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PurposePreaxial polydactyly (PPD) is a common congenital hand malformation classified into four subtypes (PPD I-IV). Variants in the zone of polarizing activity regulatory sequence (ZRS) within intron 5 of the LMBR1 gene are linked to most PPD types. However, the genes responsible for PPD I and the underlying mechanisms are unknown.MethodsA rare large four-generation family with isolated PPD I was subjected to genome-wide genotyping and sequence analysis. In vitro and in vivo functional studies were performed in Caco-2 cells, 293T cells, and a knockin transgenic mouse model.ResultsA novel g.101779T>A (reference sequence: NG_009240.2; position 446 of the ZRS) variant segregates with all PPD I-affected individuals. The knockin mouse with this ZRS variant exhibited PPD I phenotype accompanying ectopic and excess expression of Shh. We confirmed that HnRNP K can bind the ZRS and SHH promoters. The ZRS mutant enhanced the binding affinity for HnRNP K and upregulated SHH expression.ConclusionOur results identify the first PPD I disease-causing variant. The variant leading to PPD I may be associated with enhancing SHH expression mediated by HnRNP K. This study adds to the ZRS-associated syndromes classification system for PPD and clarifies the underlying molecular mechanisms.

This study presents an error flow research method for simulation models of hydraulic systems in construction machinery based on the state-space approach, aiming to ensure the reliable application of digital twin models. Initially, a comprehensive analysis of errors in the simulation modeling of hydraulic systems in construction machinery was conducted, highlighting simulation model parameters as the primary error sources. Subsequently, a set of metrics for assessing the accuracy of simulation models was developed. Following this, an error flow analysis method for simulation models of hydraulic systems in construction machinery was explored based on the state space approach, delving into the sources, transmission, and accumulation of errors in the simulation modeling of valve-controlled cylinder systems. The research results unequivocally indicate that the spring stiffness, viscous damping coefficient, and hydraulic cylinder external leakage coefficient are critical parameters affecting the accuracy of valve-controlled cylinder system simulation models. Furthermore, it was observed that the simulation model of the control valve has a significantly greater impact on the errors in the valve-controlled cylinder system simulation model than the hydraulic cylinder model. In conclusion, the reliability of the error flow model was confirmed through simulation experiments, revealing a maximum relative error of only 3.73% between the error flow model and the results of the simulation experiments. [ABSTRACT FROM AUTHOR]

Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings. Synopsis: In this study, MET was identified as a causative gene for arthrogryposis, characterized by congenital contractures of two or more parts of the body. The mutant MET p.Y1234C impaired activation of MET tyrosine kinase, resulting in muscular dysplasia of the limbs. MET p.Y1234C mutation was identified in a four‐generation arthrogryposis pedigree.Muscular dysplasia of the upper arms and hands was observed in the arthrogryposis patients.In vitro, MET p.Y1234C was responsible for the failure in MET tyrosine kinase activation.In vivo, Met p.Y1232C led to defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts. In this study, MET was identified as a causative gene for arthrogryposis, characterized by congenital contractures of two or more parts of the body. The mutant MET p.Y1234C impaired activation of MET tyrosine kinase, resulting in muscular dysplasia of the limbs. [ABSTRACT FROM AUTHOR]

Background: Multiple epiphyseal dysplasia (MED) is a heterogeneous genetic condition characterized by variable phenotypes, such as short stature (mild to moderate), joint deformities, abnormal gait, scoliosis, and brachydactyly. Recessive mutations in the SLC26A2 gene cause a phenotype of multiple epiphyseal dysplasia-4 (MED-4). In the present study, we identified novel compound heterozygous mutations in the SLC26A2 gene in a Chinese family with two affected sibs with MED-4. Case presentation: Radiographs revealed hip dysplasia, brachydactyly and scoliosis in patient 1. Radiological examinations in patient 2 also showed hip dysplasia recently. Both of them were diagnosed with MED-4. SLC26A2 c.824 T > C and SLC26A2 c.1198C > T were identified in two siblings in this family, which were inherited from both parents, one mutation from each. Conclusions: This is the first Chinese MED-4 family attributed to SLC26A2 mutations, and these results show that these novel compound heterozygous mutations in SLC26A2 contribute to MED-4. [ABSTRACT FROM AUTHOR]

