Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

The spectral energy distribution of fermi bright blazars

We have conducted a detailed investigation of the broadband spectral properties of the γ-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated Fermi γ-ray spectra with Swift, radio, infra-red, optical, and other hard X-ray/γ-ray data, collected within 3 months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous spectral energy distributions (SED) for 48 LBAS blazars. The SED of these γ-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual log ν-log ν Fν representation, the typical broadband spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SED to characterize the peak intensity of both the low- and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broadband colors (i.e., the radio to optical, αro, and optical to X-ray, αox, spectral slopes) and from the γ-ray spectral index. Our data show that the synchrotron peak frequency (νSpeak) is positioned between 1012.5 and 1014.5 Hz in broad-lined flat spectrum radio quasars (FSRQs) and between 10 13 and 1017 Hz in featureless BL Lacertae objects. We find that the γ-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron-inverse Compton scenarios. However, simple homogeneous, one-zone, synchrotron self-Compton (SSC) models cannot explain most of our SED, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. More complex models involving external Compton radiation or multiple SSC components are required to reproduce the overall SED and the observed spectral variability. While more than 50% of known radio bright high energy peaked (HBL) BL Lacs are detected in the LBAS sample, only less than 13% of known bright FSRQs and LBL BL Lacs are included. This suggests that the latter sources, as a class, may be much fainter γ-ray emitters than LBAS blazars, and could in fact radiate close to the expectations of simple SSC models. We categorized all our sources according to a new physical classification scheme based on the generally accepted paradigm for Active Galactic Nuclei and on the results of this SED study. Since the LAT detector is more sensitive to flat spectrum γ-ray sources, the correlation between νSpeak and γ-ray spectral index strongly favors the detection of high energy peaked blazars, thus explaining the Fermi overabundance of this type of sources compared to radio and EGRET samples. This selection effect is similar to that experienced in the soft X-ray band where HBL BL Lacs are the dominant type of blazars. © 2010 The American Astronomical Society

Architectural regeneration and its theoretical context

Cycles of decline and rejuvenation, and the adaptation and re-use of buildings, have been common constants of the built environment throughout the history of human settlement. The more formalised practices of building conservation and regeneration on the other hand are an outcome of movements that emerged in the nineteenth century, which were informed by theoretical standpoints that were products of the post-Enlightenment positivist, rational and romantic outlooks (Gelernter 1995). Some of these theories and standpoints continue to inform interventions in the built environment, while others have been eclipsed by alternative worldviews and environmental realities. Architectural regeneration as a notion and as a distinct discipline emerges from a number of those concurrent, symbiotic, complementary and sometimes conflicting theories. The purpose of this chapter is to position architectural regeneration into its theoretical context and to demonstrate how it continues to be informed by a range of contemporary philosophies. Worldwide, laws, policy and guidance concerning the protection and conservation of historic buildings have come to be based on a set of principles that have emerged from an international conservation movement that can be traced back to Eurocentric philosophies of the nineteenth century (Jokilehto 1999). The design of the urban realm, buildings and interiors meanwhile are regularly discussed and critiqued in the context of prevalent design theories which in the latter half of the twentieth century were deliberately separated from theories pertaining to the conservation of historic buildings. The processes of adaptive re-use, which architectural regeneration encompasses, can be seen simultaneously as part of the collective theoretical frameworks of conservation and design, and also outside of them. Although ‘architects have led the conservation world in matters of principles and philosophy’ (Muñoz Viñas 2011: 71), they have also been instrumental in de-coupling conservation from design. Architectural regeneration has emerged in this middle ground between conservation and architectural design. At the same time, the broader realm of regeneration is often positioned in the domain of policy, spatial planning and economic development. Growing environmental concerns and climate change awareness are driving innovation in multiple arenas, including urban planning and building design. The current environmental crisis has become one of the key drivers for making better use of existing resources as well as for buildings to adapt to respond to new realities (Leatherbarrow and Wesley 2018). Starting from the latter part of the twentieth century there have been an increasing number of publications on the subject of adaptive re-use. Nonetheless, a shared and accepted vocabulary and definition of what adaptive reuse is, and what it involves, remains ambiguous, with various terminologies and definitions prevailing (Plevoets and Van Cleempoel 2013: 13). The same ambiguity applies to regeneration more generally. One of the earliest books on the subject of re-use is Sherban Cantacuzino’s New Uses for Old Buildings, published in 1975. The content, as that of many others that have been published since, is prescriptive and focuses on potential new uses linked to building typologies. Many of the volumes that have followed have remained technical (Eley and Worthington 1984; Highfield 1987) and heavily depend on case studies that are used to exemplify the processes, practicalities and design potential of re-use (Austin et al. 1988; Larkham 2000; Morrison and Waterson 2019). A new perspective was introduced by Stewart Brand in his book How Buildings Learn, published in 1997, where the value of built-in flexibility is upheld as a characteristic conducive to easy adaptability and a long use-span for buildings. There remains, however, a theoretical vacuum framing the subject, which this chapter intends to redress. The chapter consists of two sections. In the first section we examine the various theories within which architectural regeneration is contextualised, and the second proposes a number of key principles that inform the processes of architectural regeneration