Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in β-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults

Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

'Context' in Durham, E., 'Symbols of power: The Silchester Bronze Eagle and eagles in Roman Britain'

Those who study Roman art and religion in Britain will know that there are a relatively small number of pieces in stone and bronze which are regularly used to illustrate arguments on Romanization, provincialism and identity. However, while these objects become familiar through such use, they are, in fact, often little studied as pieces in their own right and the only description of their appearance and context are some fifty or more years old. Re-excavation of the context from which the Silchester eagle was recovered has raised questions about the date of its deposition, as well as its origin and use, and indeed the nature of its deposition at Silchester. This paper examines the figurine in detail, the role of the eagle at Silchester and explores the significance of the eagle more widely in Roman Britain.

Genetic analysis reveals a novel locus in Vicia faba decoupling pigmentation in the flower from that in the extra-floral nectaries

The genetics of the stipule spot pigmentation (SSP) in faba bean (Vicia faba L.) was studied using four inbred lines, of which Disco/2 was zero-tannin (zt2) with colourless stipule spots, ILB938/2 was normal-tannin (ZT2) with colourless stipule spots, and both Aurora/2 and Mélodie/2 were ZT2 with coloured stipule spots. Crosses Mélodie/2 × ILB 938/2, Mélodie/2 × Disco/2, ILB 938/2 × Aurora/2 and ILB 938/2 × Disco/2 (A, B, C and D, respectively) were prepared, along with reciprocals and backcrosses, and advanced through single-seed descent. All F1 hybrid plants had pigmented stipule spots, and in the F2 generation, the segregation ratio fit 3 coloured:1 colourless in crosses A, B and C and 9:7 in cross D. In the F3 generation, the ratio fit 5:3 in crosses A and C and 25:39 in cross D, and in the F4 generation, 9:7 in cross A. SSP was linked to the zero-tannin characteristics (white flower) only in cross B. The results show that coloured stipule spot is dominant to colourless and that colouration is determined by two unlinked complementary recessive genes. We propose the symbols ssp2 for the gene associated with zt2 in Disco/2 and ssp1 for the gene not associated with tannin content in ILB938/2. The novel ssp1 locus was mapped at F5 in cross ‘A’ using Medicago truncatula-derived single-nucleotide polymorphism and was on chromosome 1 of faba bean, in a well-conserved region of M. truncatula chromosome 5 containing some candidate Myb and basic helix–loop–helix transcription factor genes.

Dominant components of the Thoroughbred metabolome characterised by 1H‐NMR spectroscopy: a metabolite atlas of common biofluids

Summary Reasons for performing study: Metabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu. Objectives: To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution 1H-NMR spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area. Study design: This study was performed using seven Thoroughbreds in race training at a single time-point. Urine and faecal samples were collected non-invasively and plasma was obtained from samples taken for routine clinical chemistry purposes. Methods: Biofluids were analysed using 1H-NMR spectroscopy. Metabolite assignment was achieved via a range of 1D and 2D experiments. Results: A total of 102 metabolites were assigned across the three biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host co-metabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short chain fatty acids were the predominant features identified within this biofluid by 1H-NMR spectroscopy. Conclusions: Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis.

Symbols of power: the Silchester bronze eagle and eagles in Roman Britain

Those who study Roman art and religion in Britain will know that there are a relatively small number of pieces in stone and bronze which are regularly used to illustrate arguments on Romanization, provincialism and identity. However, while these objects become familiar through such use, they are, in fact, often little studied as pieces in their own right and the only description of their appearance and context are some fifty or more years old. Re-excavation of the context from which the Silchester eagle was recovered has raised questions about the date of its deposition, as well as its origin and use, and indeed the nature of its deposition at Silchester. This paper examines the figurine in detail, the role of the eagle at Silchester and explores the significance of the eagle more widely in Roman Britain.

