The molybdenum isotopic compositions of I-, S- and A- type granitic suites

JY is funded by a Clarendon Scholarship and a Dr Bill Willetts Scholarship from the University of Oxford. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement No. 247422. This work has also supported by Science & Technology Facilities Council.This study reports Mo isotopic compositions for fifty-two Palaeozoic granitic rocks with contrasting source affinities (A-, I- and S-type) from the Lachlan Fold Belt (LFB) and the New England Batholith (NEB), both in SE Australia, and three compositionally zoned plutons (Loch Doon, Criffell, and Fleet) located in the South Uplands of Scotland. The results show relatively large variations in δ98Mo for igneous rocks ranging from -1.73‰ to 0.59‰ with significant overlaps between different types. No relationships between δ98Mo and δ18O or ASI (Alumina Saturation Index) are observed, indicating that Mo isotopes do not clearly distinguish igneous versus sedimentary source types. Instead, effects of igneous processes, source mixing, regional geology, as well as hydrothermal activity control the Mo isotope compositions in these granites. It is found that Mo is mainly accommodated in biotite and to a lesser extent in hornblende. Hornblende and Fe3+-rich minerals may preferentially incorporate light isotopes, as reflected by negative correlations between δ98Mo and K/Rb and [Fe2O3]. There is a positive correlation between initial 87Sr/86Sr and δ98Mo in I-type granitic rocks, reflecting the admixing of material from isotopically distinct sources. Granitic rocks from Scotland and Australia display strikingly similar curvilinear trends in δ98Mo vs. initial 87Sr/86Sr despite the differing regional geology. Localized hydrothermal effects on Mo isotopes in three samples from Loch Doon and Criffell can result in anomalously low δ98Mo of < -1‰. Based on this study, an estimate of δ98Mo = 0.14±0.07‰ (95% s.e.) for the Phanerozoic upper crust is proposed. This is slightly heavier than basalts indicating an isotopically light lower crust and / or a systematic change to the crust resulting from subduction of isotopically light dehydrated slab and / or pelagic sediment over time.Publisher PDFPeer reviewe

Heterogeneous nickel isotope compositions of the terrestrial mantle – Part 2: Mafic lithologies

We report stable Ni isotope compositions (δ⁶⁰/⁵⁸Ni, relative to SRM986) for mafic lavas with a range of -0.16 ‰ to +0.20 ‰ (n=44), similar to that of peridotite samples. Ocean island basalts (OIB) have been analysed from Iceland (n=6), the Azores (n=3), the Galápagos Islands (n=2), and Lōʻihi, Hawaii (n=1). Samples from Iceland (average δ⁶⁰/⁵⁸Ni = +0.13±0.16‰, 2s, n=7) display the greatest range in Ni isotope compositions from a single OIB location in this work, of +0.01 ‰ to +0.23 ‰. Samples from the Azores (average δ⁶⁰/⁵⁸Ni = -0.10±0.10 ‰, 2s) and Galápagos (average δ⁶⁰/⁵⁸Ni = -0.01±0.04 ‰, 2s) are generally isotopically lighter. The single Lōʻihi sample has a δ⁶⁰/⁵⁸Ni of +0.17 ‰. The lightest analysed bulk rock δ⁶⁰/⁵⁸Ni in this work, -0.16 ‰, is from the Azores island, Pico. Enriched mid ocean ridge basalts (E-MORB), which have (La/Sm)_N>1, are isotopically lighter than normal type MORB (N-MORB), as shown by data from the Mid Atlantic Ridge (n=9) and East Pacific Rise (n=3). All E-MORB average δ60/58Ni = +0.00±0.06 ‰ (2s, n=7), whereas N-MORB average δ60/58Ni = +0.14±0.10 ‰ (2s, n=5). A suite of 15 mafic samples from the Cameroon Line, comprising lithologies ranging from nephelinites to hypersthene-normative basalts, have Ni isotope compositions that are identical within analytical uncertainty (average δ⁶⁰/⁵⁸Ni = +0.08±0.06 ‰, 2s). Similarly, MORB samples display no relationship between δ⁶⁰/⁵⁸Ni and geochemical indicators of degree of partial melting or fractional crystallisation. Host lavas for two previously analysed ultramafic xenolith suites have δ⁶⁰/⁵⁸Ni identical to the average δ⁶⁰/⁵⁸Ni of their respective xenolith suites. This is consistent with previously published evidence from peridotites and komatiites that Ni isotopes are not greatly fractionated by melting. Therefore, mafic rocks may preserve the δ⁶⁰/⁵⁸Ni of their mantle source. Sampling a greater volume of mantle, their average Ni isotope composition +0.07±0.17 ‰ (2s, n=44) may also be a better representation of the Bulk Silicate Earth (BSE), than estimates based purely on peridotites. The δ⁶⁰/⁵⁸Ni of MORB co-varies with La/Sm, Rb/Sr, europium anomaly (Eu/Eu*), and K₂O/(K₂O+Na₂O). The relationships between these parameters and δ⁶⁰/⁵⁸Ni are consistent with mixing between two model endmembers. One could be depleted MORB or depleted MORB mantle (DMM) with a relatively heavy Ni isotope composition; the other a more enriched endmember that has isotopically lighter δ⁶⁰/⁵⁸Ni. The link between lighter δ⁶⁰/⁵⁸Ni and enriched lithologies in the mantle is further supported by published evidence of light Ni isotope compositions associated with some pyroxenite xenoliths. However, the curvature of the apparent mixing arrays defined by basalts is hard to reconcile with admixing of geochemically enriched but isotopically fractionated oceanic crustal lithologies. High [Ni] enriched magmas such as kimberlites may be a closer match to the enriched endmember. However, this needs further study

