Mapping genes for osteoporosis-Old dogs and new tricks

In stark contrast to its horticultural origins, modern genetics is an extremely technology-driven field. Almost all the major advances in the field over the past 20 years have followed technological developments that have permitted change in study designs. The development of PCR in the 1980s led to RFLP mapping of monogenic diseases. The development of fluorescent-tagged genotyping methods led to linkage mapping approaches for common diseases that dominated the 1990s. The development of microarray SNP genotyping has led to the genome-wide association study era of the new millennium. And now the development of next-generation sequencing technologies is about to open up a new era of gene-mapping, enabling many potential new study designs. This review aims to present the strengths and weaknesses of the current approaches, and present some new ideas about gene-mapping approaches that are likely to advance our knowledge of the genes involved in heritable bone traits such as bone mineral density (BMD) and fracture.

Mapping bound plasmon propagation on a nanoscale stripe waveguide using quantum dots: Influence of spacer layer thickness

In this paper we image the highly confined long range plasmons of a nanoscale metal stripe waveguide using quantum emitters. Plasmons were excited using a highly focused 633 nm laser beam and a specially designed grating structure to provide stronger incoupling to the desired mode. A homogeneous thin layer of quantum dots was used to image the near field intensity of the propagating plasmons on the waveguide. We observed that the photoluminescence is quenched when the QD to metal surface distance is less than 10 nm. The optimised spacer layer thickness for the stripe waveguides was found to be around 20 nm. Authors believe that the findings of this paper prove beneficial for the development of plasmonic devices utilising stripe waveguides.

Mapping the arts: Industry concentrations, distribution, and change in the US, 1980-2010

This paper studies arts industries in all 366 US metropolitan statistical areas between 1980 and 2010. Our analysis provides evidence that the arts are an important component of many regional economies, but also highlights their volatility. After radical growth and diffusion between 1980 and 2000, in the last decade, the arts industries are defined more by shrinkage and reconcentration in fewer metropolitan areas. Further, we find that the vast majority of metros have strengths in particular sets of arts industries. As we discuss in the conclusion, these conditions present challenges and opportunities for urban cultural policy that goes beyond the current focus on the arts as consumption amenities.

Medical free-text to concept mapping as an information retrieval problem

Concept mapping involves determining relevant concepts from a free-text input, where concepts are defined in an external reference ontology. This is an important process that underpins many applications for clinical information reporting, derivation of phenotypic descriptions, and a number of state-of-the-art medical information retrieval methods. Concept mapping can be cast into an information retrieval (IR) problem: free-text mentions are treated as queries and concepts from a reference ontology as the documents to be indexed and retrieved. This paper presents an empirical investigation applying general-purpose IR techniques for concept mapping in the medical domain. A dataset used for evaluating medical information extraction is adapted to measure the effectiveness of the considered IR approaches. Standard IR approaches used here are contrasted with the effectiveness of two established benchmark methods specifically developed for medical concept mapping. The empirical findings show that the IR approaches are comparable with one benchmark method but well below the best benchmark.

Sedentary behaviour and health: Mapping environmental and social contexts to underpin chronic disease prevention

The time that children and adults spend sedentary–put simply, doing too much sitting as distinct from doing too little physical activity—has recently been proposed as a population-wide, ubiquitous influence on health outcomes. It has been argued that sedentary time is likely to be additional to the risks associated with insufficient moderate-to-vigorous physical activity. New evidence identifies relationships of too much sitting with overweight and obesity, type 2 diabetes, cardiovascular disease, some cancers and other adverse health outcomes. There is a need for a broader base of evidence on the likely health benefits of changing the relevant sedentary behaviours, particularly gathering evidence on underlying mechanisms and dose–response relationships. However, as remains the case for physical activity, there is a research agenda to be pursued in order to identify the potentially modifiable environmental and social determinants of sedentary behaviour. Such evidence is required so as to understand what might need to be changed in order to influence sedentary behaviours and to work towards population-wide impacts on prolonged sitting time. In this context, the research agenda needs to focus particularly on what can inform broad, evidence-based environmental and policy initiatives. We consider what has been learned from research on relationships of environmental and social attributes and physical activity; provide an overview of recent-emerging evidence on relationships of environmental attributes with sedentary behaviour; argue for the importance of conducting international comparative studies and addressing life-stage issues and socioeconomic inequalities and we propose a conceptual model within which this research agenda may be addressed.

The revolution in human monogenic disease mapping

The successful completion of the Human Genome Project (HGP) was an unprecedented scientific advance that has become an invaluable resource in the search for genes that cause monogenic and common (polygenic) diseases. Prior to the HGP, linkage analysis had successfully mapped many disease genes for monogenic disorders; however, the limitations of this approach were particularly evident for identifying causative genes in rare genetic disorders affecting lifespan and/or reproductive fitness, such as skeletal dysplasias. In this review, we illustrate the challenges of mapping disease genes in such conditions through the ultra-rare disorder fibrodysplasia ossificans progressiva (FOP) and we discuss the advances that are being made through current massively parallel (“next generation”) sequencing (MPS) technologies.

