Establishing Galleria mellonella as an invertebrate model for the emerging multi-host pathogen Helcococcus ovis

ABSTRACTHelcococcus ovis (H. ovis) can cause disease in a broad range of animal hosts, including humans, and has been described as an emerging bacterial pathogen in bovine metritis, mastitis, and endocarditis. In this study, we developed an infection model that showed H. ovis can proliferate in the hemolymph and induce dose-dependent mortality in the invertebrate model organism Galleria mellonella (G. mellonella). We applied the model and identified H. ovis isolates with attenuated virulence originating from the uterus of a healthy post-partum dairy cow (KG38) and hypervirulent isolates (KG37, KG106) originating from the uterus of cows with metritis. Medium virulence isolates were also isolated (KG36, KG104) from the uterus of cows with metritis. A major advantage of this model is that a clear differentiation in induced mortality between H. ovis isolates was detected in just 48 h, resulting in an effective infection model able to identify virulence differences between H. ovis isolates with a short turnaround time. Histopathology showed G. mellonella employs hemocyte-mediated immune responses to H. ovis infection, which are analogous to the innate immune response in cows. In summary, G. mellonella can be used as an invertebrate infection model for the emerging multi-host pathogen Helcococcus ovis

Erratum: Correction: Transcriptional regulation of intermediate progenitor cell generation during hippocampal development (doi: 10.1242/dev.140681) (Development (Cambridge, England) (2016) 143 24 (4620-4630) PII: dev169631)

There was an error in Development (2016) 143, 4620-4630 (doi: 10.1242/dev.140681). On page 11 of the supplementary information, an equation to calculate Tc was given incorrectly as Tc=Ts/(BrdU+/BrdU–). The correct equation is Tc=Ts/(BrdU+/Radial Glia). The correct equation was used to calculate the Tc values presented in Figure 3E; therefore, this error does not affect the scientific conclusions of the paper. The authors apologise to readers for this mistake

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β 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 β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-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 β signaling and hippocampal function