Search

Background: Isoleucinyl‐tRNA synthetase (IARS) is encoded by the IARS1 gene and catalyzes the binding of isoleucine to specific tRNA. Objective: This study aims to investigate the pathogenicity of novel IARS1 variants and the genotype–phenotype association, in order to expand the spectrum of pathogenic variants and phenotypes of IARS1‐related disease and provide new evidence for the phenotypic spectrum of IARS1 variants. Methods: Clinical data of the proband were collected, and trio whole‐exome sequencing (WES) was performed on the proband and the parents. Candidate variants were validated using Sanger sequencing. Bioinformatics software was utilized to analyze the functional consequences of identified variants and predict their potential deleteriousness. Results: A 17‐month‐old female patient presented with microcephaly, left external ear malformation, decreased muscle strength and tone in all limbs, epileptic seizures, global developmental delay, and developmental regression. Trio WES identified compound heterozygous variants in the IARS1 gene, c.120‐1G>A and c.2164C>A, which were novel pathogenic and likely pathogenic variants, respectively. The phenotype of developmental regression has not been reported before. Only one patient with IARS1 compound heterozygous variants has been reported in the world to have an epileptic phenotype, and this is the second patient with an epileptic phenotype. Bioinformatics analysis revealed that the splicing variant disrupted the canonical splice donor site, while the missense variant altered the local electrostatics of the IARS1 protein surface, potentially leading to functional abnormalities. Conclusion: This study identified novel IARS1 variants and the phenotype of developmental regression, expanding the spectrum of pathogenic variants and phenotypes of IARS1‐related diseases and providing new evidence for the rare phenotype of epileptic seizures caused by IARS1 variants. [ABSTRACT FROM AUTHOR]

Most cancer‐related deaths are a result of metastasis. The development of small molecular inhibitors reversing cancer metastasis represents a promising therapeutic opportunity for cancer patients. This pan‐cancer analysis identifies oncogenic roles of membrane‐associated phosphatidylinositol transfer protein 3 (PITPNM3), which is crucial for cancer metastasis. Small molecules targeting PITPNM3 must be explored further. Here, PITPNM3‐selective small molecular inhibitors are reported. These compounds exhibit target‐specific inhibition of PITPNM3 signaling, thereby reducing metastasis of breast cancer cells. Besides, by using nanoparticle‐based delivery systems, these PITPNM3‐selective compounds loaded nanoparticles significantly repress metastasis of breast cancer in mouse xenograft models and organoid models. Notably, the results establish an important metastatic‐promoting role for PITPNM3 and offer PITPNM3 inhibition as a therapeutic strategy in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

A multi‐objective integrated optimization framework that considers the manufacturing process in the design of a tapered carbon‐fiber‐reinforced polymer (CFRP) rim structure was established. Firstly, the three‐zone symmetrically stacked CFRP rim structure was proposed and modeled. The bending and radial fatigue and 13° impact of the carbon/aluminum‐assembled wheel composed of CFRP rim and aluminum alloy spoke were analysed. Coupling lay‐up thickness, sequence and angle as design variables, multi‐objective integrated optimization design for the tapered CFRP rim structure was performed through radial basis function neural network surrogate model combined with an elitist non‐dominated sorting genetic algorithm approach. Pareto‐optimal solutions were obtained, and the trade‐off solution was selected through grey relational analysis coupled with entropy weighting method. Finally, the tapered CFRP rim was manufactured through molding and autoclave forming technology. The CFRP rim has a weight saving of 17.2% compared with the previously developed forged magnesium alloy rim of the same size. The bending and radial fatigue and 13° impact performance of the assembled wheel were then validated by corresponding physical test, results of which met GB 36581‐2018 standard. [ABSTRACT FROM AUTHOR]

Land‐use change from cereals to fruit orchards usually results in a high nutrient surplus in soil. The excessive accumulation of nitrogen (N) in soil, mainly as nitrate, leached from the root zone may serve as a long‐term source of surface or groundwater pollution. The N balances and nitrate accumulation in the soil profiles of cereal fields and kiwifruit orchards in the Yujiahe catchment, Shaanxi, China, were compared. Excessive N fertilisation resulted in an excessive N surplus (1,133 kg N ha−1 yr−1) in orchards (8‐times higher than that in cereal fields). More than 77.5% of nitrate in the soil profile (0–400 cm) of the orchards was below a soil depth of 100 cm. The average accumulated nitrate within a profile 0–400 cm of orchards was 3,288 kg N ha−1, which was 16‐fold higher than that of cereal fields. The accumulated nitrate in soil profiles on the downslope (5,959 kg N ha−1) was approximately 2 times higher than that of the upslope in the same sloping orchards. The accumulated nitrate in soil profiles at the lowland zone of the catchment was higher than that of the upland zone. Excessive nitrate moves not only vertically downwards to deeper soil depth but also laterally into lower elevations at both field and catchment scales. The total stored nitrate in the upper soil profile of 400 cm in the catchment was 464.8 Mg N, whereas 94.8% (440.8 Mg N) was in orchards. Thus, changing land use from cereal crops to orchards leads to a high nitrate accumulation in the catchment. [ABSTRACT FROM AUTHOR]