Further evidence for a parent-of-origin effect at the NOP9 locus on language-related phenotypes

Background - Specific language impairment (SLI) is a common neurodevelopmental disorder, observed in 5–10 % of children. Family and twin studies suggest a strong genetic component, but relatively few candidate genes have been reported to date. A recent genome-wide association study (GWAS) described the first statistically significant association specifically for a SLI cohort between a missense variant (rs4280164) in the NOP9 gene and language-related phenotypes under a parent-of-origin model. Replications of these findings are particularly challenging because the availability of parental DNA is required. Methods - We used two independent family-based cohorts characterised with reading- and language-related traits: a longitudinal cohort (n = 106 informative families) including children with language and reading difficulties and a nuclear family cohort (n = 264 families) selected for dyslexia. Results - We observed association with language-related measures when modelling for parent-of-origin effects at the NOP9 locus in both cohorts: minimum P = 0.001 for phonological awareness with a paternal effect in the first cohort and minimum P = 0.0004 for irregular word reading with a maternal effect in the second cohort. Allelic and parental trends were not consistent when compared to the original study. Conclusions - A parent-of-origin effect at this locus was detected in both cohorts, albeit with different trends. These findings contribute in interpreting the original GWAS report and support further investigations of the NOP9 locus and its role in language-related traits. A systematic evaluation of parent-of-origin effects in genetic association studies has the potential to reveal novel mechanisms underlying complex traits

Structure of the hDmc1-ssDNA filament reveals the principles of its architecture

In eukaryotes, meiotic recombination is a major source of genetic diversity, but its defects in humans lead to abnormalities such as Down's, Klinefelter's and other syndromes. Human Dmc1 (hDmc1), a RecA/Rad51 homologue, is a recombinase that plays a crucial role in faithful chromosome segregation during meiosis. The initial step of homologous recombination occurs when hDmc1 forms a filament on single-stranded (ss) DNA. However the structure of this presynaptic complex filament for hDmc1 remains unknown. To compare hDmc1-ssDNA complexes to those known for the RecA/Rad51 family we have obtained electron microscopy (EM) structures of hDmc1-ssDNA nucleoprotein filaments using single particle approach. The EM maps were analysed by docking crystal structures of Dmc1, Rad51, RadA, RecA and DNA. To fully characterise hDmc1-DNA complexes we have analysed their organisation in the presence of Ca2+, Mg2+, ATP, AMP-PNP, ssDNA and dsDNA. The 3D EM structures of the hDmc1-ssDNA filaments allowed us to elucidate the principles of their internal architecture. Similar to the RecA/Rad51 family, hDmc1 forms helical filaments on ssDNA in two states: extended (active) and compressed (inactive). However, in contrast to the RecA/Rad51 family, and the recently reported structure of hDmc1-double stranded (ds) DNA nucleoprotein filaments, the extended (active) state of the hDmc1 filament formed on ssDNA has nine protomers per helical turn, instead of the conventional six, resulting in one protomer covering two nucleotides instead of three. The control reconstruction of the hDmc1-dsDNA filament revealed 6.4 protein subunits per helical turn indicating that the filament organisation varies depending on the DNA templates. Our structural analysis has also revealed that the N-terminal domain of hDmc1 accomplishes its important role in complex formation through domain swapping between adjacent protomers, thus providing a mechanistic basis for coordinated action of hDmc1 protomers during meiotic recombination

Adaptação do inventário parental “Language Use Inventory (LUI)” para crianças entre 18 e 47 meses para o português europeu : estudo piloto

Language acquisition and development takes in account the child’s interaction with the surrounding environment. Daily social interactions with people and communication with others allow the child to acquire language being pragmatics considered a system of rules that support the communicative use of language. Identification and assessment of children at risk for language disorders are crucial in order to carry out an effective early intervention. This study was carried out taking into account first, the relevance of pragmatics as a component of language, and second the lack of assessment tools in Portugal to assess these abilities. Therefore, the aim of this study consists on the translation, adaptation and validation of the inventory “Language Use Inventory” (LUI), to European Portuguese. The LUI is a standardized parent report measure designed to assess pragmatic language development in children within 18- to 47-month-old.Objetivo: A aquisição e o desenvolvimento da linguagem resultam da interação da criança com o meio ambiente. As interações sociais cotidianas com as pessoas e a comunicação com outros permitem que a criança adquira linguagem, sendo a pragmática o sistema de regras que suporta o uso comunicativo da linguagem. A identificação e a avaliação de crianças em risco de desenvolverem transtornos de linguagem são cruciais, tendo em vista a intervenção precoce eficaz. Tendo em vista a relevância da pragmática como componente da linguagem e a escassez, em Portugal, de instrumentos de avaliação da linguagem validados para idades precoces, a finalidade deste estudo consistiu na tradução, adaptação e validação do instrumento Language Use Inventory (LUI), para o português europeu. O LUI é um inventário parental que avalia o desenvolvimento da pragmática entre os 18 e os 47 meses. Métodos: Foram adotados todos os procedimentos recomendados pelas diretrizes internacionais sobre a adaptação de testes, culminando em estudo piloto com uma amostra de 120 inventários, respondidos pelos pais/cuidadores de crianças portuguesas da referida faixa etária. Resultados: Os coeficientes de consistência interna (Alfa de Cronbach) para a versão portuguesa do LUI situaram-se em 0,97 para a escala total e entre 0,71 e 0,96 para as subescalas. Conclusão: Os resultados preliminares dos estudos de adaptação e de validação do LUI-Pt para crianças portuguesas são promissores e asseguram a validade interna desta escala em termos da sua dimensionalidade e consistência interna

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Age-Related Attenuation of Dominant Hand Superiority

The decline of motor performance of the human hand-arm system with age is well-documented. While dominant hand performance is superior to that of the non-dominant hand in young individuals, little is known of possible age-related changes in hand dominance. We investigated age-related alterations of hand dominance in 20 to 90 year old subjects. All subjects were unambiguously right-handed according to the Edinburgh Handedness Inventory. In Experiment 1, motor performance for aiming, postural tremor, precision of arm-hand movement, speed of arm-hand movement, and wrist-finger speed tasks were tested. In Experiment 2, accelerometer-sensors were used to obtain objective records of hand use in everyday activities

An Investigation to Validate the Grammar and Phonology Screening (GAPS) Test to Identify Children with Specific Language Impairment

The extraordinarily high incidence of grammatical language impairments in developmental disorders suggests that this uniquely human cognitive function is "fragile". Yet our understanding of the neurobiology of grammatical impairments is limited. Furthermore, there is no "gold-standard" to identify grammatical impairments and routine screening is not undertaken. An accurate screening test to identify grammatical abilities would serve the research, health and education communities, further our understanding of developmental disorders, and identify children who need remediation, many of whom are currently un-diagnosed. A potential realistic screening tool that could be widely administered is the Grammar and Phonology Screening (GAPS) test--a 10 minute test that can be administered by professionals and non-professionals alike. Here we provide a further step in evaluating the validity and accuracy (sensitivity and specificity) of the GAPS test in identifying children who have Specific Language Impairment (SLI)

Some thoughts on the monitoring and preservation of waterlogged archaeological sites in eastern England

This study reviews five hydrological monitoring projects used on archeological sites in the waterlogged landscapes of fenland East Anglia and east Yorkshire in England. The project design, recorded variables, and implications of each are discussed. In particular, the importance of understanding the landscape context is paramount, and retrieving an appropriate dataset over a sufficiently lengthy period of time to obtain reliable results and predictability. Some of the lessons learnt and outstanding problems are explored. As former wetlands are fast disappearing around the world through dewatering and a host of wider development threats such as urbanization and gravel extraction, the low intrusion suite of methods described here for measuring the degree and certainty of organic preservation is doubly important for establishing the viability of preservation in situ schemes for waterlogged archeological sites. This is crucial to get right, as wetland archeological records are an irreplaceable resource which offer extraordinarily full and diverse datasets of human lifeways which are all too often either poorly preserved or erroneously interpreted because of the skewed datasets recovered from dryland sites.English Heritage, Huntings Technical Services (for Over), ARC (Central) Ltd. (for Etton), Hanson Building Products and SLR Consulting Ltd. (for Must Farm), the Society of Antiquaries and Fenland Archaeological Trust (for Etton), Cambridge Archaeological Unit (for Over and Must Farm), the McBurney Laboratory and the McDonald Institute for Archaeological Research, University of Cambridge (for Over and Must Farm), the Department of Archaeology, University of York and the European Research Council (for Star Carr), and the Meteorological Office (for Etton and Over

Behavioral and molecular genetics of reading-related AM and FM detection thresholds

Auditory detection thresholds for certain frequencies of both amplitude modulated (AM) and frequency modulated (FM) dynamic auditory stimuli are associated with reading in typically developing and dyslexic readers. We present the first behavioral and molecular genetic characterization of these two auditory traits. Two extant extended family datasets were given reading tasks and psychoacoustic tasks to determine FM 2 Hz and AM 20 Hz sensitivity thresholds. Univariate heritabilities were significant for both AM (h2 = 0.20) and FM (h2 = 0.29). Bayesian posterior probability of linkage (PPL) analysis found loci for AM (12q, PPL = 81 %) and FM (10p, PPL = 32 %; 20q, PPL = 65 %). Bivariate heritability analyses revealed that FM is genetically correlated with reading, while AM was not. Bivariate PPL analysis indicates that FM loci (10p, 20q) are not also associated with reading

Polychlorinated Biphenyls and Biotransformation Enzymes in Three Species of Sea Turtles from the Baja California Peninsula of Mexico

Concentrations of polychlorinated biphenyls (PCBs) as well as the expression patterns of cytochrome P450 (CYP) enzymes and glutathione-S-transferase (GST) activities were measured in livers of loggerhead (Caretta caretta), green (Chelonia mydas), and olive ridley (Lepidocheyls olivacea) sea turtles from the Baja California peninsula of Mexico. The mean concentrations of total PCBs were 18.1, 10.5, and 15.2 ng/g wet weight (ww) respectively for the three species and PCB 153 was the dominant congener in all samples. Total PCB concentrations were dominated by penta- and hexa-chlorinated biphenyls. The mean estimated TEQs were 42.8, 22.9, and 10.4 pg/g (ww) for loggerhead, green, and olive ridley, respectively, and more than 70% was accounted for by non-ortho PCBs. Western blots revealed the presence of hepatic microsomal proteins that cross-reacted with anti-CYP2K1 and anti-CYP3A27 antibodies but not with anti-CYP1A antibody. There were no significant differences in GST activities between species. Grouping congeners based on structure–activity relationships for CYP isoenzymes suggested limited activity of CYP1A contribution to PCB biotransformation in sea turtles. These results suggest potential accumulation of PCBs that are CYP1A substrates and provide evidence for biotransformation capacity, which differs from known animal models, highlighting the need for further studies in reptiles, particularly those threatened with extinction