Reproductive effects in two species of native freshwater gastropod mollusc exposed to 17β-oestradiol or an environmentally relevant mixture of oestrogenic chemicals in outdoor mesocosms

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Recent evidence suggests that molluscs may be sensitive to the effects of endocrine disrupting chemicals (EDCs) in a similar manner to vertebrates, such as fish. Despite this (with the exception of TBT-induced imposex in marine gastropods), molluscs have been largely overlooked in the field of endocrine disruption. Life-cycle studies were conducted in which two species of native UK freshwater gastropod molluscs (the hermaphrodite Planorbarius corneus and the gonochorist Viviparus viviparus) were exposed to either 17β-oestradiol or environmentally relevant mixtures of chemicals known to be oestrogenic to vertebrates and to be present in UK treated sewage effluents (TSE) and rivers. Adult snails were exposed for four months in outdoor mesocosms, fed by river water, over the spring and summer (breeding season) in order to examine effects on reproductive output, growth and mortality. Furthermore, offspring (F1s) were also developmentally exposed over the same period. F1 juvenile snails were then depurated in river water for nine months (over winter) after which time their growth, survival, and reproductive success were measured in further un-dosed river water mesocosm studies in the following spring/summer. Histopathology was used to determine immediate effects of chemical exposure on adult and F1 snails’ reproductive health. Histopathology was also used to determine long lasting effects of chemical exposure on depurated F1s. Exposure to oestrogenic chemicals resulted in a range of effects, including modulated fecundity and growth in F0 adults, to retardation of growth, sexual development and fecundity in developmentally exposed F1s. Exposure to mixtures of oestrogenic chemicals also resulted in possible modulation of the immune system, resulting in increased parasitism and over winter mortality of exposed F1s compared to snails exposed to river water alone. Differences in sensitivity and response to exposure between the two species and the generations were also observed

Reproductive effects in two species of native freshwater gastropod mollusc exposed to 17β-oestradiol or an environmentally relevant mixture of oestrogenic chemicals in outdoor mesocosms

Recent evidence suggests that molluscs may be sensitive to the effects of endocrine disrupting chemicals (EDCs) in a similar manner to vertebrates, such as fish. Despite this (with the exception of TBT-induced imposex in marine gastropods), molluscs have been largely overlooked in the field of endocrine disruption. Life-cycle studies were conducted in which two species of native UK freshwater gastropod molluscs (the hermaphrodite Planorbarius corneus and the gonochorist Viviparus viviparus) were exposed to either 17β-oestradiol or environmentally relevant mixtures of chemicals known to be oestrogenic to vertebrates and to be present in UK treated sewage effluents (TSE) and rivers. Adult snails were exposed for four months in outdoor mesocosms, fed by river water, over the spring and summer (breeding season) in order to examine effects on reproductive output, growth and mortality. Furthermore, offspring (F1s) were also developmentally exposed over the same period. F1 juvenile snails were then depurated in river water for nine months (over winter) after which time their growth, survival, and reproductive success were measured in further un-dosed river water mesocosm studies in the following spring/summer. Histopathology was used to determine immediate effects of chemical exposure on adult and F1 snails’ reproductive health. Histopathology was also used to determine long lasting effects of chemical exposure on depurated F1s. Exposure to oestrogenic chemicals resulted in a range of effects, including modulated fecundity and growth in F0 adults, to retardation of growth, sexual development and fecundity in developmentally exposed F1s. Exposure to mixtures of oestrogenic chemicals also resulted in possible modulation of the immune system, resulting in increased parasitism and over winter mortality of exposed F1s compared to snails exposed to river water alone. Differences in sensitivity and response to exposure between the two species and the generations were also observed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Reproductive effects in two species of native freshwater gastropod mollusc exposed to 17β-oestradiol or an environmentally relevant mixture of oestrogenic chemicals in outdoor mesocosms

Recent evidence suggests that molluscs may be sensitive to the effects of endocrine disrupting chemicals (EDCs) in a similar manner to vertebrates, such as fish. Despite this (with the exception of TBT-induced imposex in marine gastropods), molluscs have been largely overlooked in the field of endocrine disruption. Life-cycle studies were conducted in which two species of native UK freshwater gastropod molluscs (the hermaphrodite Planorbarius corneus and the gonochorist Viviparus viviparus) were exposed to either 17β-oestradiol or environmentally relevant mixtures of chemicals known to be oestrogenic to vertebrates and to be present in UK treated sewage effluents (TSE) and rivers. Adult snails were exposed for four months in outdoor mesocosms, fed by river water, over the spring and summer (breeding season) in order to examine effects on reproductive output, growth and mortality. Furthermore, offspring (F1s) were also developmentally exposed over the same period. F1 juvenile snails were then depurated in river water for nine months (over winter) after which time their growth, survival, and reproductive success were measured in further un-dosed river water mesocosm studies in the following spring/summer. Histopathology was used to determine immediate effects of chemical exposure on adult and F1 snails’ reproductive health. Histopathology was also used to determine long lasting effects of chemical exposure on depurated F1s. Exposure to oestrogenic chemicals resulted in a range of effects, including modulated fecundity and growth in F0 adults, to retardation of growth, sexual development and fecundity in developmentally exposed F1s. Exposure to mixtures of oestrogenic chemicals also resulted in possible modulation of the immune system, resulting in increased parasitism and over winter mortality of exposed F1s compared to snails exposed to river water alone. Differences in sensitivity and response to exposure between the two species and the generations were also observed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

(Re-)Emergent Orders: Understanding the Negotiation(s) of Rebel Governance

The concept of order is often neglected in the study of conflict – seemingly such a ‘disordering’ process. With the recent increase in the examination of rebel governance however, bringing order back into our understanding of rebel and insurgent groups has much to offer in exploring the everyday politics which connect authorities, rebel movements and the population itself, in a complex mass of intersubjective and power-based interactions and negotiations. Rebels both shape and are shaped by existing forms of order in complex and ongoing ways. This article explores how varying elements interact in the negotiation, framing and enforcement of order and develops an original analytical framework to examine the perpetual negotiations of rebel movements in their attempts to cement their control

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.BCAC is funded by Cancer Research UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). Genotyping on the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C8197/A16565), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer program and the Ministry of Economic Development, Innovation and Export Trade of Quebec, grant PSR-SIIRI-701. Combination of the GWAS data was supported in part by the US National Institutes of Health (NIH) Cancer Post-Cancer GWAS initiative, grant 1 U19 CA148065-01 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.324

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH)Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024Funder: Quebec Breast cancer Foundation Genome QuebecFunder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))Funder: European Union’s Horizon 2020Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972Funder: BCAST - European Union’s Horizon 2020Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913Abstract: Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.

BACKGROUND: Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. METHODS: The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries-Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODEm), to generate cause fractions and cause-specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised