Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.

Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2 Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.

Influences on drinking choices among Indigenous and non-Indigenous pregnant women in Australia: A qualitative study.

Despite women's awareness that drinking alcohol in pregnancy can lead to lifelong disabilities in a child, it appears that an awareness alone does not discourage some pregnant women from drinking. To explore influences on pregnant women's choices around alcohol use, we conducted interviews and group discussions with 14 Indigenous Australian and 14 non-Indigenous pregnant women attending antenatal care in a range of socioeconomic settings. Inductive content analysis identified five main influences on pregnant women's alcohol use: the level and detail of women's understanding of harm; women's information sources on alcohol use in pregnancy; how this information influenced their choices; how women conceptualised their pregnancy; and whether the social and cultural environment supported abstinence. Results provide insight into how Indigenous Australian and non-Indigenous pregnant women understand and conceptualise the harms from drinking alcohol when making drinking choices, including how their social and cultural environments impact their ability to abstain. Strategies for behaviour change need to: correct misinformation about supposed 'safe' timing, quantity and types of alcohol; develop a more accurate perception of Fetal Alcohol Spectrum Disorder; reframe messages about harm to messages about optimising the child's health and cognitive outcomes; and develop a holistic approach encompassing women's social and cultural context.

Adaptive response of neonatal sepsis-derived Group B Streptococcus to bilirubin.

Hyperbilirubinemia is so common in newborns as to be termed physiological. The most common bacteria involved in early-onset neonatal sepsis are Streptococcus agalactiae, commonly called Group B Streptococcus (GBS). Whilst previous studies show bilirubin has antioxidant properties and is beneficial in endotoxic shock, little thought has been given to whether bilirubin might have antibacterial properties. In this study, we performed a transcriptomic and proteomic assessment of GBS cultured in the presence/absence of bilirubin. Our analysis revealed that increasing levels of bilirubin (>100 µmol/L) negatively correlated with GBS growth (18% reduction from 0-400 µmol/L on plate model, p < 0.001; 33% reduction from 0-100 µmol/L in liquid model, p = 0.02). Transcriptome analysis demonstrated 19 differentially expressed genes, almost exclusively up-regulated in the presence of bilirubin. Proteomic analysis identified 12 differentially expressed proteins, half over-expressed in the presence of bilirubin. Functional analysis using Gene Ontology and KEGG pathways18 revealed a differential expression of genes involved in transport and carbohydrate metabolism, suggesting bilirubin may impact on substrate utilisation. The data improve our understanding of the mechanisms modulating GBS survival in neonatal hyperbilirubinemia and suggest physiological jaundice may have an evolutionary role in protection against early-onset neonatal sepsis.