Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions.

BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations. METHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity. RESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability. CONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.

Preferential dissolution behaviour of the austenite phase in Fe-27Cr-xC high chromium cast iron.

Preferential dissolution behaviour of the austenite (γ) phase in Fe-27Cr-xC high chromium cast irons (HCCIs) immersed in 0.1 mol dm-3 H2SO4 + 0.05 mol dm-3 HCl was investigated. Potentiodynamic and potentiostatic polarisation revealed that the primary and eutectic γ phases dissolved preferentially at -0.35 and 0.00 VSilver Silverchloride Electrode potential in sat. KCl (SSE), respectively. The immersion of the HCCIs in the solution showed that the dissolution of the primary γ phase dominated for ca. 1 h, while the primary and eutectic γ phases dissolved after ca. 1 h. However, the carbide phases remained undissolved during the dissolution of the γ phases. Furthermore, the corrosion rate of the HCCIs increased with the increasing C content owing to the increase in the contact potential difference values of the γ and carbide phases. The change in electromotive force due to C addition was related to the accelerated corrosion rate of the γ phases.

Passivation of precipitation-hardened UNS N07718 in a shallow sour aqueous solution.

Passivation of precipitation-hardened UNS N07718 in 5 wt% NaCl + 0.5 wt% CH3COOH was investigated. Cyclic potentiodynamic polarisation revealed that the alloy surface was passivated without active-passive transition behaviour. The alloy surface was in a stable passive state during potentiostatic polarisation at 0.5 VSSE for 12 h. Bode and Mott-Schottky plots showed that the passive film became electrically resistive and less defective with n-type semiconductive properties during the polarisation. X-ray photoelectron spectra revealed that Cr- and Fe-enriched hydro/oxide layers were formed on the outer and inner layers of the passive film, respectively. The thickness of the film was almost constant with the increase of the polarisation time. The outer Cr-hydroxide layer changed into a Cr-oxide layer during the polarisation, resulting in a decreased donor density in the passive film. The film's composition change during the polarisation should be related to the corrosion resistance of the alloy in the shallow sour conditions.

Effect of carbon addition on the passivity of hypoeutectic high chromium cast irons.

The effect of adding C on the passivity of hypoeutectic high chromium cast iron (HCCI) was investigated in a pH 8.4 boric-borate buffer solution. The microstructure of HCCI is composed of austenite and carbide phases, whose fractions and chemical compositions are influenced by the amount of C added. Electrochemical and surface analyses revealed that the addition of C in the HCCI increased the defect densities in the n-type and p-type semiconductive oxide layers on the austenite and carbide phases, respectively.

First-Principles-Based Machine-Learning Molecular Dynamics for Crystalline Polymers with van der Waals Interactions.

Machine-learning (ML) techniques have drawn an ever-increasing focus as they enable high-throughput screening and multiscale prediction of material properties. Especially, ML force fields (FFs) of quantum mechanical accuracy are expected to play a central role for the purpose. The construction of ML-FFs for polymers is, however, still in its infancy due to the formidable configurational space of its composing atoms. Here, we demonstrate the effective development of ML-FFs using kernel functions and a Gaussian process for an organic polymer, polytetrafluoroethylene (PTFE), with a data set acquired by first-principles calculations and ab initio molecular dynamics (AIMD) simulations. Even though the training data set is sampled only with short PTFE chains, structures of longer chains optimized by our ML-FF show an excellent consistency with density functional theory calculations. Furthermore, when integrated with molecular dynamics simulations, the ML-FF successfully describes various physical properties of a PTFE bundle, such as a density, melting temperature, coefficient of thermal expansion, and Young's modulus.

Optimizing machine learning models for granular NdFeB magnets by very fast simulated annealing.

The macroscopic properties of permanent magnets and the resultant performance required for real implementations are determined by the magnets' microscopic features. However, earlier micromagnetic simulations and experimental studies required relatively a lot of work to gain any complete and comprehensive understanding of the relationships between magnets' macroscopic properties and their microstructures. Here, by means of supervised learning, we predict reliable values of coercivity (µ0Hc) and maximum magnetic energy product (BHmax) of granular NdFeB magnets according to their microstructural attributes (e.g. inter-grain decoupling, average grain size, and misalignment of easy axes) based on numerical datasets obtained from micromagnetic simulations. We conducted several tests of a variety of supervised machine learning (ML) models including kernel ridge regression (KRR), support vector regression (SVR), and artificial neural network (ANN) regression. The hyper-parameters of these models were optimized by a very fast simulated annealing (VFSA) algorithm with an adaptive cooling schedule. In our datasets of randomly generated 1,000 polycrystalline NdFeB cuboids with different microstructural attributes, all of the models yielded similar results in predicting both µ0Hc and BHmax. Furthermore, some outliers, which deteriorated the normality of residuals in the prediction of BHmax, were detected and further analyzed. Based on all of our results, we can conclude that our ML approach combined with micromagnetic simulations provides a robust framework for optimal design of microstructures for high-performance NdFeB magnets.

Effect of Different Raw Material Property for the Fabrication on Al/CNT Nanocomposite Using a Ball Mill with a Discrete Element Method (DEM) Simulation.

Carbon nanotubes (CNTs) have received interest as an attractive reinforcing agent metal matrix composites regarded as an increase to mechanical properties of the final product. Aluminum/carbon nanotubes (Al/CNTs) nanocomposites were observed with different raw material at the optimized experimental condition. In this study, Al-based CNTs composites were three different samples, including un-milled Al, un-milled Al with CNTs, and milled Al with CNTs nanocomposites in the presence of additional CNTs with various experimental conditions while using a traditional ball mill (TBM). The particle morphology and CNT dispersions of milled composites were respectively analysed by scanning electron microscopy (SEM) and field emission scanning electron microscopy (FESEM), and the mechanical properties of the fabricated composites were tested. In each sample, CNTs were well dispersed on the surface of Al powder at different experimental conditions for milling in a TBM. The Al/CNTs nanocomposites were processed by compacting, sintering and rolling process. The Vickers hardness was used to characterize the mechanical properties. The hardness of Al/CNTs nanocomposites that were fabricated with milled Al with CNT was higher than the reached to in the nanocomposites prepared with the use of un-milled Al with CNT nanocomposites. Therefore, the discrete element method (DEM) simulation was used to complete quantitative analysis. The flow pattern, impact force, and energy at various experimental conditions are considered. The results of the simulations are compared with experimental data.

Simultaneous increase in strength and ductility by decreasing interface energy between Zn and Al phases in cast Al-Zn-Cu alloy.

Cast-Al alloys that include a high amount of the second element in their matrix have comparatively high strength but low ductility because of the high volume fraction of strengthening phases or undesirable inclusions. Al-Zn alloys that have more than 30 wt% Zn have a tensile strength below 300 MPa, with elongation under 5% in the as-cast state. However, we found that after substitution of 2% Zn by Cu, the tensile strength of as-cast Al-Zn-Cu alloys was 25% higher and ductility was four times higher than for the corresponding Al-35% Zn alloy. Additionally, for the Al-43% Zn alloy with 2% Cu after 1 h solution treatment at 400 °C and water quenching, the tensile strength unexpectedly reached values close to 600 MPa. For the Al-33% Zn alloy with 2% Cu, the tensile strength was 500 MPa with 8% ductility. The unusual trends of the mechanical properties of Al-Zn alloys with Cu addition observed during processing from casting to the subsequent solution treatment were attributed to the precipitation of Zn in the Al matrix. The interface energy between the Zn particles and the Al matrix decreased when using a solution of Cu in Zn.

Effect of processing method on platycodin D content in Platycodon grandiflorum roots.

Platycodon grandiflorum root is a traditional medicine and food material rich in triterpenoid saponins. Its major constituent, platycodin D (PD), is known to have various pharmacological properties, but processing methods may influence the PD content. In this study, a fully validated HPLC-ELSD method was developed for the quantification of PD in various states of 73 P. grandiflorum root samples from East Asia, and it exhibited a marked variation of the content. Furthermore, the effects of processing procedures such as peeling and drying temperature on the PD content were investigated using UPLC-ELSD analysis, and as a result, a significant influence of processing methods such as peeling and heating of samples on the content was confirmed. Specifically, unpeeled samples that were dried at 40 °C showed the greatest PD content. The obtained results could facilitate the reliable standardization of P. grandiflorum for precise authentication and efficacious applications.

Displacement measurement using an optoelectronic oscillator with an intra-loop Michelson interferometer.

We report on measurement of small displacements with sub-nanometer precision using an optoelectronic oscillator (OEO) with an intra-loop Michelson interferometer. In comparison with conventional homodyne and heterodyne detection methods, where displacement appears as a power change or a phase shift, respectively, in the OEO detection, the displacement produces a shift in the oscillation frequency. In comparison with typical OEO sensors, where the frequency shift is proportional to the OEO oscillation frequency in radio-frequency domain, the frequency shift in our method with an intra-loop interferometer is proportional to an optical frequency. We constructed a hybrid apparatus and compared characteristics of the OEO and heterodyne detection methods.