Mapping the experiential in contemporary dance

The research questions how a ‘lived experience’ of contemporary dance could be deepened for the audience. It presents a series of choreographic ‘tools’ to create alternative frameworks of presentation that challenge the dominant modes of creation, presentation and meaning making in contemporary dance. The five tools established and applied in this research are: variations of site, liminality, audience agency, audience-performer proximity and performer qualities. These tools are framed as a series of calibrated scales that allow choreographers to map decisions made in the studio in relation to potential audience engagement. The research houses multiple presentation formats from the traditional to the avant-garde and opens up possibilities for analysis of a wide range of artistic dance works. This research presents options for choreographers to map how audiences experience their work and offers opportunities to engage audiences in new and exciting ways.

Mapping the regulatory sequences controlling 93 breast cancer-associated miRNA genes leads to the identification of two functional promoters of the Hsa-mir-200b cluster, methylation of which is associated with metastasis or hormone receptor status in advanced breast cancer

MicroRNAs (miRNAs) are small non-coding RNAs of 20 nt in length that are capable of modulating gene expression post-transcriptionally. Although miRNAs have been implicated in cancer, including breast cancer, the regulation of miRNA transcription and the role of defects in this process in cancer is not well understood. In this study we have mapped the promoters of 93 breast cancer-associated miRNAs, and then looked for associations between DNA methylation of 15 of these promoters and miRNA expression in breast cancer cells. The miRNA promoters with clearest association between DNA methylation and expression included a previously described and a novel promoter of the Hsa-mir-200b cluster. The novel promoter of the Hsa-mir-200b cluster, denoted P2, is located 2 kb upstream of the 5′ stemloop and maps within a CpG island. P2 has comparable promoter activity to the previously reported promoter (P1), and is able to drive the expression of miR-200b in its endogenous genomic context. DNA methylation of both P1 and P2 was inversely associated with miR-200b expression in eight out of nine breast cancer cell lines, and in vitro methylation of both promoters repressed their activity in reporter assays. In clinical samples, P1 and P2 were differentially methylated with methylation inversely associated with miR-200b expression. P1 was hypermethylated in metastatic lymph nodes compared with matched primary breast tumours whereas P2 hypermethylation was associated with loss of either oestrogen receptor or progesterone receptor. Hypomethylation of P2 was associated with gain of HER2 and androgen receptor expression. These data suggest an association between miR-200b regulation and breast cancer subtype and a potential use of DNA methylation of miRNA promoters as a component of a suite of breast cancer biomarkers.

Fine mapping and replication of genetic risk Loci in primary sclerosing cholangitis

Background and aims. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the bile ducts eventually leading to biliary cirrhosis. Recent genetic studies in PSC have identified associations at 2q13, 2q35, 3p21, 4q27, 13q31 and suggestive association at 10p15. The aim of this study was to further characterize and refine the genetic architecture of PSC. Methods. We analyzed previously reported associated SNPs at four of these non-HLA loci and 59 SNPs tagging the IL-2/IL-21 (4q27) and IL2RA (10p15) loci in 992 UK PSC cases and 5162 healthy UK controls. Results. The most associated SNPs identified were rs3197999 (3p21 (MST1), p = 1.9 × 10 -6, OR A vs G = 1.28, 95% CI (1.16-1.42)); rs4147359 (10p15 (IL2RA), p = 2.6 × 10 -4, OR A vs G = 1.20, 95% CI (1.09-1.33)) and rs12511287 (4q27 (IL-2/IL-21), p = 3.0 × 10 -4, OR A vs T = 1.21, 95% CI (1.09-1.35)). In addition, we performed a meta-analysis for selected SNPs using published summary statistics from recent studies. We observed genome-wide significance for rs3197999 (3p21 (MST1), P combined = 3.8 × 10 -12) and rs4147359 (10p15 (IL2RA), P combined = 1.5 × 10 -8). Conclusion. We have for the first time confirmed the association of PSC with genetic variants at 10p15 (IL2RA) locus at genome-wide significance and replicated the associations at MST1 and IL-2/IL-21 loci in a large homogeneous UK population. These results strongly implicate the role of IL-2/IL2RA pathway in PSC and provide further confirmation of MST1 association. © Informa Healthcare.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis

Objective. The heritability of RA has been estimated to be ∼55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. Methods. Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404 - carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2β and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and β2-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. Results. Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. Conclusions. The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

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 region.