Background: The aim of this research is to establish and validate a prognostic model for predicting prognosis in non-small cell lung cancer (NSCLC) patients with bone metastases. Methods: Overall, 176 NSCLC patients with bone metastases were retrospectively evaluated in the research. We employed the LASSO-Cox regression method to select the candidate indicators for predicting the prognosis among NSCLC patients complicated with bone metastases. We employed the receiver operating characteristic curve (ROC) and the concordance index (C-index) to assess the discriminative ability. Results: Based on the LASSO-Cox regression analysis, 9 candidate indicators were screened to build the prognostic model. The prognostic model had a higher C-index in the training cohort (0.738, 95% CI: 0.680-0.796) and the validation cohort (0.660, 95% CI: 0.566-0.754) than the advanced lung cancer inflammation index (ALI). Furthermore, the AUCs of the 1-, 2-, and 3-year OS predictions for the prognostic model were higher than ALI in both cohorts. Kaplan-Meier curves and the estimated restricted mean survival time (RMST) values showed that the patients in the low-risk subgroup had the lower probabilities of cancer-specific mortality than high-risk subgroup. Conclusions: The prognostic model could provide clinicians with precise information and facilitate individualized treatment for patients with bone metastases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Mutation of the MAPK7 gene was related to human scoliosis. Mapk7 regulated the development of limb bones and skulls in mice. However, the role of MAPK7 in vertebral development is still unclear. In this study, we constructed Col2a1-cre; Mapk7 f/f transgenic mouse model to delete Mapk7 in cartilage, which displayed kyphosis and osteopenia. Mechanistically, Mapk7 loss decreased MEF2C expression and thus activated PTEN to oppose PI3K/AKT signaling in vertebral growth plate chondrocytes, which impaired chondrocyte hypertrophy and attenuated vertebral ossification. In vivo , systemic pharmacological activation of AKT rescued impaired chondrocyte hypertrophy and alleviated mouse vertebral defects caused by Mapk7 deficiency. Our study firstly clarified the mechanism by which MAPK7 was involved in vertebral development, which might contribute to understanding the pathology of spinal deformity and provide a basis for the treatment of developmental disorders of the spine., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Intervertebral disc degeneration (IDD) is the leading cause of low back pain (LBP). However, effective therapeutic drugs for IDD remain to be further explored. Inflammatory cytokines play a pivotal role in the onset and progression of IDD. Dihydroartemisinin (DHA) has been well reported to have powerful anti-inflammatory effects, but whether DHA could ameliorate the development of IDD remained unclear. In this study, the effects of DHA on extracellular matrix (ECM) metabolism and cellular senescence were firstly investigated in nucleus pulposus cells (NPCs) under tumor necrosis factor alpha (TNF α )-induced inflammation. Meanwhile, AKT agonist sc-79 was used to determine whether DHA exerted its actions through regulating PI3K/AKT and NF- κ B signaling pathways. Next, the therapeutic effects of DHA were tested in a puncture-induced rat IDD model. Finally, we detected the activation of PI3K/AKT and NF- κ B signaling pathways in clinical degenerative nucleus pulposus specimens. We demonstrated that DHA ameliorated the imbalance between anabolism and catabolism of extracellular matrix and alleviated NPCs senescence induced by TNF α in vitro . Further, we illustrated that DHA mitigated the IDD progression in a puncture-induced rat model. Mechanistically, DHA inhibited the activation of PI3K/AKT and NF- κ B signaling pathways induced by TNF α , which was undermined by AKT agonist sc-79. Molecular docking predicted that DHA bound to the PI3K directly. Intriguingly, we also verified the activation of PI3K/AKT and NF- κ B signaling pathways in clinical degenerative nucleus pulposus specimens, suggesting that DHA may qualify itself as a promising drug for mitigating IDD., Competing Interests: The authors declare no conflict of interest regarding the publication of this paper., (Copyright © 2022 Zhiheng Liao et al.)