Palaeomagnetic Studies in the Scottish Paratectonic Caledonides

Presented in this thesis are three studies which document the palaeomagnetic record of rocks forming constituents of the Scottish paratectonic Caledonides. The early Arenig Slockenray Formation within the Ballantrae Ophiolite, southwest Scotland, displays a multivectorial natural remanent magnetisation. Two components (S and M) are identified delineated by differing blocking temperature/coercivity spectra. Component (S) is removed following treatment to 200C/10mT and is regarded as of recent viscous origin. Component (M) forms the characteristic formation magnetisation and resides in both magnetite and hematite. Extensive sampling of all exposed lithologies reveals an (in situ) non-Fisherian distribution of the characteristic magnetisation defining an envelope from SE moderate positive to SW shallow negative directions. A negative intra-formation conglomerate test identifies this component as a pervasive overprint. A second conglomerate test performed on the Benan Conglomerate of Llandeilo age, reveals dispersely directed magnetisations over a stability range equivalent to that of component M. This field test therefore defines a maximum remagnetisation window of 30 million years for the characteristic remanence. Structurally-corrected site mean results from the Slockenray Formation are also non-Fisherian forming a small circle partial arc centred on a vertical axis (NW moderate positive to SW moderate positive diections). A combined palaeomagnetic fold and fault test suggests that acquisition of component M pre-dates both folding and faulting. The resulting palaeolatitude of remanence acquisition (28.8S) implies a tectonic position close to the southern Laurentian margin for the Ballantrae ophiolite in Arenig times. A palaeomagnetic study of the late Silurian - early Devonian St. Abbs Head outlier, SE Scotland, reveals a multicomponent magnetic remanence structure. Three components of magnetisation are recognised termed (L), (I) & (H) pertaining to 'Low', 'Intermediate' and 'High' unblocking treatments respectively, (L: 60

Advocacy in the tail: Exploring the implications of ‘climategate’ for science journalism and public debate in the digital age

This paper explores the evolving practices of science journalism and public debate in the digital age. The vehicle for this study is the release of digitally stored email correspondence, data and documents from the Climatic Research Unit at the University of East Anglia in the weeks immediately prior to the United Nations Copenhagen Summit (COP-15) in December 2009. Described using the journalistic shorthand of ‘climategate’, and initially promoted through socio-technical networks of bloggers, this episode became a global news story and the subject of several formal reviews. ‘Climategate’ illustrates that media literate critics of anthropogenic explanations of climate change used digital tools to support their cause, making visible selected, newsworthy aspects of scientific information and the practices of scientists. In conclusion, I argue that ‘climategate’ may have profound implications for the production and distribution of science news, and how climate science is represented and debated in the digitally-mediated public sphere

Baltica. A synopsis of vendian-permian palaeomagnetic data and their palaeotectonic implications

