Accumulation of Sellafield-derived radiocarbon (14C) in Irish Sea and West of Scotland intertidal shells and sediments

The nuclear energy industry produces radioactive waste at various stages of the fuel cycle. In the United Kingdom, spent fuel is reprocessed at the Sellafield facility in Cumbria on the north west coast of England. Waste generated at the site comprises a wide range of radionuclides including radiocarbon (14C) which is disposed of in various forms including highly soluble inorganic carbon within the low level liquid radioactive effluent, via pipelines into the Irish Sea. This 14C is rapidly incorporated into the dissolved inorganic carbon (DIC) reservoir and marine calcifying organisms, e.g. molluscs, readily utilise DIC for shell formation. This study investigated a number of sites located in Irish Sea and West of Scotland intertidal zones. Results indicate 14C enrichment above ambient background levels in shell material at least as far as Port Appin, 265 km north of Sellafield. Of the commonly found species (blue mussel (Mytilus edulis), common cockle (Cerastoderma edule) and common periwinkle (Littorina littorea)), mussels were found to be the most highly enriched in 14C due to the surface environment they inhabit and their feeding behaviour. Whole mussel shell activities appear to have been decreasing in response to reduced discharge activities since the early 2000s but in contrast, there is evidence of continuing enrichment of the carbonate sediment component due to in-situ shell erosion, as well as indications of particle transport of fine 14C-enriched material close to Sellafield

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C). Part 1. The Irish Sea

Ecosystem uptake and transfer processes of Sellafield-derived radiocarbon (14C) within the Irish Sea were examined. Highly variable activities in sediment, seawater and biota indicate complex 14C dispersal and uptake dynamics. All east basin biota exhibited 14C enrichments above ambient background while most west basin biota had 14C activities close to background, although four organisms including two slow-moving species were significantly enriched. The western Irish Sea gyre is a suggested pathway for transfer of 14C to the west basin and retention therein. Despite ongoing Sellafield 14C discharges, organic sediments near Sellafield were significantly less enriched than associated benthic organisms. Rapid scavenging of labile, 14C-enriched organic material by organisms and mixing to depth of 14C-enriched detritus arriving at the sediment/water interface are proposed mechanisms to explain this. All commercially important fish, crustaceans and molluscs showed 14C enrichments above background; however, the radiation dose from their consumption is extremely low and radiologically insignificant

Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2−/− mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes

Load transfer at the distal ulna following simulated distal radius fracture malalignment.

PURPOSE: To measure the effects of distal radius malalignment on loading at the distal ulna. METHODS: Using an adjustable mechanism to simulate angulated and translated malalignments, clinically relevant distal radius deformities were simulated in a cadaveric model. A custom-built load cell was inserted just proximal to the native ulna head to measure the resultant force and torque in the distal ulna. Loads were measured before and after transecting the triangular fibrocartilage complex (TFCC). RESULTS: There was an increase in distal ulna load and torque with increasing dorsal translation and angulation. Combined conditions of angulation and translation increased force and torque in the distal ulna to a greater extent than with either condition in isolation. Transecting the TFCC resulted in a reduction in distal ulna load and torque. CONCLUSIONS: A progressive increase in load at the distal ulna was observed with increasing severity of malalignment, which may be an important contributor to residual ulnar wrist pain and dysfunction. However, no clear-cut threshold of malalignment of a dorsally angulated and translated distal radius fracture was identified. These observations suggest that radius deformities cause articular incongruity, which increases TFCC tension and distal radioulnar joint load. Cutting of the TFCC decreased distal ulna loading, likely by releasing the articular constraining effect of the TFCC on the distal radioulnar joint, allowing the radius to rotate more freely with respect to the ulna. CLINICAL RELEVANCE: Anatomical reduction of a distal radius fracture minimizes the forces in the distal ulna and may reduce residual ulnar wrist pain and dysfunction

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C) part 2 : the west of Scotland