Heterogeneous nickel isotopic compositions in the terrestrial mantle – Part 1: Ultramafic lithologies

High precision nickel stable isotopic compositions (δ⁶⁰/⁵⁸Ni) are reported for 22 peridotite xenoliths from the USA (Kilbourne Hole, New Mexico), Tanzania, and Cameroon. For a subset of these, δ⁶⁰/⁵⁸Ni is also reported for their constituent mineral separates (olivine, orthopyroxene, clinopyroxene, and spinel). Bulk peridotites show significant heterogeneity in Ni isotopic composition, ranging from +0.02‰ to +0.26‰. Unmetasomatised fertile peridotites from three localities, define an average δ⁶⁰/⁵⁸Ni of +0.19±0.09‰ (n = 18). This value is comparable to previous estimates for the δ⁶⁰/⁵⁸Ni of the bulk silicate earth (BSE), but is unlikely to be representative, given observed heterogeneity, presented here and elsewhere. Samples with reaction rims and interstitial glass (interpreted as petrographic indications of minor metasomatism) were excluded from this average; their Ni isotopic compositions extend to lighter values, spanning nearly the entire range observed in peridotite worldwide. Dunites (n = 2) are lighter in δ⁶⁰/⁵⁸Ni than lherzolites and harzburgites from the same location, and pyroxenites (n = 5) range from +0.16‰ to as light as −0.38‰. The δ⁶⁰/⁵⁸Ni in the Kilbourne Hole xenoliths correlate negatively with bulk-rock Fe concentration and positively with ¹⁴³Nd/¹⁴⁴Nd, providing evidence that light δ⁶⁰/⁵⁸Ni is associated with mantle fertility and enrichment. The trend between δ⁶⁰/⁵⁸Ni and Fe concentration in bulk rocks appears to be global, replicated across the peridotites in this work from other localities, and in literature data. The inter-mineral fractionations are small; the maximum difference between heaviest and lightest phase is 0.12‰. This provides evidence that bulk rock δ⁶⁰/⁵⁸Nii variation does not result from differences in modal mineralogy, fractional crystallization or degrees of partial melting. The δ⁶⁰/⁵⁸Ni fractionation appears to be an equilibrium effect and usually is in the decreasing order spinel > olivine = orthopyroxene > clinopyroxene. However, the fractionation between clinopyroxene and orthopyroxene varies in magnitude and sign, and is correlated with pyroxene Si/Fe positively, and Fe/Mg negatively. The magnitude of inter-pyroxene fractionation also correlates with other pyroxene compositional ratios (e.g. La/Sm_clinopyroxene); as well as bulk rock δ⁶⁰/⁵⁸Ni, and [U]. These data provide evidence that Ni isotopes fractionate at the bulk rock and mineral scale in response to mantle enrichment processes, possibly related to recycling of isotopically light subducted components

