Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.

Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA

Californian Science Students' Perceptions of their Classoom Learning Environments.

This study utilised the What Is Happening In this Class (WIHIC) questionnaire to examine factors that influence Californian student perceptions of their learning environment. Data were collected from 665 USA middle school science students in 11 Californian schools. Several background variables were included in the study to investigate their effects on students’ perceptions, such as student and teacher gender, student ethnic background and socio-economic status (SES), and student age. Class and school variables, such as class ethnic composition, class size and school socioeconomic status were also collected. A hierarchical analysis of variance was conducted to investigate separate and joint effects of these variables. Results from this study indicate that some scales of the WIHIC are more inclined to measure personal or idiosyncratic features of student perceptions of their learning environment whereas other scales contain more variance at the class level. Also, it was found that different variables affect different scale scores. A variable that consistently affected students' perceptions, regardless of the element of interest in the learning environment was student gender. Generally speaking girls perceived their learning environment more positively than did boys

Textured hexagonal and cubic phases of AlN films deposited on Si (100) by DC magnetron sputtering and high power impulse magnetron sputtering

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