The 5q31-linked corneal dystrophies are heterogeneous autosomal-dominant eye disorders pathologically characterized by the progressive accumulation of aggregated proteinaceous deposits in the cornea, which manifests clinically as severe vision impairment. The 5q31-linked corneal dystrophies are commonly caused by mutations in the TGFBI (transforming growth factor-β-induced) gene. However, despite the identification of the culprit gene, the cellular roles of TGFBI and the molecular mechanisms underlying the pathogenesis of corneal dystrophy remain poorly understood. Here we report the identification of periostin, a molecule that is highly related to TGFBI, as a specific TGFBI-binding partner. The association of TGFBI and periostin is mediated by the amino-terminal cysteine-rich EMI domains of TGFBI and periostin. Our results indicate that the endogenous TGFBI and periostin colocalize within the trans-Golgi network and associate prior to secretion. The corneal dystrophy-associated R124H mutation in TGFBI severely impairs interaction with periostin in vivo. In addition, the R124H mutation causes aberrant redistribution of the mutant TGFBI into lysosomes. We also find that the periostin-TGFBI interaction is disrupted in corneal fibroblasts cultured from granular corneal dystrophy type II patients and that periostin accumulates in TGFBI-positive corneal deposits in granular corneal dystrophy type II (also known as Avellino corneal dystrophy). Together, our findings suggest that TGFBI and periostin may play cooperative cellular roles and that periostin may be involved in the pathogenesis of 5q31-linked corneal dystrophies.
This paper presents a strategy for mitigating the electric field of 170kW GIS spacers. Improve electric field concentration using RMSE techniques using gradient variation. Since the boundary between the two media with different permittivity affects the change in the electric field, it was designed using the optimal technique proposed from the viewpoint of shape control based on the boundary. The proposed from the viewpoint of shape control based on the boundary. The proposed optimal technique was optimized using the RMSE technique using the gradient variation to compare the degree of mitigation of the electric field mitigation conditions with several deformed shapes. Also, the optimal shape for electric field mitigation is selected among the modified shapes suggested in this paper through the verified RMSE-based optimal technique using gradient variation.
The progressive degeneration of granular corneal dystrophy type 2 (GCD2) corneal fibroblasts is associated with altered mitochondrial function, but the underlying mechanisms are incompletely understood. We investigated whether an imbalance of mitochondrial dynamics contributes to mitochondrial dysfunction of GCD2 corneal fibroblasts. Transmission electron microscopy revealed several small, structurally abnormal mitochondria with altered cristae morphology in GCD2 corneal fibroblasts. Confocal microscopy showed enhanced mitochondrial fission and fragmented mitochondrial tubular networks. Western blotting revealed higher levels of MFN1, MFN2, and pDRP1 and decreased levels of OPA1 and FIS1 in GCD2. OPA1 reduction by short hairpin RNA (shRNA) resulted in fragmented mitochondrial tubular networks and increased susceptibility to mitochondrial stress-induced apoptosis. A decrease in the mitochondrial biogenesis-related transcription factors NRF1 and PGC1α was observed, while there was an increase in the mitochondrial membrane proteins TOM20 and TIM23. Additionally, reduced levels of mitochondrial DNA (mtDNA) were exhibited in GCD2 corneal fibroblasts. These observations suggest that altered mitochondrial fission/fusion and biogenesis are the critical molecular mechanisms that cause mitochondrial dysfunction contributing to the degeneration of GCD2 corneal fibroblasts.
Abstract We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced ( TGFBI ) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole- TGFBI . The patient’s family was tested to determine the pedigrees. Five novel mutations (p.His174Asp, p.Ile247Asn, p.Tyr88Cys, p.Arg257Pro, and p.Tyr468*) and two known mutations (p.Asn544Ser and p.Arg179*) in TGFBI were identified, along with p.Arg124His, in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.Arg124His and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.Ile247Asn and p.Asn544Ser); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.Ile247Asn). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype-phenotype correlation and additional care when treating TGFBI corneal dystrophies.
This paper presents the small-signal models of a three-phase transformer. The derived small-signal models reflect the circuit's practical impedances caused by the distribution and the low frequency magnetic transformers which are parts of the hybrid transformer. To simplify the model derivations, the impedances are incorporated in the LC filters which are attached to the input and the output of the back-to-back power converter. The state equations of the hybrid transformer are established, and the small-signal models are derived. Furthermore, the simplified models are suggested and compared with the originally derived small-signal models. Using the derived simplified models, the secondary constant voltage controller of the power stage is designed. The simulation and experimental results verify the effectiveness of the derived small-signal models and the controller design method.
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