Dominant role of greenhouse-gas forcing in the recovery of Sahel rainfall

Sahelian summer rainfall, controlled by the West African monsoon, exhibited large-amplitude multidecadal variability during the twentieth century. Particularly important was the severe drought of the 1970s and 1980s, which had widespread impacts1–6. Research into the causes of this drought has identified anthropogenic aerosol forcing3,4,7 and changes in sea surface temperatures (SSTs; refs 1,2,6,8–11) as the most important drivers. Since the 1980s, there has been some recovery of Sahel rainfall amounts2–6,11–14, although not to the pre-drought levels of the 1940s and 1950s. Here we report on experiments with the atmospheric component of a state-of-the-art global climate model to identify the causes of this recovery. Our results suggest that the direct influence of higher levels of greenhouse gases in the atmosphere was the main cause, with an additional role for changes in anthropogenic aerosol precursor emissions. We find that recent changes in SSTs, although substantial, did not have a significant impact on the recovery. The simulated response to anthropogenic greenhouse-gas and aerosol forcing is consistent with a multivariate fingerprint of the observed recovery, raising confidence in our findings. Although robust predictions are not yet possible, our results suggest that the recent recovery in Sahel rainfall amounts is most likely to be sustained or amplified in the near term.

Robustness despite uncertainty: regional climate data reveal the dominant role of humans in explaining global extinctions of Late Quaternary megafauna

Debate over the late Quaternary megafaunal extinctions has focussed on whether human colonisation or climatic changes were more important drivers of extinction, with few extinctions being unambiguously attributable to either. Most analyses have been geographically or taxonomically restricted and the few quantitative global analyses have been limited by coarse temporal resolution or overly simplified climate reconstructions or proxies. We present a global analysis of the causes of these extinctions which uses high-resolution climate reconstructions and explicitly investigates the sensitivity of our results to uncertainty in the palaeological record. Our results show that human colonisation was the dominant driver of megafaunal extinction across the world but that climatic factors were also important. We identify the geographic regions where future research is likely to have the most impact, with our models reliably predicting extinctions across most of the world, with the notable exception of mainland Asia where we fail to explain the apparently low rate of extinction found in in the fossil record. Our results are highly robust to uncertainties in the palaeological record, and our main conclusions are unlikely to change qualitatively following minor improvements or changes in the dates of extinctions and human colonisation.

Moisture can be the dominant environmental parameter governing cadaver decomposition in soil

Forensic taphonomy involves the use of decomposition to estimate postmortem interval (PMI) or locate clandestine graves. Yet, cadaver decomposition remains poorly understood, particularly following burial in soil. Presently, we do not know how most edaphic and environmental parameters, including soil moisture, influence the breakdown of cadavers following burial and alter the processes that are used to estimate PMI and locate clandestine graves. To address this, we buried juvenile rat (Rattus rattus) cadavers (∼18 g wet weight) in three contrasting soils from tropical savanna ecosystems located in Pallarenda (sand), Wambiana (medium clay), or Yabulu (loamy sand), Queensland, Australia. These soils were sieved (2 mm), weighed (500 g dry weight), calibrated to a matric potential of -0.01 megapascals (MPa), -0.05 MPa, or -0.3 MPa (wettest to driest) and incubated at 22 °C. Measurements of cadaver decomposition included cadaver mass loss, carbon dioxide-carbon (CO2-C) evolution, microbial biomass carbon (MBC), protease activity, phosphodiesterase activity, ninhydrin-reactive nitrogen (NRN) and soil pH. Cadaver burial resulted in a significant increase in CO2-C evolution, MBC, enzyme activities, NRN and soil pH. Cadaver decomposition in loamy sand and sandy soil was greater at lower matric potentials (wetter soil). However, optimal matric potential for cadaver decomposition in medium clay was exceeded, which resulted in a slower rate of cadaver decomposition in the wettest soil. Slower cadaver decomposition was also observed at high matric potential (-0.3 MPa). Furthermore, wet sandy soil was associated with greater cadaver decomposition than wet fine-textured soil. We conclude that gravesoil moisture content can modify the relationship between temperature and cadaver decomposition and that soil microorganisms can play a significant role in cadaver breakdown. We also conclude that soil NRN is a more reliable indicator of gravesoil than soil pH.

