generation Chinese family with 57 members. Whole-exome sequencing (WES) was performed on samples from one unaffected and two affected individuals to systematically search for deafness susceptibility genes, and the candidate mutations and the co-segregation of the phenotype were verified by polymerase chain reaction amplification and by Sanger sequencing in all of the family members. Then, we identified a novel EYA4 mutation in exon 8, c.511G>C; p.G171R, which segregated with postlingual and progressive autosomal dominant sensorineural hearing loss (SNHL). This report is the first to describe a missense mutation in the variable region domain of the EYA4 gene, which is not highly conserved in many species, indicating that the potential unconserved role of 171G>R in human EYA4 function is extremely important.
Autosomal recessive non-syndromic hearing loss (ARNSHL) is highly heterogeneous, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) have been implicated in its development. To ...date, 35 homozygous mutations in TMC1, identified in over 60 families worldwide, have been shown to be associated with ARNSHL. However, few of these mutations were detected in the Chinese population. In this study, we describe a pathogenic missense mutation located in the T5-T6 domain of TMC1 in a three-generation Chinese family with 14 members.
Whole exome sequencing was performed using samples from one unaffected individual and two affected individuals to systematically search for deafness susceptibility genes. Candidate mutations and cosegregation of the phenotype were verified by polymerase chain reaction and Sanger sequencing in all of the family members.
We identified a novel TMC1 mutation in exon 20, c.1979C>T, p.P660L, which segregated with prelingual autosomal recessive sensorineural hearing loss.
We found a new missense mutation in the T5-T6 domain of TMC1, which is highly conserved in many species. These data support the potential conserved role of p.P660L in human TMC1 function.
Hearing loss is one of the most prevalent human birth defects. Genetic factors contribute to the pathogenesis of deafness. It is estimated that one-third of deafness genes have already been ...identified. The current work is an attempt to find novel genes relevant to hearing loss using guilt-by-profiling and guilt-by-association bioinformatics analyses of approximately 80 known non-syndromic hereditary hearing loss (NSHL) genes. Among the 300 newly identified candidate deafness genes, slc26a2 were selected for functional studies in zebrafish. The slc26a2 gene was knocked down using an antisense morpholino (MO), and significant defects were observed in otolith patterns, semicircular canal morphology, and lateral neuromast distributions in morphants. Loss-of-function defects are caused primarily by apoptosis, and morphants are insensitive to sound stimulation and imbalanced swimming behaviours. Morphant defects were found to be partially rescued by co-injection of human SLC26A2 mRNA. All the results suggest that bioinformatics is capable of predicting new deafness genes and this showed slc26a2 is to be a critical otic gene whose dysfunction may induce hearing impairment.
Twisted and coiled polymer (TCP) artificial muscles represent a promising class of actuators capable of emulating natural skeletal muscle, offering substantial linear actuation and energy density. ...The actuation characteristics of the thermally-activated TCP muscle and twisted fiber are characterized experimentally, emphasizing the influence of the temperature-softening effect. We find that the recovered torque of twisted fiber increases monotonically with temperature while showing a non-monotonical variation with the fiber bias angle. The variations of actuation strain and end torque with three structural parameters of TCP muscles, i.e., fiber bias angle, helical angle, and spring index, are comprehensively investigated. An optimal bias angle and spring index are present. A significant temperature-softening effect of precursor fiber is observed; a polymer becomes softer and more pliable as the temperature increases. A thermo-mechanical model for predicting the effect of temperature-softening on TCP muscle is established and validated with experimental data. This work facilitates precise control and guides the structural optimization design of the thermally-activated TCP muscle.
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•The actuation characteristics of TCP muscles with different structural parameters are investigated experimentally.•The recovered torque of twisted fiber increases monotonically with temperature.•An optimal bias angle and spring index are present.•The temperature-softening effect significantly weakens the actuation performance of TCP muscles.