Fetal alcohol spectrum disorder: development of concensus referral criteria for specialist diagnostic assessment in Australia

Background: Fetal alcohol spectrum disorder (FASD) is known to be under-recognised in Australia. The use of standard methods to identify when to refer individuals who may have FASD for specialist assessment could help improve the identification of this disorder. The purpose of this study was to develop referral criteria for use in Australia. Method: An online survey about FASD screening and diagnosis in Australia, which included 23 statements describing criteria for referral for fetal alcohol syndrome (FAS) and FASD based on published recommendations for referral in North America, was sent to 139 health professionals who had expertise or involvement in FASD screening or diagnosis. Survey findings and published criteria for referral were subsequently reviewed by a panel of 14 investigators at a consensus development workshop where criteria for referral were developed.Results: Among the 139 health professionals who were sent the survey, 103 (74%) responded, and 90 (65%) responded to the statements on criteria for referral. Over 80% of respondents agreed that referral for specialist evaluation should occur when there is evidence of significant prenatal alcohol exposure, defined as 7 or more standard drinks per week and at least 3 standard drinks on any one day, and more than 70% agreed with 13 of the16 statements that described criteria for referral other than prenatal alcohol exposure. Workshop participants recommended five independent criteria for referral: confirmed significant prenatal alcohol exposure; microcephaly and confirmed prenatal alcohol exposure; 2 or more significant central nervous system (CNS) abnormalities and confirmed prenatal alcohol exposure; 3 characteristic FAS facial anomalies; and 1 characteristic FAS facial anomaly, growth deficit and 1 or more CNS abnormalities .Conclusion: Referral criteria recommended for use in Australia are similar to those recommended in North America. There is a need to develop resources to raise awareness of these criteria among health professionals and evaluate their feasibility, acceptability and capacity to improve the identification of FASD in Australia

Development and evaluation of low-volume tests to detect and characterize antibodies to SARS-CoV-2

Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilized pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID-19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in-house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterized samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries

Ocean Acidification at High Latitudes: Potential Effects on Functioning of the Antarctic Bivalve Laternula elliptica

Ocean acidification is a well recognised threat to marine ecosystems. High latitude regions are predicted to be particularly affected due to cold waters and naturally low carbonate saturation levels. This is of concern for organisms utilising calcium carbonate (CaCO3) to generate shells or skeletons. Studies of potential effects of future levels of pCO2 on high latitude calcifiers are at present limited, and there is little understanding of their potential to acclimate to these changes. We describe a laboratory experiment to compare physiological and metabolic responses of a key benthic bivalve, Laternula elliptica, at pCO2 levels of their natural environment (430 µatm, pH 7.99; based on field measurements) with those predicted for 2100 (735 µatm, pH 7.78) and glacial levels (187 µatm, pH 8.32). Adult L. elliptica basal metabolism (oxygen consumption rates) and heat shock protein HSP70 gene expression levels increased in response both to lowering and elevation of pH. Expression of chitin synthase (CHS), a key enzyme involved in synthesis of bivalve shells, was significantly up-regulated in individuals at pH 7.78, indicating L. elliptica were working harder to calcify in seawater undersaturated in aragonite (ΩAr = 0.71), the CaCO3 polymorph of which their shells are comprised. The different response variables were influenced by pH in differing ways, highlighting the importance of assessing a variety of factors to determine the likely impact of pH change. In combination, the results indicate a negative effect of ocean acidification on whole-organism functioning of L. elliptica over relatively short terms (weeks-months) that may be energetically difficult to maintain over longer time periods. Importantly, however, the observed changes in L. elliptica CHS gene expression provides evidence for biological control over the shell formation process, which may enable some degree of adaptation or acclimation to future ocean acidification scenarios

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe