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 regio

Polymorphism of human mu class glutathione transferases

Objectives and methods: A combined database mining approach was used to detect polymorphisms in the mu class glutathione-S-transferase (GST) genes. Although a large number of potential polymorphisms were detected in the five genes that comprise the Mu class GSTs using sequence alignment programs and by searching single nucleotide polymorphism databases, the majority were not validated or detected in three major ethnic populations (African, Southern Chinese and Australian European). Results: Two new polymorphisms were detected and characterized in the GSTM3 gene. A rare pG147W substitution was detected only in the Southern Chinese subjects. A more common pV224I substitution was found in each of the ethnic groups studied, and significant differences in allele frequencies were observed between each group. These two polymorphisms can combine to form four distinct haplotypes (GSTM3A [p.G147;V224], GSTM3C [p.G147;I224], GSTM3D [p.W147;V224], GSTM3E [p.W147;I224]). The four isoforms were expressed in Escherichia coli and characterized enzymatically with several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), cumene hydroperoxide and t-nonenal. GSTM3-3 containing the variant p.W147 residue tended to show diminished specific activity and catalytic efficiency with CDNB. In contrast, GSTM3-3 containing the variant p.I224 residue tended to show increased specific activity and catalytic efficiency with CDNB. Interactions between the different p.147 and p.224 residues were also observed, with the GSTM3C isoform exhibiting the greatest activity with each substrate, and GSTM3E the lowest Conclusion: These functional polymorphisms may play a significant role in modulating the ability of GSTM3-3 to metabolize substrates such as the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea

Reconnecting society with its ecological roots

Recent high-profile analyses of trajectories and prognoses of ecosystem decline around the world have called for a renewed focus on embedding the values of the natural world across all areas of public policy. This paper reports the results of a UK-based deliberative process involving experts from a wide range of policy domains and across societal sectors: government departments, associated agencies, national and international NGOs, professional institutions, academia and independent experts. A symposium, based on a collaborative learning approach, explored instances in which ecosystem values have successfully been embedded into public policy, identified challenges to their more widespread embedding despite commitments to do so over generational timescales, and took a backcasting approach to develop actionable outcomes required to deliver transformation change across state and civil society. Emergent themes were expressed in social, technological, environmental, economic and political terms. Recommendations for interventions in complex social-ecological systems are cross-sectoral in scope and will necessarily entail multiple agents of change, well beyond governmental leadership, within any given sphere of societal activity and interest. We identify strategic challenges for, and between, a spectrum of societal policy areas, many currently overlooking ecosystem dependencies, impacts and potential benefits. Reflections on the collaborative learning approach are also provided

Palaeontology from Australasia and beyond: Abstracts from Palaeo Down Under 3 Perth, Western Australia, July 2023

