Regulators of genetic risk of breast cancer identified by integrative network analysis.

Genetic risk for breast cancer is conferred by a combination of multiple variants of small effect. To better understand how risk loci might combine, we examined whether risk-associated genes share regulatory mechanisms. We created a breast cancer gene regulatory network comprising transcription factors and groups of putative target genes (regulons) and asked whether specific regulons are enriched for genes associated with risk loci via expression quantitative trait loci (eQTLs). We identified 36 overlapping regulons that were enriched for risk loci and formed a distinct cluster within the network, suggesting shared biology. The risk transcription factors driving these regulons are frequently mutated in cancer and lie in two opposing subgroups, which relate to estrogen receptor (ER)(+) luminal A or luminal B and ER(-) basal-like cancers and to different luminal epithelial cell populations in the adult mammary gland. Our network approach provides a foundation for determining the regulatory circuits governing breast cancer, to identify targets for intervention, and is transferable to other disease settings.This work was funded by Cancer Research UK and the Breast Cancer Research Foundation. MAAC is funded by the National Research Council (CNPq) of Brazil. TEH held a fellowship from the US DOD Breast Cancer Research Program (W81XWH-11-1-0592) and is currently supported by an RAH Career Development Fellowship (Australia). TEH and WDT are funded by the NHMRC of Australia (NHMRC) (ID: 1008349 WDT; 1084416 WDT, TEH) and Cancer Australia/National Breast Cancer Foundation (ID 627229; WDT, TEH). BAJP is a Gibb Fellow of Cancer Research UK. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.345

Increased brain expression of GPNMB is associated with genome wide significant risk for Parkinson's disease on chromosome 7p15.3

Genome wide association studies (GWAS) for Parkinson's disease (PD) have previously revealed a significant association with a locus on chromosome 7p15.3, initially designated as the glycoprotein non-metastatic melanoma protein B (GPNMB) locus. In this study, the functional consequences of this association on expression were explored in depth by integrating different expression quantitative trait locus (eQTL) datasets (Braineac, CAGEseq, GTEx, and Phenotype-Genotype Integrator (PheGenI)). Top risk SNP rs199347 eQTLs demonstrated increased expressions of GPNMB, KLHL7, and NUPL2 with the major allele (AA) in brain, with most significant eQTLs in cortical regions, followed by putamen. In addition, decreased expression of the antisense RNA KLHL7-AS1 was observed in GTEx. Furthermore, rs199347 is an eQTL with long non-coding RNA (AC005082.12) in human tissues other than brain. Interestingly, transcript-specific eQTLs in immune-related tissues (spleen and lymphoblastoid cells) for NUPL2 and KLHL7-AS1 were observed, which suggests a complex functional role of this eQTL in specific tissues, cell types at specific time points. Significantly increased expression of GPNMB linked to rs199347 was consistent across all datasets, and taken in combination with the risk SNP being located within the GPNMB gene, these results suggest that increased expression of GPNMB is the causative link explaining the association of this locus with PD. However, other transcript eQTLs and subsequent functional roles cannot be excluded. This highlights the importance of further investigations to understand the functional interactions between the coding genes, antisense, and non-coding RNA species considering the tissue and cell-type specificity to understand the underlying biological mechanisms in PD

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Analysis of hard X- and gamma-rays and microwave emissions during the flare of July 18, 2002

The Nobeyama Radioheliograph observation results and data from the KONUS-Wind spectrometer mounted at the Wind and RHESSI satellites on several solar flares are jointly analyzed. The analysis results for data on the flare of July 18, 2002 are described. The hard X-rays were measured in the 18 keV-15 MeV range (KONUS-Wind), and spectroheliograph measurements were carried out in the radio range at frequencies of 17 and 34 GHz. Spatial distributions of the radio brightness were calculated for the flare of July 18, 2002; they show the presence of two sources at the footpoints and one source at the top of the supposed flaring loop. The energy spectra of hard X-rays, energy flux, and the total number of accelerated electrons were found from the KONUS spectrometer data. The number of accelerated X-ray emitted electrons was estimated as N a parts per thousand yen 10(36), and the maximum X-ray energy flux was estimated as 5 x 10(-6) erg cm(-2) s(-1). The spectrum index varies in time from -4.6 to -3.6, i.e., the soft-hard-harder trend is implemented. The spectral index of the radio waves is alpha a parts per thousand -0.3 at the flare start, attains the value alpha a parts per thousand -0.5 at the flux maximum, and even change the sign further. The accelerated electron transport model in the flare loop plasma is suggested for interpretation of relationships between parameters of the radio emission and hard X-rays

Surrogate tree cavities : boxes with artificial substrate can serve as temporary habitat for Osmoderma barnabita (Motsch.) (Coleoptera, Cetoniinae)

Many saproxylic insects have declined or became extinct, mainly due to habitat loss and fragmentation, and their survival increasingly depends on active conservation. Efforts to achieve this goal may be supported by the introduction of new methods, including creation of artificial habitats. Here we present results of studies on the use of wooden boxes mimicking tree cavities for an endangered saproxylic species, Osmoderma barnabita. Boxes were filled with the feeding substrate for larvae and installed on trees. Second and third-instar O. barnabita larvae were introduced in half of the boxes; the remaining ones were left uninhabited. Later inspection of boxes showed a high survival rate of introduced larvae, as well as successful breeding of a new generation inside the boxes. At the same time boxes were not colonized by the local population of O. barnabita, although other cetoniids did so. The co-occurring larvae of other cetoniids did not affect O. barnabita larvae. Thermal conditions inside boxes and natural tree cavities were almost identical and based on the results of our studies we conclude that wooden boxes may serve as temporary habitat for O. barnabita. They may be particularly useful in cases of destruction of species natural habitat, in restoration programs, and have the potential to act as a stepping stones in cases of a lack of habitat continuity.Funding Agencies|General Directorate of State Forests in Poland</p