19 research outputs found
Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk
Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
This corrects the article DOI: 10.1038/ncomms5999
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe
From Australia with love: Australian romance novels, 1950-2000
Deposited with permission of the author. © 2001 Dr. Juliet Ella FleschA revised edition of this thesis was published as “From Australia with love : a history of modern Australian popular romance novels” by Fremantle Press, 2004. http://www.fremantlepress.com.au/Mass market romance fiction has attracted considerable scholarly attention, much of it unfavourable. Some scholars have accused it of perpetuating the subjection of women, of setting up inappropriate role models and unattainable (not to mention undesirable) goals for its readers. Others have seen in the popular romance, exemplified by the output of f-Harlequin Mills & Boon, the obliteration of individual difference with authors following a template or formula to produce an undifferentiated and unchanging product, to be consumed by an undiscriminating public.
My thesis examines the romance novel in general, suggesting that the 'global phenomenon' is not as uniform as the term implies and revealing national differences in the publishing, marketing, authorship and readership. I argue that as well as being nationally distinctive, the production and consumption of romance fiction have not remained constant over time.
I challenge the perception of these texts as unchanging and uniform, presenting evidence of change over time and differences within the work of individuals as well as between writers. I argue that within this diversity romance novels can be found which strongly endorse women’s rights and aspirations. I suggest that the world-view proposed by many novelists is more progressive than many critics have discerned, notably in terms of gender and race relations.
The belief that the global appeal of romance fiction as entails the loss of national distinctiveness is also questionable. My thesis explores the Australianness of Australian mass market romance novels of the latter half of the twentieth century. I argue that the output of Australian authors remains distinct from that of American and British writers. There is an ‘Australian voice’ and it reflects and interprets Australian society for a local and world readership. Romance writers commonly assert that they reflect ‘community attitudes’ rather than attempting to change them. My thesis examines this claims in terms of the values implicitly and explicitly endorsed and concludes that the Australian romance novel of the end of the twentieth century reflects the more liberal and enlightened end of the spectrum of Australian public opinion
Spanning the centuries: A history of AE Smith and Son Pty Ltd
"Spanning the Centuries" written by Juliet Flesch & Rosemary Francis in 2008, is the story of a family-owned firm and its part in the construction of Australia over more than a hundred years. Beginning as a one-man plumbing business in 1898, AE Smith & Son Pty Ltd has grown to become one of the largest privately-owned building and mechanical services contractors in Australia, with construction, maintenance and engineering facilities across Australia and New Zealand. Spanning the Centuries is the story of the AE Smith family, including, as well as the three men who owned the company from the end of the last century, some of the many men and women who worked with them for up to thirty years. Through the history of one firm, we glimpse the changing built environment of Australia as AE Smith & Son put their mark on stately homes and gardens, modest suburban houses, towering City apartment blocks, prisons, shopping centres, hospitals, hotels and many other buildings across the country
It was delivered at the Ninth George Rude Seminar in French History and
This paper is an account of a survey of the holdings of the University o
Plant reproduction in the alpine landscape : reproductive ecology, genetic diversity and gene flow of the rare monocarpic "Campanula thyrsoides" in the Swiss Alps
Aims & Objectives
The work presented in this thesis forms part of a larger project “How patchy
habitat and isolation affect alpine plant life: genetic diversity, gene flow and mating
systems”, which includes the PhD studies of Patrick Kuss and the author under the
supervision of Professor Jürg Stöcklin.
This doctoral thesis investigates the consequences of the natural fragmentation
and patchiness of alpine landscapes on the life of alpine plant populations. The central
focus of the thesis is on the mating system, the role of inbreeding and/or outbreeding
depression, genetic diversity and geographic structure within and among populations
of the rare Alpine monocarpic perennial Campanula thyrsoides. The main objectives
and research questions addressed are:
• Is Campanula thyrsoides self-compatible (SI) and if not, does the SI system
break down with flower age? Do inbred C. thyrsoides offspring in the common
garden suffer from inbreeding depression?
• Do we find a distance related inbreeding depression (poorer reproducive
output) or outbreeding depression (increased reproductive output) in field
populations of C. thyrsoides following crosses of different crossing distances
(selfing, 1m, 10m, 100m and among distant populations)?
• How much genetic diversity exists within populations of C. thyrsoides and
how does it relate to population size and altitude? Has the natural habitat
fragmentation let to strong genetic differentiation and restricted gene flow
among populations of C. thyrsoides resulting in a pronounced geographic
structure?
Study species
In order to seek answers to our research questions, we choose to study a
yellow bellflower; Campanula thyrsoides. The choice was based on the information
that C. thyrsoides is a rare plant species, which is only found on calcarious soils
within the European Alps and adjacent mountain ranges (Aeschimann et al. 2005).
The plants selectiveness for carbonate bearing soils together with the fact that its
seeds are not adapted to long-distance dispersal (Tackenberg 2003) are the main
reasons for the isolation and small sizes of many of its populations. These population
characteristics, therefore, made C. thyrsoides a suitable study species. Another
important characteristic of C. thyrsoides, and one of the main reasons for its inclusion
in the study is because it is a monocarpic perennial which flowers once and
subsequently dies (Jäger 2000). Monocarpic plants species, which are more
commonly found in subtropical and tropical mountain systems (e.g. the giant rosettes
of Puya spp, Espeletia spp., Echium spp. etc., Smith & Young 1987; Young &
Augspurger 1991) are rare amidst the temperate alpine flora (for the Alps, see
Aeschimann et al. 2005). Monocarpy can promote genetic differentiation between
populations by reducing the effective population size due to a shorter generation time
and lower density of populations (Loveless & Hamrick 1984; Vitalis et al. 2004).
When studying the effects of population isolation and habitat fragmentation on
plant reproduction (e.g. mating system and inbreeding depression), it is, moreover,
ideal to study a Campanula species. Although most Campanula species are selfincompatible
and allogamous (Nyman 1993), both a break-down in the SI system with
flower age (Vogler et al. 1998) and an evolution towards complete self-compatibility
(Ægisdóttir & Thórhallsdóttir 2006) have been recorded.
Design
We studied the reproductive ecology and genetic diversity of Campanula
thyrsoides by firstly setting up pollination experiments in the common garden and in
the field and secondly by sampling leaf material in 32 field populations in
Switzerland. In the common garden study, we set up a pollination experiment in order
to study the breeding system of C. thyrsoides, including the consequences of selfing,
half-sibling crossings and outcrossing on reproductive output and seedling
performance. Moreover, field experiments in four populations were set up in the
Swiss Alps in order to study the effect of different crossing distances on reproduction
in C. thyrsoides and to see if evidence would be found of hidden inbreeding
depression or outbreeding depression following large-distance crossings compared to
within-population crossings. In addition, we studied the genetic diversity, gene flow
and geographical structure within and among 32 field populations of C. thyrsoides in
Switzerland, covering both large geographical and altitudinal ranges. The genetic
study was conducted using 5 co-dominant microsatellite markers. In addition, we
studied the genetic diversity in C. thyrsoides and two other alpine plants using random
amplified polymorphic DNA (RAPD) marker as well as studing the evolutionary
demography of C. thyrsoides