In light of recent additions to the Palaeozoic palaeo-magnetic data-base, particularly for the Ordovician era, a revised apparent polar wander (APW) path for Baltica has been constructed following a rigorous synthesis of all Late Precambrian-Permian data. The APW path is characterized by two prominent loops. Firstly, a Late Precambrian-Cambrian loop probably relating to a rifting event and secondly, a younger loop relating to a Mid-Silurian (Scandian) collision event. These features imply major change in plate-tectonic reconfiguration.Baltica probably represented an individual continental unit in Early Palaeozoic times and was positioned in high southerly latitudes in an "inverted" geographic orientation. In such a reconstruction Baltica was separated from the northern margin of Gondwana by the Tornquist Sea and from Laurentia by the Iapetus Ocean. The Tornquist Zone is thus interpreted as a passive or dextral transform margin during the early Palaeozoic.While undergoing counter-clockwise rotations (up to 1.6[deg]/Ma), Baltica drifted northward through most of the Palaeozoic; except for a short period of southerly movement in Late Silurian-Early Devonian times after collision with Laurentia. Rapid movements in latitude (up to 9 cm/yr) are noted in Late Precambrian/early Palaeozoic times and significant decrease in velocities throughout Palaeozoic time probably reflect the progressive amalgamation of a larger continent by Early-Devonian (Euramerica) and Permian (Pangea) times.The Tornquist Sea had a principal component of palaeo-east-west orientation. Hence it is difficult to be precise in the timing of when micro-continents such as Eastern Avalonia and the European Massifs ultimately collided along the southwestern margin of Baltica. These micro-continents are considered to have been peripheral to Gondwana (in high southerly latitudes) during the Early Ordovician. Eastern Avalonia clearly had rifted off Gondwana by Llanvirn-Llandeilo times and may have collided with Baltica during Late Ordovician times, although the present available Silurian palaeomagnetic data from Eastern Avalonia may suggest collision in Late Silurian times.Across the Iapetus facing margin of Baltica, Laurentia was situated in equatorial to southerly latitudes during most of the Lower Palaeozoic. These continents collided in Mid-Silurian times, i.e. a first collision between southwestern Norway and Greenland/Scotland which gave rise to the early Scandian Orogeny (425 Ma) in southwestern Norway possible followed by a later, but less dramatic, Scandian event in northern Norway at around 410 Ma. Since Baltica was geographically inverted in early Palaeozoic times, the collisional margin could not have been a margin that once rifted off Laurentia as assumed in a number of plate-tectonic models.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29743/1/0000080.pd

Learning and Expertise in Mineral Exploration Decision-Making: An Ecological Dynamics Perspective

The declining discovery rate of world-class ore deposits represents a significant obstacle to future global metal supply. To counter this trend, there is a requirement for mineral exploration to be conducted in increasingly challenging, uncertain, and remote environments. Faced with such increases in task and environmental complexity, an important concern in exploratory activities are the behavioural challenges of information perception, interpretation and decision-making by geoscientists tasked with discovering the next generation of deposits. Here, we outline the Dynamics model, as a diagnostic tool for situational analysis and a guiding framework for designing working and training environments to maximise exploration performance. The Dynamics model is based on an Ecological Dynamics framework, combining Newell’s Constraints model, Self Determination Theory, and including feedback loops to define an autopoietic system. By implication of the Dynamics model, several areas are highlighted as being important for improving the quality of exploration. These include: (a) provision of needs-supportive working environments that promote appropriate degrees of effort, autonomy, creativity and technical risk-taking; (b) an understanding of the wider motivational context, particularly the influence of tradition, culture and other ‘forms of life’ that constrain behaviour; (c) relevant goal-setting in the design of corporate strategies to direct exploration activities; and (d) development of practical, representative scenario-based training interventions, providing effective learning environments, with digital media and technologies presenting decision-outcome feedback, to assist in the development of expertise in mineral exploration targeting

ABCB1 (MDR1) polymorphisms and ovarian cancer progression and survival: A comprehensive analysis from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas

<b>Objective</b> <i>ABCB1</i> encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).<p></p> <b>Methods</b> The best candidates from fine-mapping analysis of 21 <i>ABCB1</i> SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either ‘standard’ first-line paclitaxel–carboplatin chemotherapy (n = 1158) or any first-line chemotherapy regimen (n = 2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.<p></p> <b>Result</b> Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77–1.01; p = 0.07). In contrast, <i>ABCB1</i> expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.<p></p> <b>Conclusion</b> Our study represents the largest analysis of <i>ABCB1</i> SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.<p></p&gt

rs495139 in the TYMS-ENOSF1 Region and Risk of Ovarian Carcinoma of Mucinous Histology