A rare structure at the syntax-discourse interface: heritage and Spanish-dominant native speakers weigh in

The present study examines knowledge of the discourse-appropriateness of Clitic Right Dislocation (CLRD) in a population of Heritage (HS) and Spanish-dominant Native Speakers in order to test the predictions of the Interface Hypothesis (IH; Sorace 2011). The IH predicts that speakers in language contact situations will experience difficulties with integrating information involving the interface of syntax and discourse modules. CLRD relates a dislocated constituent to a discourse antecedent, requiring integration of syntax and pragmatics. Results from an acceptability judgment task did not support the predictions of the IH. No statistical differences between the HSs’ performance and that of L1-dominant native speakers were evidenced when participants were presented with an offline task. Thus, our study did not find any evidence of “incomplete acquisition” (Montrul 2008) as it pertains to this specific linguistic structure.

Science learning and graphic symbols: an exploration of early years teachers’ views and use of graphic symbols when teaching science

The study investigated early years teachers’ understanding and use of graphic symbols, defined as the visual representation(s) used to communicate one or more “linguistic” concepts, which can be used to facilitate science learning. The study was conducted in Cyprus where six early years teachers were observed and interviewed. The results indicate that the teachers had a good understanding of the role of symbols, but demonstrated a lack of understanding in regards to graphic symbols specifically. None of the teachers employed them in their observed science lesson, although some of them claimed that they did so. Findings suggest a gap in participants’ acquaintance with the terminology regarding different types of symbols and a lack of awareness about the use and availability of graphic symbols for the support of learning. There is a need to inform and train early years teachers about graphic symbols and their potential applications in supporting children’s learning.

Oculoauriculovertebral spectrum: report of nine familial cases with evidence of autosomal dominant inheritance and review of the literature

Oculoauriculovertebral spectrum (OAVS; OMIM 164210) is a complex condition characterized by defects of aural, oral, mandibular and vertebral development. The aetiology of this condition is likely to be heterogeneous; most cases are sporadic, however, familial cases suggesting autosomal recessive end autosomal dominant inheritance have been reported. In this study, we describe the clinical aspects of nine familial cases with evidence of autosomal dominant inheritance and compare them with reports in the literature. Interfamilial and intrafamilial clinical variabilities were observed in this study (reinforcing the necessity of careful examination of familial members). We suggest that oculoauriculovertebral spectrum with autosomal dominant inheritance is characterized mainly by bilateral auricular involvement and rarely presents extracranial anomalies. Clin Dysmorphol 18:67-77 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Mandibulofacial Syndrome With Growth and Mental Retardation, Microcephaly, Ear Anomalies With Skin Tags, and Cleft Palate in a Mother and Her Son: Autosomal Dominant or X-Linked Syndrome?

We report on a Brazilian mother and her son affected with mandibulofacial dysostosis, growth and mental retardation, microcephaly, first branchial arch anomalies, and cleft palate. To date only three males and one female, all sporadic cases, with a similar condition have been reported. This article describes the first familial case with this rare condition indicating autosomal dominant or X-linked inheritance. (C) 2009 Wiley-Liss, Inc.

Non-random reef use by fishes at two dominant zones in a tropical, algal-dominated coastal reef

Habitat use and the processes which determine fish distribution were evaluated at the reef flat and reef crest zones of a tropical, algal-dominated reef. Our comparisons indicated significant differences in the majority of the evaluated environmental characteristics between zones. Also, significant differences in the abundances of twelve, from thirteen analyzed species, were observed within and between-sites. According to null models, non-random patterns of species co-occurrences were significant, suggesting that fish guilds in both zones were non-randomly structured. Unexpectedly, structural complexity negatively affected overall species richness, but had a major positive influence on highly site-attached species such as a damselfish. Depth and substrate composition, particularly macroalgae cover, were positive determinants for the fish assemblage structure in the studied reef, prevailing over factors such as structural complexity and live coral cover. Our results are conflicting with other studies carried out in coral-dominated reefs of the Caribbean and Pacific, therefore supporting the idea that the factors which may potentially influence reef fish composition are highly site-dependent and variable.