Publisher Correction: Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability.

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Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability.

Mutations in the HECT, UBA and WWE domain-containing 1 (HUWE1) E3 ubiquitin ligase cause neurodevelopmental disorder X-linked intellectual disability (XLID). HUWE1 regulates essential processes such as genome integrity maintenance. Alterations in the genome integrity and accumulation of mutations have been tightly associated with the onset of neurodevelopmental disorders. Though HUWE1 mutations are clearly implicated in XLID and HUWE1 regulatory functions well explored, currently much is unknown about the molecular basis of HUWE1-promoted XLID. Here we showed that the HUWE1 expression is altered and mutation frequency increased in three different XLID individual (HUWE1 p.R2981H, p.R4187C and HUWE1 duplication) cell lines. The effect was most prominent in HUWE1 p.R4187C XLID cells and was accompanied with decreased DNA repair capacity and hypersensitivity to oxidative stress. Analysis of HUWE1 substrates revealed XLID-specific down-regulation of oxidative stress response DNA polymerase (Pol) λ caused by hyperactive HUWE1 p.R4187C. The subsequent restoration of Polλ levels counteracted the oxidative hypersensitivity. The observed alterations in the genome integrity maintenance may be particularly relevant in the cortical progenitor zones of human brain, as suggested by HUWE1 immunofluorescence analysis of cerebral organoids. These results provide evidence that impairments of the fundamental cellular processes, like genome integrity maintenance, characterize HUWE1-promoted XLID.

Diet and diet-related disorders in captive ruminants at the national zoological gardens of South Africa.

Although diet-related disorders have received much attention in the zoo literature, evidence-based results on relationships between diet and disease are still rare, often due to a lack of quantitative dietary information that can be linked to clinical or necropsy reports. We investigated 24 species of captive ruminants from one facility for which quantitative feeding instructions and necropsy reports between 1991 and 2012 were available. Species were classified as grazer (GR), intermediate feeder (IM), or browser (BR). Feeding type and body mass were significantly correlated to the diet fed, with smaller and BR species receiving higher proportions of non-roughage diet items. There were no significant differences between feeding types in the occurrence of parakeratosis/ruminitis/acidosis (PRA) at necropsy, but in body condition score, with BR more often in poor and less often in excellent body condition at necropsy. While there was no direct correlation between the proportion of non-roughage diet items and PRA across species, there was a significant effect of the proportion of non-roughage diet items on PRA when body mass was also taken into account: larger species, and those that received more non-roughage diet items, had higher prevalence of PRA. The results underline that diet and lack of structured feed items can be associated with the disease complex of acidosis in ruminants, but also suggest that this is modified by factors related to animal size. These latter may include susceptibility to acidosis, or husbandry-related opportunities to monopolize non-roughage feeds and ingest higher proportions than intended by feeding instructions.