An Automated Procedure to Identify Biomedical Articles that Contain Cancer-associated Gene Variants

The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and imprecise. More effective mechanisms for identifying articles containing mutation information would be beneficial both for the curation of mutation databases and for individual researchers. We developed an automated method that uses information extraction, classifier, and relevance ranking techniques to determine the likelihood of MEDLINE abstracts containing information regarding genomic variation data suitable for inclusion in mutation databases. We targeted the CDKN2A (p16) gene and the procedure for document identification currently used by CDKN2A Database curators as a measure of feasibility. A set of abstracts was manually identified from a MEDLINE search as potentially containing specific CDKN2A mutation events. A subset of these abstracts was used as a training set for a maximum entropy classifier to identify text features distinguishing relevant from not relevant abstracts. Each document was represented as a set of indicative word, word pair, and entity tagger-derived genomic variation features. When applied to a test set of 200 candidate abstracts, the classifier predicted 88 articles as being relevant; of these, 29 of 32 manuscripts in which manual curation found CDKN2A sequence variants were positively predicted. Thus, the set of potentially useful articles that a manual curator would have to review was reduced by 56%, maintaining 91% recall (sensitivity) and more than doubling precision (positive predictive value). Subsequent expansion of the training set to 494 articles yielded similar precision and recall rates, and comparison of the original and expanded trials demonstrated that the average precision improved with the larger data set. Our results show that automated systems can effectively identify article subsets relevant to a given task and may prove to be powerful tools for the broader research community. This procedure can be readily adapted to any or all genes, organisms, or sets of documents

High Pressure Processing of Dairy Foods

End of Project ReportThe term High Pressure Processing (HPP) is used to describe the technology whereby products are exposed to very high pressures in the region of 50 - 800 MPa (500 - 8000 Atmospheres). The potential application of HPP in the food industry has gained popularity in recent years, due to developments in the construction of HPP equipment which makes the technology more affordable. Applying HPP to food products results in modifications to interactions between individual components, rates of enzymatic reactions and inactivation of micro-organisms. The first commercial HPP products appeared on the market in 1991 in Japan, where HPP is now being used commercially for products such as jams, sauces, fruit juices, rice cakes and desserts. The pioneering research into the application of HPP to milk dates back to the end of the 19th century. Application of HPP to milk has been shown to modify its gel forming characteristics as well as reducing its microbial load. HPP offers the potential to induce similar effects to those generated by heat on milk protein. Recent reports have also indicated that HPP could accelerate the ripening of cheese. Much of the Irish cheese industry is based on the production of Cheddar cheese, the ripening time for which can vary from 4 - 12 months or more, depending on grade. A substantial portion of the cost associated with Cheddar manufacture is therefore attributed to storage under controlled conditions during ripening. Thus, any technology which may accelerate the ripening of Cheddar cheese while maintaining a balanced flavour and texture is of major economic significance. While food safety is a dominant concern, consumers are increasingly demanding foods that maintain their natural appearance and flavour, while free of chemical preservatives. HPP offers the food industry the possibility of achieving these twin goals as this technology can lead to reduced microbial loads without detrimentally effecting the nutritional or sensory qualities of the product. The development of food ingredients with novel functional properties offers the dairy industry an opportunity to revitalise existing markets and develop new ones. HPP can lead to modifications in the structure of milk components, in particular protein, which may provide interesting possibilities for the development of high value nutritional and functional ingredients. Hence these projects set out to investigate the potential of HPP in the dairy industry and to identify products and processes to which it could be applied.Department of Agriculture, Food and the Marin

Novel methods of targeting IL-1 signalling for the treatment of breast cancer bone metastasis

Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis

Elevated circulating and placental SPINT2 is associated with placental dysfunction

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights

Schools out : Adam Smith and pre-disciplinary international political economy

In this article, I argue that invocations of Adam Smith in international political economy (IPE) often reveal the influence therein of a disciplinary ontological disaggregation of economic and non-economic rationality, which I claim is obscured by the tendency to map its complex intellectual contours in terms of competing schools. I trace the origins of the disciplinary characterisation of Smith as the founder of IPE's liberal tradition to invocations of his thought by centrally important figures in the perceived Austrian, Chicago and German historical schools of economics, and reflect upon the significance to IPE of the reiteration of this portrayal by apparent members of its so-called American and British schools. I additionally contrast these interpretations to those put forward by scholars who seek to interpret IPE and Smith's contribution to it in pre-disciplinary terms, which I claim reflects a distinct ontology to that attributed to the British school of IPE with which their work is often associated. I therefore contend that reflection upon invocations of Smith's thought in IPE problematises the longstanding tendency to map its intellectual terrain in terms of competing schools, reveals that the disciplinary ontological consensus that informs this tendency impacts upon articulations of its core concerns and suggests that a pre-disciplinary approach offers an alternative lens through which such concerns might be more effectively framed