Nonlinear dielectric spectroscopy for label-free detection of respiratory activity in whole cells

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Calcium and vitamin D metabolism in granulomatous diseases.

Overproduction of the active metabolite of vitamin D 1,25-dihydroxyvitamin D (1,25(OH)2D) has been described in sarcoidosis and other granulomatous diseases. High circulating concentrations of 1,25(OH)2D lead to increased intestinal absorption of calcium, possibly to enhanced bone resorption, and may result in hypercalcaemia and/or hypercalciuria. Data obtained in vivo and in vitro demonstrated that the unregulated production of 1,25(OH)2D lies within the granulomatous tissue and is controlled by glucocorticoids. This abnormal production of 1,25(OH)2D seems to be a general phenomenon of granulomatous processes, which is not exceptional in sarcoidosis, but appears seldom in tuberculosis. These abnormalities, however, are not pathognomonic of granulomatous processes, since they have been described in other diseases such as lymphomas.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: re.jinfo:eu-repo/semantics/publishe

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor beta Signaling

BACKGROUND: The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.METHODS: We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.RESULTS: Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocannpal-dependent learning and memory.CONCLUSIONS: Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor beta signaling and hippocampal function.Genetics of disease, diagnosis and treatmen