Candidate gene variant effects on language disorders in Robinson Crusoe Island

Abstract

Background: Robinson Crusoe Island is a geographically and socially isolated settlement located over 600?km west of the Port of Valparíso, Chile. An unusually high incidence (30%) of the Chilean equivalent of developmental language disorder (in Spanish, trastorno especifico de lenguaje (TEL)), has been reported in Islander children, with 90% of these affected children found to be direct descendants of a pair of original founder-brothers, therefore strongly suggesting a shared genetic basis.

Aim: This study reports a comprehensive examination of 34 genes that have been previously directly implicated in language-related mechanisms. It utilises whole-genome sequencing to investigate potential underlying variants in seven TEL affected and 10 unaffected islanders. The aim was to identify the underlying genetic cause of the TEL phenotype under two inheritance model paradigms; Mendelian monogenic and complex susceptibility.

Subjects and methods: A targeted candidate gene approach was used to look for rare, shared variants that may underlie the diagnosis of TEL in a Mendelian genetic model. This study tested whether an overall burden of rare variants is enriched in individuals affected by TEL or with Islanders related to the founder-brother lineage. It further examined if any variants segregate with affection status or with founder-brother-related status and, therefore, may increase risk of developing a language disorder as part of a complex model. Finally, gene-based tests were performed to evaluate relationships between combined variation across candidate genes and TEL affection status.

Results: No single pathogenic rare variant segregated with either affection or founder-related status within the 34 candidate genes. Additionally, no evidence was found of an overall increased variant burden in TEL individuals compared to those with TLD. Gene-based analysis found no clear association between the combined effects of variants across the 34 genes and affection status or founder-brother-relatedness.

Conclusion: The high prevalence of language disorders found on Robinson Crusoe Island is not caused by either a shared high-impact variant, or an increased burden of variants within candidate genes previously implicated in language disorders. We have comprehensively tested for ‘low hanging fruit’ in genes implicated in language disorders. Therefore, the underlying cause of TEL on Robinson Crusoe lies outside of these known language disorder genes, or within a complex susceptibility model.     

Structure and Mechanical Properties of Shipbuilding Steel Obtained by Direct Laser Deposition and Cold Rolling

The study of the formation of microstructural features of low-alloy bainite-martensitic steel 09CrNi2MoCu are of particular interest in additive technologies. In this paper, we present a study of cold-rolled samples after direct laser deposition (DLD). We investigated deposited samples after cold plastic deformation with different degrees of deformation compression (50, 60 and 70%) of samples from steel 09CrNi2MoCu. The microstructure and mechanical properties of samples in the initial state and after heat treatment (HT) were analyzed and compared with the samples obtained after cold rolling. The effect on static tensile strength and impact toughness at −40 °C in the initial state and after cold rolling was investigated. The mechanical properties and characteristics of fracture in different directions were determined. Optimal modes and the degree of cold rolling deformation compression required to obtain balanced mechanical properties of samples obtained by additive method were determined. The influence of structural components and martensitic-austenitic phase on the microhardness and mechanical properties of the obtained samples was determined.     

Paeonol extracted from Paeonia suffruticosa Andr. ameliorated UVB‐induced skin photoaging via DLD/Nrf2/ARE and MAPK/AP‐1 pathway

Paeonia suffruticosa Andr. (PS) has been used in traditional Chinese medicine for a long time. However, there are no studies that investigate the preventive effects of PS on ultraviolet B (UVB)‐induced photoaging. In this study, paeonol (PA) was detected the main compound in PS root. In vitro, PS and PA significantly inhibited UVB‐induced phosphorylation of mitogen‐activated protein kinase and activator protein 1 in keratinocytes, which consequently led to degradation of procollagen type I. On the other hand, PS and PA increased NAD(P)H:quinone oxidoreductase 1 and heme oxygenase‐1 expression, confirmed by greater nuclear accumulation of nuclear factor E2‐releated factor 2 (Nrf2). Furthermore, this study proved that the endogenous antioxidant system Nrf2/antioxidant response element was regulated by dihydrolipoamide dehydrogenase, a tricarboxylic acid (TCA) cycle‐associated protein whose level was decreased after UVB exposure. PS and PA promoted the production of dihydrolipoamide dehydrogenase, as well as the activation of Nrf2 and antioxidant response element, resulting in preventing procollagen type I ruined caused by UVB. In vivo, topical application of PS and PA attenuated UVB‐induced matrix metalloproteinase‐1 production and promoted procollagen type I in hairless mice. These results suggested PA a promising botanical in protecting skin from UVB‐induced photoaging.