Low volumes of quartz cement in deeply buried Fulmar Formation sandstones explained by a low effective stress burial history

Upper Jurassic Fulmar Formation sandstones from the Fulmar Field in the Central North Sea are buried to 3.2 km and 128 °C but contain only 3.7 ± 1.7% (1σ) quartz cement, substantially less than volumes predicted by models based on temperature-related quartz precipitation kinetics. Oxygen isotope microanalysis of quartz overgrowths suggests that only limited cementation occurred at temperatures above 110 °C. We suggest that the anomalously low volumes of quartz cement are most readily explained by the effective stress history of the Fulmar Formation. Regional pore pressure analysis strongly suggests that pore fluid pressures in the Fulmar Formation decreased substantially in the last <0.5 Ma as a result of lateral seal failure, increasing effective stress from ca. 10 MPa to the current 31 MPa. A recent increase in effective stress is supported by the common occurrence of grains that are both fractured and unhealed by quartz cement. Intergranular pressure dissolution can account for around one third of the observed quartz cement, with the remainder from deep burial feldspar dissolution. We argue that the continuous history of low effective stress, until the very recent geological past, limited the rate of silica supply by intergranular pressure dissolution, and thus the rate of quartz cementation. Effective stress histories should be incorporated into predictive models of quartz cementation of sandstones

Seasonal SIMS δ18O record in Astarte borealis from the Baltic Sea tracks a modern regime shift in the NAO

IntroductionAstarte borealis holds great potential as an archive of seasonal paleoclimate, especially due to its long lifespan (several decades to more than a century) and ubiquitous distribution across high northern latitudes. Furthermore, recent work demonstrates that the isotope geochemistry of the aragonite shell is a faithful proxy of environmental conditions. However, the exceedingly slow growth rates of A. borealis in some locations (&lt;0.2mm/year) make it difficult to achieve seasonal resolution using standard micromilling techniques for conventional stable isotope analysis. Moreover, oxygen isotope (δ18O) records from species inhabiting brackish environments are notoriously difficult to use as paleoclimate archives because of the simultaneous variation in temperature and δ18Owater values.MethodsHere we use secondary ion mass spectrometry (SIMS) to microsample an A. borealis specimen from the southern Baltic Sea, yielding 451 SIMS δ18Oshell values at sub-monthly resolution.ResultsSIMS δ18Oshell values exhibit a quasi-sinusoidal pattern with 24 local maxima and minima coinciding with 24 annual growth increments between March 1977 and the month before specimen collection in May 2001.DiscussionAge-modeled SIMS δ18Oshell values correlate significantly with both in situ temperature measured from shipborne CTD casts (r2 = 0.52, p&lt;0.001) and sea surface temperature from the ORAS5-SST global reanalysis product for the Baltic Sea region (r2 = 0.42, p&lt;0.001). We observe the strongest correlation between SIMS δ18Oshell values and salinity when both datasets are run through a 36-month LOWESS function (r2 = 0.71, p &lt; 0.001). Similarly, we find that LOWESS-smoothed SIMS δ18Oshell values exhibit a moderate correlation with the LOWESS-smoothed North Atlantic Oscillation (NAO) Index (r2 = 0.46, p&lt;0.001). Change point analysis supports that SIMS δ18Oshell values capture a well-documented regime shift in the NAO circa 1989. We hypothesize that the correlation between the SIMS δ18Oshell time series and the NAO is enhanced by the latter’s influence on the regional covariance of water temperature and δ18Owater values on interannual and longer timescales in the Baltic Sea. These results showcase the potential for SIMS δ18Oshell values in A. borealis shells to provide robust paleoclimate information regarding hydroclimate variability from seasonal to decadal timescales

Vertical effective stress as a control on quartz cementation in sandstones

Temperature-controlled precipitation kinetics has become the overwhelmingly dominant hypothesis for the control of quartz cementation in sandstones. Here, we integrate quantitative petrographic data, high spatial resolution oxygen isotope analyses of quartz cement, basin modelling and a kinetic model for quartz precipitation to suggest that the supply of silica from stress-sensitive intergranular pressure dissolution at grain contacts is in fact a key control on quartz cementation in sandstones. We present data from highly overpressured sandstones in which, despite the current burial temperature of 190 °C, quartz cement occurs in low amounts (4.6 ± 1.2% of bulk volume). In situ oxygen isotope data across quartz overgrowths suggest that cementation occurred over 100 Ma and a temperature range of 80–150 °C, during which time high fluid overpressures resulted in consistently low vertical effective stress. We argue that the very low amounts of quartz cement can only be explained by the low vertical effective stress which occurred throughout the burial history and which restricted silica supply as a result of a low rate of intergranular pressure dissolution at grain contacts

Hopping between Random Locations: Spectrum and Instanton

Euclidean random matrices appear in a broad class of physical problems involving disorder. The problem of determining their spectra can be mapped, using the replica method, into the study of a scalar field theory with an interaction of the type e^(psi^2). We apply the instanton method to study their spectral tails.Comment: 9 pages, Revtex, 2 postscript figure

High‐resolution Mg/Ca and δ 18 O patterns in modern Neogloboquadrina pachyderma from the Fram Strait and Irminger Sea

Neogloboquadrina pachyderma is the dominant species of planktonic foraminifera found in polar waters and is therefore invaluable for paleoceanographic studies of the high latitudes. However, the geochemistry of this species is complicated due to the development of a thick calcite crust in its final growth stage and at greater depths within the water column. We analyzed the in situ Mg/Ca and δ18O in discrete calcite zones using LA‐ICP‐MS, EPMA and SIMS within modern N. pachyderma shells from the highly dynamic Fram Strait and the seasonally isothermal/isohaline Irminger Sea. Here we compare shell geochemistry to the measured temperature, salinity and δ18Osw in which the shells calcified to better understand the controls on N. pachyderma geochemical heterogeneity. We present a relationship between Mg/Ca and temperature in N. pachyderma lamellar calcite that is significantly different than published equations for shells that contained both crust and lamellar calcite. We also document highly variable SIMS δ18O results (up to a 3.3‰ range in single shells) on plankton tow samples which we hypothesize is due to the granular texture of shell walls. Finally, we document that the δ18O of the crust and lamellar calcite of N. pachyderma from an isothermal/isohaline environment are indistinguishable from each other, indicating that shifts in N. pachyderma δ18O are primarily controlled by changes in environmental temperature and/or salinity rather than differences in the sensitivities of the two calcite types to environmental conditions

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Application of a Key Events Dose-Response Analysis to Nutrients: A Case Study with Vitamin A (Retinol)

The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast 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