Palaeo Down Under 3 (PDU3), the now quadrennial conference of the Australasian Palaeontologists (AAP) association, was held in Perth, Western Australia, from the 10th-14th of July 2023. PDU3 showcased innovative research, outreach and education initiatives being conducted across Australasia and beyond by both local and international scientists. A total of 78 talks, 17 posters and 6 plenaries were presented across the five days, and covered a wide range of topics, geological timeframes, and fossil groups. AAP is proud to publish this compilation of PDU3 abstracts to illustrate the current and ongoing strength of Australasian palaeontology. Sarah K. Martin [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Michael Archer [ [email protected] ], School of Biological, Earth & Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia; Heidi J. Allen [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Daniel D. Badea [ [email protected] ], Faculty of Geography and Geology, "Alexandru Ioan Cuza" University, Bulevard "Carol I", Nr.11, 707006, Iași, Romania; Eleanor Beidatsch [ [email protected] ], Palaeoscience Research Centre, University of New England, Armidale, New South Wales 2351, Australia; Marissa J. Betts [ [email protected] ], Palaeoscience Research Centre/LLUNE, University of New England, Armidale, New South Wales 2351, Australia; Maria Blake [ [email protected] ], School of Earth, Atmosphere and Environment, Monash University, 9 Rainforest Walk, Clayton, Victoria 3800, Australia; Phillip C. Boan [ [email protected] ], University of California, Riverside, Geology 1242, 900 University Ave, Riverside, CA 92521, U.S.A.; Tory Botha [ [email protected] ], School of Biological Sciences, Molecular Life Sciences Building, North Terrace Campus, The University of Adelaide, Adelaide, South Australia 5005, Australia; Glenn A. Brock [ [email protected] ], School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; Luke Brosnan [ [email protected] ], WA Organic and Isotope Geochemistry Centre, The Institute for Geoscience Research, School of Earth and Planetary Sciences, Building 500, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Jack Castle-Jones [ [email protected] ], School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; Jonathan Cramb [ [email protected] ], Queensland Museum, PO Box 3300, South Brisbane BC, Queensland 4101, Australia; Vanesa L. De Pietri [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; Sherri Donaldson [ [email protected] ], School of Geosciences, University of Edinburgh, Grant Institute, The King's Buildings, James Hutton Road, Edinburgh, EH9 3FE, Scotland, U.K.; Elizabeth M. Dowding [ [email protected] ], Friedrich-Alexander-Universität Erlangen-Nürnberg, Loewenichstraße 28 91054 Erlangen, Germany; Ruairidh Duncan [ [email protected] ], Evans EvoMorph Lab, Room 226, 18 Innovation Walk, School of Biological Sciences, Monash University, Clayton, Victoria 3800, Australia; Amy L. Elson [ [email protected] ], WA Organic and Isotope Geochemistry Centre, The Institute for Geoscience Research, School of Earth and Planetary Sciences, Building 500, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Roy M. Farman [ [email protected] ], School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia; Mahala A. Fergusen [ [email protected] ], School of Biological Sciences, Benham Building, North Terrace Campus, The University of Adelaide, Adelaide, South Australia 5005, Australia; Alyssa Fjeld [ [email protected] ], School of Biological Sciences, 18 Innovation Walk, Monash University, Clayton, Victoria 3800, and School of Natural Sciences, Macquarie University, New South Wales 2109, Australia; David Flannery [ [email protected] ], School of Earth and Atmospheric Sciences, Queensland University of Technology, 2 George St, Brisbane, Queensland 4000, Australia; Timothy G. Frauenfelder [ [email protected] ], University of New England, Armidale, New South Wales 2351, Australia; John D. Gorter [ [email protected] ], PO Box 711, Claremont, Western Australia 6910, Australia; Michelle Gray [ [email protected] ], School of Life and Environmental Sciences, Deakin University, Geelong, Victoria 3216, Australia; Nigel Gray [ [email protected] ], GPO Box 2902, Brisbane, Queensland 4001, Australia; Peter Haines [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Lachlan J. Hart [ [email protected] ], Australian Museum Research Institute, 1 William Street, Sydney, New South Wales 2010, Australia; Brooke E. Holland [ [email protected] ], School of Biological Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia; James D. Holmes [ [email protected] ], Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, Uppsala 752 36, Sweden; Lars Holmer [ [email protected] ], Department of Earth Sciences, Palaeobiology, Uppsala University, Villavägen 16, Uppsala 752 36, Sweden; Ashleigh V.S. Hood [ [email protected] ], School of Geography, Earth and Atmospheric Sciences, University of Melbourne, Parkville, Victoria 3010, Australia; Alexey P. Ippolitov [ [email protected]] , School of Geography, Environment and Earth Sciences, Victoria University of Wellington | Te Herenga Waka, 21 Kelburn Parade, Wellington 6012, New Zealand; Christine M. Janis [ [email protected] ], Bristol Palaeobiology Group, School of Earth Sciences, University of Bristol, Wills Memorial Building, Bristol, BS8 1RJ, U.K.; Benjamin P. Kear [ [email protected] ], The Museum of Evolution, Uppsala University, Norbyvägen 16, SE-752 36 Uppsala, Sweden; Sophie Kelly [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; Justin L. Kitchener [ [email protected] ], School of Environmental and Rural Science, University of New England, Armidale, New South Wales 2351, Australia; John R. Laurie [ [email protected] ], Geoscience Australia, Symonston, Australian Capital Territory 2601, and School of Natural Sciences, Macquarie University, North Ryde, New South Wales 2109, Australia; Lucy G. Leahey [ [email protected] ], The University of Queensland, Brisbane, Queensland 4072, Australia; John A. Long [ [email protected] ], College of Science and Engineering, Flinders University, PO Box 2100, Adelaide, South Australia 5001, Australia; Daniel Mantle [ [email protected] ], MGPalaeo, Unit 1, 5 Arvida Street, Malaga, Western Australia 6090, Australia; David McB. Martin [ [email protected] ], Geological Survey of Western Australia, Department of Energy, Mines, Industry Regulation and Safety, 100 Plain St, East Perth, Western Australia 6004, Australia; Chris Mays [ [email protected] ], School of Biological, Earth and Environmental Sciences, Environmental Research Institute, University College Cork, Distillery Fields, Cork T23 N73K, Ireland; Matthew R. McCurry [ [email protected] ], Australian Museum, 1 William St, Sydney, New South Wales 2010, Australia; Peter McGoldrick [ [email protected] ], CODES, University of Tasmania, Locked Bag 66, Hobart, Tasmania 7001, Australia; Corinne L. Mensforth [ [email protected] ], Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia; Rhys D. Meyerkort [ [email protected] ], University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia 6009, Australia; Christina Nielsen-Smith [ [email protected] ], School of Biological Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia; Ryan Nel [ [email protected] ], Geology Department, Rhodes University, Grahamstown, South Africa; Jake Newman-Martin [ [email protected] ], Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Yeongju Oh [ [email protected] ], Division of Earth Sciences, Korea Polar Research Institute, 26 Songdomirae-ro, Yeonsu-gu, 21990 Incheon, Republic of Korea, and Polar Science, University of Science and Technology, Daejeon, 34113, Republic of Korea; John R. Paterson [ [email protected] ], Palaeoscience Research Centre, School of Environmental and Rural Science, University of New England, Armidale, New South Wales 2351, Australia; Jacob Pears [ [email protected] ], School of Molecular and Life Sciences, Curtin University, Kent St, Bentley, Western Australia 6102, Australia; Stephen F. Poropat [ [email protected] ], Western Australian Organic and Isotope Geochemistry Centre, School of Earth and Planetary Science, Curtin University, Kent St, Bentley, Western Australia 6102, and Australian Age of Dinosaurs Museum of Natural History, Winton, Queensland 4735, Australia; Catherine M. Reid [ [email protected] ], School of Earth and Environment, University of Canterbury, Private Bag 4800, Christchurch 8140, New Zealand; R. Pamela Reid [ [email protected] ], Department of Marine Geosciences, Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, Miami, FL 33149, U.S.A., and Bahamas Marine EcoCentre, Miami, FL 3315