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.Peer reviewe

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer

Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.The OCAC Oncoarray genotyping project was funded through grants from the U.S. National Institutes of Health 2 (NIH) (CA1X01HG007491-01, U19-CA148112, R01-CA149429 and R01-CA058598); Canadian Institutes of Health 3 Research (MOP-86727) and the Ovarian Cancer Research Fund (OCRF). Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. AUS studies (Australian Ovarian Cancer Study and the Australian Cancer Study) were funded by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia (Multi-State Application Numbers 191, 211 and 182). The Bavarian study (BAV) was supported by ELAN Funds of the University of Erlangen-Nuremberg. The Belgian study (BEL) was funded by Nationaal Kankerplan. The BVU study was funded by Vanderbilt CTSA grant from the National Institutes of Health (NIH)/National Center for Advancing Translational Sciences (NCATS) (ULTR000445). The CNIO Ovarian Cancer Study (CNI) study was supported by Instituto de Salud Carlos III (PI 12/01319); Ministerio de Economía y Competitividad (SAF2012). The Hawaii Ovarian Cancer Study (HAW) was supported the U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001). The Hannover-Jena Ovarian Cancer Study (HJO) study was funded by intramural funding through the Rudolf-Bartling Foundation. The Hormones and Ovarian Cancer Prediction study (HOP) was supported by US National Cancer Institute: K07-CA80668; R01CA095023; P50-CA159981; R01-CA126841; US Army Medical Research and Materiel Command: DAMD17-02-1-0669; NIH/National Center for Research Resources/General Clinical Research Center grant MO1- RR000056. The Women’s Cancer Program (LAX) was supported by the American Cancer Society Early Detection Professorship (120950-SIOP-06-258-06-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. The Mayo Clinic Case-Only Ovarian Cancer Study (MAC) and the Mayo Clinic Ovarian Cancer Case-Control Study (MAY) were funded by the National Institutes of Health (R01-CA122443, P30-CA15083, P50-CA136393); Mayo Foundation; Minnesota Ovarian Cancer Alliance; Fred C. and Katherine B. Andersen Foundation; Fraternal Order of Eagles. The MALOVA study (MAL) was funded by research grant R01- CA61107 from the National Cancer Institute, Bethesda, Md; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project. The North Carolina Ovarian Cancer Study (NCO) National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666). The New England-based Case-Control Study of Ovarian Cancer (NEC) was supported by NIH grants R01 CA 054419-10 and P50 CA105009, and Department of Defense CDMRP grant W81XWH-10-1-0280. The University of Bergen, Haukeland University Hospital, Norway study (NOR) was funded by Helse Vest, The Norwegian Cancer Society, The Research Council of Norway. The Oregon study (ORE) was funded by the Sherie Hildreth Ovarian Cancer Research Fund and the OHSU Foundation. The Ovarian Cancer Prognosis and Lifestyle Study (OPL) was funded by National Health and Medical Research Council (NHMRC) of Australia (APP1025142) and Brisbane Women’s Club. The Danish Pelvic Mass Study (PVD) was funded by Herlev Hospitals Forskningsråd, Direktør Jacob Madsens og Hustru Olga Madsens fond, Arvid Nilssons fond, Gangsted fonden, Herlev Hospitals Forskningsråd and Danish Cancer Society. The Royal Brisbane Hospital (RBH) study was funded by the National Health and Medical Research Council of Australia. The Scottish Randomised Trial in Ovarian Cancer study (SRO) was funded by Cancer Research UK (C536/A13086, C536/A6689) and Imperial Experimental Cancer Research Centre (C1312/A15589). The Princess Margaret Cancer Centre study (UHN) was funded by Princess Margaret Cancer Centre Foundation-Bridge for the Cure. The Gynaecological Oncology Biobank at Westmead (WMH) is a member of the Australasian Biospecimen Network-Oncology group, funded by the Australian National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 and 15/RIG/1-16. OVCARE Gynecologic Tissue Bank and Outcomes Unit (VAN) study was funded by BC Cancer Foundation, VGH & UBC Hospital Foundation. Stuart MacGregor acknowledges funding from an Australian Research Council Future Fellowship and an Australian National Health and Medical Research Council project grant (APP1051698). Anna deFazio was funded by the University of Sydney Cancer Research Fund and the Cancer Institute NSW through the Sydney West-Translational Cancer Research Centre. Dr. Beth Y. Karlan is supported by American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. Irene Orlow was supported by NCI CCSG award (P30-CA008748). GCT, PW and TO’M were funded by NHMRC Fellowships