RESUMEN
ßIV spectrin links ankyrinG (AnkG) and clustered ion channels at axon initial segments (AISs) and nodes of Ranvier to the axonal cytoskeleton. Here, we report bi-allelic pathogenic SPTBN4 variants (three homozygous and two compound heterozygous) that cause a severe neurological syndrome that includes congenital hypotonia, intellectual disability, and motor axonal and auditory neuropathy. We introduced these variants into ßIV spectrin, expressed these in neurons, and found that 5/7 were loss-of-function variants disrupting AIS localization or abolishing phosphoinositide binding. Nerve biopsies from an individual with a loss-of-function variant had reduced nodal Na+ channels and no nodal KCNQ2 K+ channels. Modeling the disease in mice revealed that although ankyrinR (AnkR) and ßI spectrin can cluster Na+ channels and partially compensate for the loss of AnkG and ßIV spectrin at nodes of Ranvier, AnkR and ßI spectrin cannot cluster KCNQ2- and KCNQ3-subunit-containing K+ channels. Our findings define a class of spectrinopathies and reveal the molecular pathologies causing nervous-system dysfunction.
Asunto(s)
Axones/patología , Discapacidad Intelectual/genética , Enfermedad de la Neurona Motora/genética , Hipotonía Muscular/congénito , Hipotonía Muscular/genética , Proteínas del Tejido Nervioso/genética , Espectrina/genética , Alelos , Animales , Axones/metabolismo , Células COS , Niño , Preescolar , Chlorocebus aethiops , Femenino , Células HEK293 , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Lípidos , Masculino , Ratones Noqueados , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/fisiopatología , Hipotonía Muscular/complicaciones , Hipotonía Muscular/fisiopatología , Proteínas Mutantes/metabolismo , Mutación/genética , Ratas Sprague-DawleyRESUMEN
This study explores the relationship between the scoring structure and the win or loss of a badminton match, while providing quantitative analytic data using binary entropy to determine the uncertainty of said win or loss. Scoring structure data were collected from the official match records of the top 16 events of the World Badminton Championships from 2006 to 2020 (a total of 10 editions) as collection objects (745 matches and 1,734 sets in all) and were analyzed by means of notational analysis. Our entropy analysis showed that the main factor affecting the certainty of win or loss in men's singles, men's doubles and mixed doubles comes from the number of leading points, and in women's singles and women's doubles from whether the current point is closer to the match point. Our binary-entropy analysis based on scoring structure showed that, to maintain high uncertainty so that players stay competitive, the scoring points of two sides should differ in less than 5; in addition, the decisive factors for victory strongly depend on gender, also justifying research results of previous studies.
RESUMEN
Axon initial segments (AISs) initiate action potentials and regulate the trafficking of vesicles between somatodendritic and axonal compartments. However, the mechanisms controlling AIS assembly remain poorly defined. We performed differential proteomics and found nuclear mitotic apparatus protein 1 (NuMA1) is downregulated in AIS-deficient neonatal mouse brains and neurons. NuMA1 is transiently located at the AIS during development where it interacts with the scaffolding protein 4.1B and the dynein regulator lissencephaly 1 (Lis1). Silencing NuMA1 or protein 4.1B by shRNA disrupts AIS assembly, but not maintenance. Silencing Lis1 or overexpressing NuMA1 during AIS assembly increased the density of AIS proteins, including ankyrinG and neurofascin-186 (NF186). NuMA1 inhibits the endocytosis of AIS NF186 by impeding Lis1's interaction with doublecortin, a potent facilitator of NF186 endocytosis. Our results indicate the transient expression and AIS localization of NuMA1 stabilizes the developing AIS by inhibiting endocytosis and removal of AIS proteins.
Asunto(s)
Segmento Inicial del Axón/metabolismo , Proteínas de Ciclo Celular/genética , Dineínas/genética , Endocitosis/genética , Proteómica , 1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Animales , Ancirinas/genética , Axones/metabolismo , Moléculas de Adhesión Celular/genética , Citoesqueleto/genética , Regulación de la Expresión Génica/genética , Humanos , Ratones , Proteínas de Microfilamentos/genética , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Asociadas a Microtúbulos/genética , Factores de Crecimiento Nervioso/genética , Neuronas/metabolismo , Transporte de Proteínas/genética , ARN Interferente Pequeño/farmacologíaRESUMEN
CONTEXT: Aberrant activation of MAPK has been implicated to play important roles in pathological processes of endometriosis. However, how MAPK are constitutively activated in endometriotic tissues remains largely unknown. microRNA are small noncoding RNA that regulate the stability or translational efficiency of target mRNA by interacting with the 3' untranslated region. Thus, miRNA are thought to be modulators of the transcriptional response, fine-tuning gene expression. OBJECTIVE: The aim of this study was to evaluate the functional roles of microRNA-20a (miR20a) in MAPK activation and the pathogenesis of endometriosis. DESIGN: miR20a expression was analyzed in nonpaired (endometrium = 17; endometriosis = 37) and paired (n = 12) endometriotic tissues by quantitative RT-PCR. Overexpression of miR20a in eutopic endometrial stromal cells or inhibition of miR20a in ectopic endometriotic stromal cells was used to evaluate its impact on ERK phosphorylation and subsequently angiogenesis- and proliferation-related gene expression. RESULTS: Levels of miR20a were up-regulated in endometriotic stromal cells. Elevation of miR20a was up-regulated by hypoxia inducible factor-1α. The up-regulation of miR20a causes the down-regulation of dual-specificity phosphatase-2, which leads to prolonged ERK phosphorylation and an increase in the expression of several angiogenic genes. Furthermore, the up-regulation of miR20a enhances the prostaglandin E(2)-induced expression of fibroblast growth factor-9, a potent mitogen that stimulates both endothelial and endometrial cell proliferation. CONCLUSION: Our findings provide the novel mechanism that not only functionally links together hypoxic stress, miR20a expression, aberrant ERK phosphorylation, and angiogenesis but also demonstrates that miR20a is an important modulator in the development of endometriosis.