A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy.

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.

Environmental factors affecting the risk of generalization for ocular-onset myasthenia gravis: a nationwide cohort study.

BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.

Investigation of Friction and Wear Behavior of Cast Aluminum Alloy Piston Skirt with Graphite Coating Using a Designed Piston Skirt Test Apparatus.

A piston skirt friction and wear apparatus that simulates the contact and the relative motion of piston and cylinder liner in a real engine has been designed and constructed. With this apparatus, the friction and wear behavior of a cast aluminum alloy piston with a graphite coating under different loads was studied, and the effectiveness of the apparatus was confirmed. The total wear of the piston skirt was higher under a higher load, and the upper part of the skirt surface (around the height of the piston pin) was worn more severely. The wear mechanisms were studied and, based on the test results and surface analyses, three main wear modes were believed to occur in the wear process of the piston skirt: abrasive, adhesive, and fatigue wear. The effects of skirt profile design, coating, and surface texturing on the friction and wear behavior of the piston skirt can be investigated well using the proposed apparatus, which can truly reflect actual working conditions and is useful to improve the tribological performances of piston skirts.

Exposure to di-(2-ethylhexyl) phthalate reduces secretion of GDNF via interfering with estrogen pathway and downregulating ERK/c-fos signaling pathway in astrocytes.

Di-(2-ethylhexyl) phthalate (DEHP) is a typical endocrine-disrupting chemical (EDC) that can increase the risk of central nervous system disease. This study aimed to investigate the in vitro and in vivo effects of DEHP exposure on GDNF secretion and the underlying mechanisms. Pregnant Wistar rats were randomly assigned into four groups and administered 0, 30, 300, or 750 mg/kg DEHP daily by oral gavage. In addition, primary astrocytes were exposed to mono-(2-ethylhexyl) phthalate (MEHP), the main metabolite of DEHP. Our results showed that DEHP exposure reduced GDNF levels and downregulated the ERK/c-fos signaling pathway in the cerebral cortex of male, but not female, offspring. Moreover, exogenous estrogen could overcome the decreased GDNF levels in astrocytes caused by MEHP exposure. MEHP also decreased p300 levels and downregulated the ERK/c-fos signaling pathway in primary astrocytes. Honokiol restored GDNF levels following MEHP exposure by activating the ERK/c-fos signaling pathway, while the inhibitor U0126 further reduced the GDNF levels. These results suggested that DEHP exposure could interfere with the normal effects of estrogen in the brain and downregulate the ERK/c-fos signaling pathway to decrease the GDNF secretion from astrocytes in the cerebral cortex.

Artesunate inhibits epithelial-mesenchymal transition in non-small-cell lung cancer (NSCLC) cells by down-regulating the expression of BTBD7.

In recent years, more and more studies have shown that antiparasitic drugs can affect a variety of biological processes of tumor cells and exhibit a potential anti-tumor activity. Although artesunate (ART), a strong bioactive derivative of artemisinin and widely used clinically against malaria, was found to have an inhibitory effect on tumor cells, it is still unclear whether ART could regulate the tumor malignancy of non-small-cell lung cancer (NSCLC) cells. In this study, we aimed to investigate the effect of ART on migration capacities in NSCLC cell lines of A549 and H1975. Cell migration capacity was remarkably inhibited by ART treatment. The expression of epithelial marker E-cadherin was upregulated, while mesenchymal markers (N-cadherin, vimentin and FN1) were inhibited by ART in both protein and mRNA levels in A549 and H1975 cells, indicating ART could suppress the epidermal interstitial transformation (EMT) of NSCLC cells. Meanwhile, BTBD7 was found highly expressed in tumor tissues of NSCLC patient and associated with poor prognosis. The anti-migration activity of ART was found to be mediated by the inhibition of BTBD7 mRNA expression and was reversed when the cells were transiently transfected with the BTBD7 overexpression plasmid. Our study demonstrated the potent anti-migratory activity of ART, thereby presenting it as a new candidate for clinical therapy in NSCLC.

Angiogenesis and Hepatic Fibrosis: Western and Chinese Medicine Therapies on the Road.

Hepatic fibrosis is a common feature of almost all chronic liver diseases. Formation of new vessels (angiogenesis) is a process strictly related to the progressive fibrogenesis which leads to cirrhosis and liver cancer. This review mainly concerns the relationship between angiogenesis and hepatic fibrosis, by considering the mechanism of angiogenesis, cells in angiogenesis, anti-angiogenic and Chinese medicine therapies.