ABSTRACT
Primary ciliary dyskinesia (PCD) is a congenital, motile ciliopathy with pleiotropic symptoms. Although nearly 50 causative genes have been identified, they only account for approximately 70% of definitive PCD cases. Dynein axonemal heavy chain 10 (DNAH10) encodes a subunit of the inner arm dynein heavy chain in motile cilia and sperm flagella. Based on the common axoneme structure of motile cilia and sperm flagella, DNAH10 variants are likely to cause PCD. Using exome sequencing, we identified a novel DNAH10 homozygous variant (c.589C > T, p.R197W) in a patient with PCD from a consanguineous family. The patient manifested sinusitis, bronchiectasis, situs inversus, and asthenoteratozoospermia. Immunostaining analysis showed the absence of DNAH10 and DNALI1 in the respiratory cilia, and transmission electron microscopy revealed strikingly disordered axoneme 9+2 architecture and inner dynein arm defects in the respiratory cilia and sperm flagella. Subsequently, animal models of Dnah10-knockin mice harboring missense variants and Dnah10-knockout mice recapitulated the phenotypes of PCD, including chronic respiratory infection, male infertility, and hydrocephalus. To the best of our knowledge, this study is the first to report DNAH10 deficiency related to PCD in human and mouse models, which suggests that DNAH10 recessive mutation is causative of PCD.
Subject(s)
Humans , Male , Animals , Mice , Semen/metabolism , Dyneins/metabolism , Cilia/metabolism , Mutation , Ciliary Motility Disorders/geneticsABSTRACT
ABSTRACT:Objective To detect the expressions of thioredoxin (TRX1)and c-jun-activation-domain binding protein-1 (JAB1)in patients with acute myelogenous leukemia (AML)and healthy controls,and measure the TRX1 level in AML patients at different stages for evaluating its clinical significance.Methods The expressions of TRX1 and JAB1 in leukemia samples were analyzed by RT-PCR and Western blot at mRNA and protein levels, respectively.The correlation between TRX1 and JAB1,and the relationship between the gene expression and peripheral blood leukocytes count were also analyzed.Furthermore,serum TRX1 was measured by ELISA.Results TRX1 and JAB1 expressions at both mRNA and protein levels were obviously upregulated in leukemia patients (P<0.05). TRX1 was positively related to JAB1 in both newly diagnosed and recurrent AML patients.And high levels of TRX1 and JAB1 expressions were associated with white blood cell (WBC)counts in AML patients (P<0.05).Moreover, abundance of TRX1 in serum was significantly greater in AML patients,especially in the patients with recurrent AML,than in healthy donors (P<0.05).Conclusion There is a positive correlation between the expressions of TRX1 and JAB1 ,which is closely related to the occurrence and progression of AML.
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Objective To study the mechanism of oxidative stress involved in the pathogenesis and relapse of acute monocytic leukemia (M5 ).Methods We detected reactive oxide species (ROS)levels,conducted plasma analysis obtained from 76 M5 patients at diagnosis and at relapse,and observed the ultrastructure of mitochondria of mononuclear cells in peripheral blood by transmission electron microscope.Results Compared with that in the control group,the average fluorescence intensity of intracellular ROS was significantly increased in M5 groups, especially in the relapse patients (P < 0.05 ).Low total antioxidative capacity (T-AOC)and antioxidant enzyme activity were characteristic of M5 at both diagnosis and relapse. However, lactate dehydrogenase (LDH ), malondialdehyde (MDA)and 8-hydroxy-2’-deoxyguanine (8-OHdG)increased significantly at both diagnosis and relapse (P < 0.05 ).Prominent ultrastructural abnormalities (mitochondrial swelling,outer membrane blebs,and aberrant cristae disorder)were present in patients with primary M5,and they were obviously abnormal in relapsing M5 patients.Conclusion Oxidative stress is the initiating factor of M5.Mitochondria are the main intracellular location for ROS generation.To maintain the dynamic balance between ROS and antioxidant defence may be the critical factor for preventing relapse.
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Atherosclerosis is the most important cause of ischemic stroke. microRNAs can play an important role in the lipid metabolism, vascular inflammatory response, angiogenesis, as wel as smooth muscle cel proliferation and phenotypic conversion, etc. by regulating the functions of vascular endothelial cel s, vascular smooth muscle cel s, and mononuclear macrophages. It is closely associated with the occurrence and development of atherosclerosis. This article mainly reviews the regulatory effect of microRNAs on lipid metabolism and vascular inflammatory response in pathogenesis of atherosclerosis.
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DNA methylation is closely related to the genesis and development of glioma.The CpG islands hypermethylation in promoter region of DNA repair genes,cell cycle controlling genes,apoptosis related genes,tumor suppressor genes and invasion related genes are found in glioma.Finding the specific methylation profile and molecular marker of glioma is helpful for the pathology class,early diagnosis and prognostic evalua-tion.Meanwhile,DNA methylation has the characteristic of reversibility,which may provide new ways for the treatment of glioma.