Resonant vortex-core reversal in magnetic nano-spheres as robust mechanism of efficient energy absorption and emission.

We report on novel vortex-core reversal dynamics in nano-spheres of single-vortex spin configuration as revealed by micromagnetic simulations combined with analytical derivations. When the frequency of an AC magnetic field is tuned to the frequency of the vortex-core precession around the direction of a given static field, oscillatory vortex-core reversals occur, and additionally, the frequency is found to change with both the strength of the applied AC field and the particle size. Such resonant vortex-core reversals in nano-spheres may provide a new and efficient means of energy absorption by, and emission from, magnetic nanoparticles, which system can be effectively implemented in bio-applications such as magnetic hyperthermia.

Increasing strength and conductivity of Cu alloy through abnormal plastic deformation of an intermetallic compound.

The precipitation strengthening of Cu alloys inevitably accompanies lowering of their electric conductivity and ductility. We produced bulk Cu alloys arrayed with nanofibers of stiff intermetallic compound through a precipitation mechanism using conventional casting and heat treatment processes. We then successfully elongated these arrays of nanofibers in the bulk Cu alloys to 400% of original length without breakage at room temperature using conventional rolling process. By inducing such an one-directional array of nanofibers of intermetallic compound from the uniform distribution of fine precipitates in the bulk Cu alloys, the trade-off between strength and conductivity and between strength and ductility could be significantly reduced. We observed a simultaneous increase in electrical conductivity by 1.3 times and also tensile strength by 1.3 times in this Cu alloy bulk compared to the conventional Cu alloys.

Identification of cytoprotective constituents of the flower buds of Tussilago farfara against glucose oxidase-induced oxidative stress in mouse fibroblast NIH3T3 cells and human keratinocyte HaCaT cells.

A new cytoprotective compound, 1-[(4S)-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl]-ethanone (1) was isolated from the flower buds of Tussilago farfara L. (Compositae), together with eight known compounds, 3,4-dicaffeoyl isoquinic acid (2), trans-cinnamic acid (3), 4-hydroxyacetophenone (4), 4,5-dicaffeoylquinic acid methyl ester (5), 3,5-dicaffeoylquinic acid methyl ester (6), 4-hydroxybenzoic acid (7), isoquercetrin (8), and ligucyperonol (9). Compounds 2-4 were found in this plant for the first time. The isolates 1-9, were tested for their cytoprotective activities against glucose oxidase-induced oxidative stress in mouse fibroblast NIH3T3 cells and human keratinocyte HaCaT cells. Among them, 1 and 3 showed significant cytoprotective activities as determined by MTT assay and lactate dehydrogenase leakage, indicating their possibility as the potent cytoprotective agents. The structure of 1 was determined by spectroscopic data analysis including 1D- and 2D-NMR experiments, and its absolute configuration was elucidated by a circular dichroism.

Design of exceptionally strong and conductive Cu alloys beyond the conventional speculation via the interfacial energy-controlled dispersion of γ-Al2O3 nanoparticles.

The development of Cu-based alloys with high-mechanical properties (strength, ductility) and electrical conductivity plays a key role over a wide range of industrial applications. Successful design of the materials, however, has been rare due to the improvement of mutually exclusive properties as conventionally speculated. In this paper, we demonstrate that these contradictory material properties can be improved simultaneously if the interfacial energies of heterogeneous interfaces are carefully controlled. We uniformly disperse γ-Al2O3 nanoparticles over Cu matrix, and then we controlled atomic level morphology of the interface γ-Al2O3//Cu by adding Ti solutes. It is shown that the Ti dramatically drives the interfacial phase transformation from very irregular to homogeneous spherical morphologies resulting in substantial enhancement of the mechanical property of Cu matrix. Furthermore, the Ti removes impurities (O and Al) in the Cu matrix by forming oxides leading to recovery of the electrical conductivity of pure Cu. We validate experimental results using TEM and EDX combined with first-principles density functional theory (DFT) calculations, which all consistently poise that our materials are suitable for industrial applications.

Reliable and cost effective design of intermetallic Ni2Si nanowires and direct characterization of its mechanical properties.