Elastic ribbons possess the capacity to undergo stretching, bending, and twisting, resulting in a diverse range of morphologies. In this study, we conduct both experimental and numerical ...investigations into the torsional instabilities of clamped ribbons subjected to stretching and twisting loads. The extended Föppl-von Kármán plate model is employed to describe the torsional and tensile responses prior to buckling. Through finite element simulations, we accurately capture the observed evolution of morphologies, spanning from the initial helicoid to a double-layer helicoid, and ultimately to a scrolled yarn structure. As the formation of the double-layer helicoid, the torque, which decreases with the twist during the transverse bending and folding process, gradually increases with the twist until the occurrence of a secondary instability. Furthermore, initial pre-tension enhances the ribbon's capacity to endure torsional deformation, leading to corresponding increases in torque and tension. These findings hold implications for comprehending the intricate deformation mechanisms of slender structures.
•The experimental morphological transitions of a twisted ribbon, from helicoid to double-layer helicoid, and finally to a yarn configuration, are captured through FE simulation.•The formation of the double-layer helicoid in the ribbon enables it to withstand transverse bending once more until the occurrence of secondary instability.•Pre-tension enhances the ribbon's capacity to endure torsional deformation, resulting in corresponding increases in torque and tension.
Cyclic torsion tests are performed on micron-scale copper wires with and without surface passivation to study the role of the higher-order condition in the plastic behavior of thin wires under ...non-proportional loading. A typical strengthening size effect is observed in the symmetric cycles. More obvious strength enhancement exists in the torsional response of passivated copper wires. An unusual Bauschinger effect is found during the loading-unloading cycles, which is more pronounced in passivated wires. The finite element implementation based on Gudmundson's strain gradient plasticity theory is developed for wire torsion to characterize the observed size-dependent phenomena. The higher-order boundary conditions are introduced to simulate the passivated surface. The predicted radial distributions of plastic strain, stress components, and geometrically necessary dislocation density for the passivated and unpassivated wires are given and compared. This work provides a reasonable basis for understanding the role of higher-order conditions of strain gradient plasticity.
•Cyclic torsion tests are performed on micron-scale passivated copper wires.•More pronounced unusual Bauchinger effects exist in passivated wires.•The finite element model is developed based on strain gradients theory.•Passivation effects are predicted by introducing higher-order conditions.
•A micro-torsion instrument with a broad capacity and a high resolution is established.•A high-sensitivity torque transducer based on the flexural pivot is addressed.•Torsion tests on Nylon 6 ...filaments, copper wires, and PET ribbons, are performed.•Torsional instabilities of soft filaments and ribbons, and size effect in the torsion of thin metallic wires are discussed.
A universal torsion instrument with a broad torque capacity and a high resolution for small-scale components is constructed. A high-sensitivity torque transducer based on the flexural pivot with a wide measurement range is addressed. The torque transducer consists of a cylindrical flexural pivot acting as the elastic element, and an optical angle detector involving dual laser displacement sensors. The instrument can measure the torque accurately using the flexural pivot with a known torsional spring constant. By selecting suitable pivots, it allows for a torque capacity ranging from 1.94 × 10-4 to 1.91 × 10-2 N∙m, corresponding to a resolution ranging from 1.94 × 10-9 to 1.91 × 10-7N∙m. The relative uncertainty for the torque measurement is less than 0.8%. Torsion tests on Nylon 6 filaments, copper wires, and soft ribbons were performed with the developed instrument. It shows that the instrument is a helpful tool for characterizing the torsional properties of miniaturized components.
Hereditary hearing impairment is a clinically and genetically heterogeneous disease. Whole‐exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with ...autosomal‐dominant nonsyndromic hearing loss. The pathogenic variant of the gene encoding human topoisomerase IIβ TOP2B (c.G4837C:p.D1613H) was cosegregated with hearing loss in this pedigree and another two variants of TOP2B were detected in 66 sporadic patients with hearing loss. top2b knockdown led to significant defects in zebrafish inner ears and caused downregulation of akt which resulted in inactivation of PI3K‐Akt signalling. As a result, supporting cell and hair cell numbers were reduced through inhibition of the PI3K‐Akt pathway. Therefore, we hypothesized that mutations in TOP2B can cause autosomal‐dominant nonsyndromic hearing impairment through inhibition of the PI3K‐Akt signalling pathway.
Database
The whole‐exome sequence data in the study are available at the Sequence Read Archive database (NCBI) under the accession numbers SRR9050868, SRR9050867, SRR90508676, SRR90508675, SRR90508674, SRR90508673, SRR90508672, SRR90508671, SRR90508679, SRR90508670, SRR9050859. SRR9050858 and SRR9050857, respectively.
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