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

Oxidative stress and mule-driven X-linked intellectual disability

Oxidative Schädigung von Proteinen, Lipiden, RNA und DNA sind die Quelle vieler Erkrankungen, die durch intakte Reparaturmechanismen verhindert werden können. Oxidative DNA Schäden werden, neben Alterung und Krebs, mit neurodegenerativen Erkrankungen in Verbindung gebracht. Eine der häufigsten oxidativen DNA Schäden ist 7,8-dihydro-8-oxoguanin (8-oxo-G), welches falsche Basenpaarung mit Adenosin eingeht und dadurch das Risiko von G:C→T:A Transversionsmutationen birgt. Die Proteine MutY Homolog (MutYH) und DNA Polymerase λ (Pol λ) reparieren neu generierte mutagene A:8-oxo-G Paare. Dieser Prozess wird auch durch die Mcl-1 Ubiquitin Ligase E3 (Mule) kontrolliert, indem Mule Pol λ ubiquitiniert und somit zu dessen Degradation führt. Um die physiologische Bedeutung der MutYH/Pol λ vermittelten Basenexzisionsreparatur (BER) zu erläutern, wurden die Auswirkungen mutierten Mules in Patienten mit X-assoziierter mentaler Behinderung (XLID) untersucht. Die Resultate zeigen, dass die Proteinmengen wie auch Aktivität von MutYH und Pol λ im Vergleich mit einem gesunden Individuum in den Zellen von XLID-Patienten mit mutiertem Mule verändert sind. Diese Ergebnisse unterstützen einen ursächlichen Zusammehang zwischen mutiertem Mule und der Entstehung neurodegenerativer Erkrankungen

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 nonroughage 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

Supply chain environmental R&D cooperation and product performance: Exploring the network dynamics of positional embeddedness

Companies increasingly need to work with their partners to address sustainability issues, but benefits from environmental R&D cooperation can be limited by the complexity of its management. This paper examines how the interplay between dyadic and network relationships can contribute to increase the success of environmental R&D cooperation. Using secondary data, we examine whether the positional embeddedness in the supply network structure of partners engaged in environmental R&D cooperation amplifies the effects of cooperation on product performance. Non-monotonic effects of environmental R&D cooperation and embeddedness are also tested. The results indicate that the positional embeddedness of partners triggered by multiple sourcing strategy amplifies the effects of environmental R&D cooperation on product environmental performance. The interaction effects become however insignificant in the presence of increasing complexity and excessive environmental R&D cooperation