We report that a single crystal Ni2Si nanowire (NW) of intermetallic compound can be reliably designed using simple three-step processes: casting a ternary Cu-Ni-Si alloy, nucleate and growth of Ni2Si NWs as embedded in the alloy matrix via designing discontinuous precipitation (DP) of Ni2Si nanoparticles and thermal aging, and finally chemical etching to decouple the Ni2Si NWs from the alloy matrix. By direct application of uniaxial tensile tests to the Ni2Si NW we characterize its mechanical properties, which were rarely reported in previous literatures. Using integrated studies of first principles density functional theory (DFT) calculations, high-resolution transmission electron microscopy (HRTEM), and energy-dispersive X-ray spectroscopy (EDX) we accurately validate the experimental measurements. Our results indicate that our simple three-step method enables to design brittle Ni2Si NW with high tensile strength of 3.0 GPa and elastic modulus of 60.6 GPa. We propose that the systematic methodology pursued in this paper significantly contributes to opening innovative processes to design various kinds of low dimensional nanomaterials leading to advancement of frontiers in nanotechnology and related industry sectors.

Resonantly excited precession motion of three-dimensional vortex core in magnetic nanospheres [corrected].

We found resonantly excited precession motions of a three-dimensional vortex core in soft magnetic nanospheres and controllable precession frequency with the sphere diameter 2R, as studied by micromagnetic numerical and analytical calculations. The precession angular frequency for an applied static field HDC is given as ωMV = γeffHDC, where γeff = γ〈mΓ〉 is the effective gyromagnetic ratio in collective vortex dynamics, with the gyromagnetic ratio γ and the average magnetization component 〈mΓ〉 of the ground-state vortex in the core direction. Fitting to the micromagnetic simulation data for 〈mΓ〉 yields a simple explicit form of 〈mΓ〉 ≈ (73.6 ± 3.4)(lex/2R)(2.20±0.14), where lex is the exchange length of a given material. This dynamic behavior might serve as a foundation for potential bio-applications of size-specific resonant excitation of magnetic vortex-state nanoparticles, for example, magnetic particle resonance imaging.

Suppression of splenic lymphocyte proliferation by Eucommia ulmoides and genipin.

We investigated the modulation of innate and adaptive immune cell activation by Eucommia ulmoides Oliver extract (EUE) and its ingredient genipin. As an innate immunity indicator, the phagocytic activity of macrophages was determined by measuring engulfed, fluorescently labeled Escherichia coli. As a surrogate marker for the respective activation of cellular and humoral adaptive immunity, concanavalin A (Con A) and lipopolysaccharide (LPS) induction of primary splenocyte proliferation was assayed in in vitro and ex vivo systems. EUE and genipin suppressed the proliferation of primary splenic lymphocytes induced by Con A or LPS, but not macrophage phagocytosis. Oral administration of EUE and genipin to mice decreased splenic lymphocyte proliferation induced by Con A or LPS. These results revealed that E. ulmoides and genipin suppressed cellular and humoral adaptive immunity, and they suggest that E. ulmoides and genipin are promising candidates for immunosuppressive drugs that target diseases that involve excessive activation of adaptive immunity.

Metabolomics approach for the discrimination of raw and steamed Gastrodia elata using liquid chromatography quadrupole time-of-flight mass spectrometry.

A liquid chromatography quadrupole time-of-flight mass spectrometry-based metabolomics approach was applied to metabolite profiling of Gastrodia elata in order to identify raw and steamed G. elata and explore potential biomarkers for each processing state. A statistical classification method, significant analysis of microarrays, was used to select influential metabolites from the different forms. Through metabolite selection, several potential biomarkers were determined and assigned by matching mass information with that of reference compounds or by comparing it with data in the literature. Furthermore, the developed method was cross-checked using two validation procedures. The first validation was performed simultaneously with the metabolite profiling of G. elata using all detected metabolites, and the second was performed after the metabolite profiling using representative standard compounds of G. elata. Overall, this study can be applied to quality assurance of G. elata.

A metabolomic approach to determine the geographical origins of Anemarrhena asphodeloides by using UPLC-QTOF MS.

An ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS) method was developed for metabolite profiling of Anemarrhena asphodeloides Bunge from two different geographical origins. In this study, the metabolite profile data obtained using UPLC-QTOF MS was subjected to multivariate statistical analyses, such as the principal component analysis and the hierarchical clustering analysis, to compare metabolite patterns among A. asphodeloides samples. Furthermore, a metabolite selection method known as significance analysis of microarrays (SAM) was applied to further select metabolites and to identify key constituents to efficiently distinguish between geographical origins. The UPLC-QTOF MS analysis successfully classified 21 samples into two distinct groups according to their geographical origins. The validation method used to assess the analytical stability and accuracy of these data is also described. These results suggest that this proposed method is reliable, accurate, and effective for geographic classification of A. asphodeloides, thus guiding its proper use for therapeutic purposes.