Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Antisense RNA protects mRNA from RNase E degradation by RNA–RNA duplex formation during phage infection

The ecologically important cyanobacterium Prochlorococcus possesses the smallest genome among oxyphototrophs, with a reduced suite of protein regulators and a disproportionately high number of regulatory RNAs. Many of these are asRNAs, raising the question whether they modulate gene expression through the protection of mRNA from RNase E degradation. To address this question, we produced recombinant RNase E from Prochlorococcus sp. MED4, which functions optimally at 12 mM Mg2+, pH 9 and 35°C. RNase E cleavage assays were performed with this recombinant protein to assess enzyme activity in the presence of single- or double-stranded RNA substrates. We found that extraordinarily long asRNAs of 3.5 and 7 kb protect a set of mRNAs from RNase E degradation that accumulate during phage infection. These asRNA–mRNA duplex formations mask single-stranded recognition sites of RNase E, leading to increased stability of the mRNAs. Such interactions directly modulate RNA stability and provide an explanation for enhanced transcript abundance of certain mRNAs during phage infection. Protection from RNase E-triggered RNA decay may constitute a hitherto unknown regulatory function of bacterial cis-asRNAs, impacting gene expression

Dissolved inorganic carbon export from rivers of Great Britain: Spatial distribution and potential catchment-scale controls

Dissolved inorganic carbon (DIC) fluxes from the land to ocean have been quantified for many rivers globally. However, CO2 fluxes to the atmosphere from inland waters are quantitatively significant components of the global carbon cycle that are currently poorly constrained. Understanding, the relative contributions of natural and human-impacted processes on the DIC cycle within catchments may provide a basis for developing improved management strategies to mitigate free CO2 concentrations in rivers and subsequent evasion to the atmosphere. Here, a large, internally consistent dataset collected from 41 catchments across Great Britain (GB), accounting for ∼36% of land area (∼83,997 km2) and representative of national land cover, was used to investigate catchment controls on riverine dissolved inorganic carbon (DIC), bicarbonate (HCO3−) and free CO2 concentrations, fluxes to the coastal sea and annual yields per unit area of catchment. Estimated DIC flux to sea for the survey catchments was 647 kt DIC yr−1 which represented 69% of the total dissolved carbon flux from these catchments. Generally, those catchments with large proportions of carbonate and sedimentary sandstone were found to deliver greater DIC and HCO3− to the ocean. The calculated mean free CO2 yield for survey catchments (i.e. potential CO2 emission to the atmosphere) was 0.56 t C km−2 yr−1. Regression models demonstrated that whilst river DIC (R2 = 0.77) and HCO3− (R2 = 0.77) concentrations are largely explained by the geology of the landmass, along with a negative correlation to annual precipitation, free CO2 concentrations were strongly linked to catchment macronutrient status. Overall, DIC dominates dissolved C inputs to coastal waters, meaning that estuarine carbon dynamics are sensitive to underlying geology and therefore are likely to be reasonably constant. In contrast, potential losses of carbon to the atmosphere via dissolved CO2, which likely constitute a significant fraction of net terrestrial ecosystem production and hence the national carbon budget, may be amenable to greater direct management via altering patterns of land use

Molecular Mechanisms of Neuroinflammation in Alzheimer's Disease

Peer reviewed: YesNRC publication: Ye

ABCG2 reduces ROS-mediated toxicity and inflammation : A potential role in Alzheimer's disease

Alzheimer\ufffds disease is characterized by accumulation and deposition of A\u3b2 peptides in the brain. A\u3b2 deposition generates reactive-oxygen species (ROS), which are involved in Alzheimer\ufffds inflammatory and neurodegenerative pathology. We have previously observed that, in Alzheimer\ufffds disease brain, ABCG2 is up-regulated and AP-1 is activated, but NFkB is not activated. In the present study, we examine the roles and mechanism of ABCG2 on ROS generation, inflammatory gene expression and signaling, heme homeostasis and A\u3b2 production in cell models and on inflammatory signaling and A\u3b2 deposition in Abcg2-knockout and wild-type mice. Our results show that ABCG2 plays a protective role against oxidative stress by decreasing ROS generation, enhancing antioxidant capacity, regulating heme level, and inhibiting inflammatory response in cell models. ABCG2 inhibits NF-kB activation but has less effect on AP-1 activation induced by ROS. This results in inhibition of interleukin-8 and growth-related oncogene (GRO) expression induced by ROS via NF-kB pathway. Abcg2 deficiency increased Ab deposition and NF-kB activation in the brains of Abcg2-knockout mice compared with controls. These findings suggest that ABCG2 may relieve oxidative stress and inflammatory response via inhibiting NF-kB signaling pathway in cell models and brain tissues and thus may play a potential protective role in Alzheimer\ufffds neuroinflammatory response.Peer reviewed: YesNRC publication: Ye

Towards universal high quality early childhood education

The Australian Government has committed $970 million over 5 years to fund the expansion of preschool education and has established a National Early Childhood Education Partnership Agreement with States and Territories to achieve universal preschool access by 2013. The Partnership Agreement acknowledges the role of State and Territory Government in preschool education, and different approaches to preschool provision. It also recognises differences in current preschool participation rates across states and territories. This paper offers snapshots of a number of different models of preschool provision, spanning traditional sessional approaches to some integrated and innovative approaches within the long day care context. The paper explores the newer long day care model and offers recommendations for the delivery of preschool education within this different context