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C) were examined within the West of Scotland marine environment. The dissolved inorganic carbon component of seawater, enriched in14C, is transported to the West of Scotland where it is transferred through the marine food web. Benthic and pelagic biota with variable life-spans living in the North Channel and Clyde Sea show comparable14C activities. This suggests that mixing of14C within the Irish Sea results in a relatively constant northwards dispersal of activity. Benthic species in the Firth of Lorn have similar14C enrichments, demonstrating that Irish Sea residual water is the dominant source to this area. Measured14C activities in biota show some similarity to western Irish Sea activities, indicating that dispersion to the West of Scotland is significant with respect to the fate of Sellafield14C releases. Activities measured in commercially important species do not pose any significant radiological risk

Modelling marine trophic transfer of radiocarbon (14C) from a nuclear facility

Sellafield marine discharges of 14C are the largest contributor to the global collective dose from the nuclear fuel industry. As such, it is important to understand the fate of these discharges beyond the limitations and scope of empirical analytical investigations for this highly mobile radioactive contaminant. Ecopath with Ecosim (EwE) is widely used to model anthropogenic impacts on ecosystems, such as fishing, although very few EwE studies have modelled the fate of bioavailable contaminants. This work presents, for the first time, a spatial-temporal 14C model utilising recent developments in EwE software to predict the ecological fate of anthropogenic 14C in the marine environment. The model predicted observed trends in 14C activities between different species and through time. It also provided evidence for the integration of Sellafield 14C in species at higher trophic levels through time

The AIB1 glutamine repeat polymorphism is not associated with risk of breast cancer before age 40 years in Australian women

INTRODUCTION: AIB1, located at 20q12, is a member of the steroid hormone coactivator family. It contains a glutamine repeat (CAG/CAA) polymorphism at its carboxyl-terminal region that may alter the transcriptional activation of the receptor and affect susceptibility to breast cancer through altered sensitivity to hormones. METHODS: We evaluated this repeat polymorphism in the context of early-onset disease by conducting a case-control study of 432 Australian women diagnosed with breast cancer before the age of 40 years and 393 population-based control individuals who were frequency matched for age. Genotyping was performed using a scanning laser fluorescence imager. RESULTS: There were no differences in genotype frequencies between cases and control individuals, or between cases categorized by family history or by BRCA1 and BRCA2 germline mutation status. There was no evidence that the presence of one or two alleles of 26 glutamine repeats or fewer was associated with breast cancer (odds ratio = 1.03, 95% confidence interval = 0.73–1.44), or that women with alleles greater than 29 repeats were at increased risk of breast cancer. Exclusion of women who carried a BRCA1 or BRCA2 mutation (24 cases) and non-Caucasian women (44 cases) did not alter the risk estimates or inferences. We present raw data, including that on mutation carriers, to allow pooling with other studies. CONCLUSION: There was no evidence that risk of breast cancer depends on AIB1 CAG/CAA polymorphism status, even if affected women carry a mutation in BRCA1 or BRCA2

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers.

INTRODUCTION: The androgen receptor (AR) gene exon 1 CAG repeat polymorphism encodes a string of 9-32 glutamines. Women with germline BRCA1 mutations who carry at least one AR allele with 28 or more repeats have been reported to have an earlier age at onset of breast cancer. METHODS: A total of 604 living female Australian and British BRCA1 and/or BRCA2 mutation carriers from 376 families were genotyped for the AR CAG repeat polymorphism. The association between AR genotype and disease risk was assessed using Cox regression. AR genotype was analyzed as a dichotomous covariate using cut-points previously reported to be associated with increased risk among BRCA1 mutation carriers, and as a continuous variable considering smaller allele, larger allele and average allele size. RESULTS: There was no evidence that the AR CAG repeat polymorphism modified disease risk in the 376 BRCA1 or 219 BRCA2 mutation carriers screened successfully. The rate ratio associated with possession of at least one allele with 28 or more CAG repeats was 0.74 (95% confidence interval 0.42-1.29; P = 0.3) for BRCA1 carriers, and 1.12 (95% confidence interval 0.55-2.25; P = 0.8) for BRCA2 carriers. CONCLUSION: The AR exon 1 CAG repeat polymorphism does not appear to have an effect on breast cancer risk in BRCA1 or BRCA2 mutation carriers