Disease mapping using Bayesian hierarchical models

description and analysis of geographically indexed health data with respect to demographic, environmental, behavioural, socioeconomic, genetic, and infectious risk factors (Elliott andWartenberg 2004). Disease maps can be useful for estimating relative risk; ecological analyses, incorporating area and/or individual-level covariates; or cluster analyses (Lawson 2009). As aggregated data are often more readily available, one common method of mapping disease is to aggregate the counts of disease at some geographical areal level, and present them as choropleth maps (Devesa et al. 1999; Population Health Division 2006). Therefore, this chapter will focus exclusively on methods appropriate for areal data...

Design studio terrains: Mapping the learning landscapes of Australian architectural education

It has been nearly 25 years since the problems associated with passive learning in large undergraduate classes were first established by McDermott (1991). STEM education, for example North Carolina State University’s SCALE-UP project, has subsequently been influenced by some unique aspects of design studio education. While there are now many institutions applying SCALE-UP or similar approaches to enable lively interaction, enhanced learning, increased student engagement, and to teach many different content areas to classes of all sizes, nearly all of these have remained in the STEM fields (Beichner, 2008). Architectural education, although originally at the forefront of this field, has arguably been left behind. Architectural practice is undergoing significant change, globally. Access to new technology and the development of specialised architectural documentation software has scaffolded new building procurement methods and allowed consultant teams to work more collaboratively, efficiently and even across different time zones. Up until recently, the spatial arrangements, pedagogical approaches, and project work outcomes in the architectural design studio, have not been dissimilar to its inception. It is not possible to keep operating architectural design studios the same way that they have for the past two hundred years, with this new injection of high-end technology and personal mobile Wi-Fi enabled devices. Employing a grounded theory methodology, this study reviews the current provision of architectural design learning terrains across a range of tertiary institutions, in Australia. Some suggestions are provided for how these spaces could be modified to address the changing nature of the profession, and implications for how these changes may impact the design of future SCALE-UP type spaces outside of the discipline of architecture, are also explored.

Delineating environmental envelopes to improve mapping of species distributions, via a hurdle model with CART &/or MaxEnT

Species distribution modelling (SDM) typically analyses species’ presence together with some form of absence information. Ideally absences comprise observations or are inferred from comprehensive sampling. When such information is not available, then pseudo-absences are often generated from the background locations within the study region of interest containing the presences, or else absence is implied through the comparison of presences to the whole study region, e.g. as is the case in Maximum Entropy (MaxEnt) or Poisson point process modelling. However, the choice of which absence information to include can be both challenging and highly influential on SDM predictions (e.g. Oksanen and Minchin, 2002). In practice, the use of pseudo- or implied absences often leads to an imbalance where absences far outnumber presences. This leaves analysis highly susceptible to ‘naughty-noughts’: absences that occur beyond the envelope of the species, which can exert strong influence on the model and its predictions (Austin and Meyers, 1996). Also known as ‘excess zeros’, naughty noughts can be estimated via an overall proportion in simple hurdle or mixture models (Martin et al., 2005). However, absences, especially those that occur beyond the species envelope, can often be more diverse than presences. Here we consider an extension to excess zero models. The two-staged approach first exploits the compartmentalisation provided by classification trees (CTs) (as in O’Leary, 2008) to identify multiple sources of naughty noughts and simultaneously delineate several species envelopes. Then SDMs can be fit separately within each envelope, and for this stage, we examine both CTs (as in Falk et al., 2014) and the popular MaxEnt (Elith et al., 2006). We introduce a wider range of model performance measures to improve treatment of naughty noughts in SDM. We retain an overall measure of model performance, the area under the curve (AUC) of the Receiver-Operating Curve (ROC), but focus on its constituent measures of false negative rate (FNR) and false positive rate (FPR), and how these relate to the threshold in the predicted probability of presence that delimits predicted presence from absence. We also propose error rates more relevant to users of predictions: false omission rate (FOR), the chance that a predicted absence corresponds to (and hence wastes) an observed presence, and the false discovery rate (FDR), reflecting those predicted (or potential) presences that correspond to absence. A high FDR may be desirable since it could help target future search efforts, whereas zero or low FOR is desirable since it indicates none of the (often valuable) presences have been ignored in the SDM. For illustration, we chose Bradypus variegatus, a species that has previously been published as an exemplar species for MaxEnt, proposed by Phillips et al. (2006). We used CTs to increasingly refine the species envelope, starting with the whole study region (E0), eliminating more and more potential naughty noughts (E1–E3). When combined with an SDM fit within the species envelope, the best CT SDM had similar AUC and FPR to the best MaxEnt SDM, but otherwise performed better. The FNR and FOR were greatly reduced, suggesting that CTs handle absences better. Interestingly, MaxEnt predictions showed low discriminatory performance, with the most common predicted probability of presence being in the same range (0.00-0.20) for both true absences and presences. In summary, this example shows that SDMs can be improved by introducing an initial hurdle to identify naughty noughts and partition the envelope before applying SDMs. This improvement was barely detectable via AUC and FPR yet visible in FOR, FNR, and the comparison of predicted probability of presence distribution for pres/absence.