Calcium and neodymium radiogenic isotopes of igneous rocks: Tracing crustal contributions in felsic magmas related to super-eruptions and continental rifting

Radioactive decay of 40K within the continental crust produces a unique Ca isotopic reservoir, with measurable radiogenic 40Ca excesses compared to Earth's mantle (εCa = 0). Thus, igneous rocks with values of εCa > 1 unambiguously indicate a significant old, crustal contribution to their source magma. At our current level of analytical precision, values of εCa < 0.5 are indistinguishable from mantle-like Ca isotope compositions. So, whereas 40Ca excesses clearly define crustal contributions, the source contributions of igneous rocks with mantle-like Ca isotopic composition are less certain. The calcium in these rocks could be derived from partial melting of: young crust, crust with mantle-like K/Ca compositions, or the mantle itself. Here we present Ca isotopic measurements of intermediate to felsic igneous rocks from the western United States, and two crustal xenoliths found within the Fish Canyon Tuff (FCT) of the southern Rocky Mountain volcanic field (SRMVF), USA. Their isotope geochemistry is used to explore their source compositions and to help distinguish new mantle-derived additions to the crust from reworked older crust. Irrespective of age or tectonic setting a majority of the intermediate to silicic igneous rocks studied exhibit mantle-like Ca isotope compositions. Mantle-like Ca isotopic data for leucogranites associated with the beginning of Rio Grande rifting in Colorado indicate that felsic melts were generated from newly formed lower crust related to earlier calc-alkaline magmatism. These data also indicate that the Nd isotopic signature in early rift magmas is controlled by the lithospheric mantle, even if the major mantle source reservoir is the asthenospheric mantle. The two crustal xenoliths found within the 28.2 Ma FCT yield εCa values of 3.6 and 7.0, respectively. The 40Ca excesses of these Precambrian source rocks are supported by K–Ca geochronology. However, like several other ignimbrites from the SRMVF and from Yellowstone, USA, the FCT (εCa ∼ 0.3) has a Ca isotope composition that is indistinguishable from the mantle. Nd isotopic analyses of the FCT imply that it was generated from 10–75% of an enriched component, and so the Ca isotopic data appear to restrict that component to newly formed lower crust, low K/Ca crust, or enriched mantle. Contrary to these findings, several large ignimbrites and one granitoid from the SRMVF show significant 40Ca excesses. These tuffs (Wall Mountain, Blue Mesa, and Grizzly Peak) and one granitoid (Mt. Princeton) are sourced from near, or within the Colorado Mineral Belt. Collectively, these data indicate that felsic, Precambrian crust likely contributed less than 50% of the material to the petrogenesis of many of the large ignimbrites that have erupted across the western United States. However, the crustal components that contributed to magmas in the Colorado Mineral Belt have 40Ca excesses; consistent with felsic, Precambrian crust

Water in alkali feldspar: The effect of rhyolite generation on the lunar hydrogen budget

Recent detection of indigenous hydrogen in a diversity of lunar materials, including volcanic glass (Saal et al., 2008), melt inclusions (Hauri et al., 2011), apatite (Boyce et al., 2010; McCubbin et al., 2010), and plagioclase (Hui et al., 2013) suggests water played a role in the chemical differentiation of the Moon. Water contents measured in plagioclase feldspar, a dominant mineral in the ancient crustal lunar highlands have been used to predict that 320 ppm water initially existed in the lunar magma ocean (Hui et al., 2013) whereas measurements in apatite, found as a minor mineral in lunar rocks, representing younger potassium-enriched melt predict a bulk Moon with <100 ppm water. Here we show that water in alkali feldspar, a common mineral in potassium-enriched rocks, can have ∼20 ppm water, which implies magmatic water contents of ∼1 wt. % in chemically evolved rhyolitic magmas. The source for these wet, potassium-rich magmas probably contained ∼1000 ppm H2O. Thus, lunar granites with ages from 4.3-3.9 Ga (Meyer et al., 1996) likely crystallised from relatively wet melts that degassed upon crystallisation. Geochemical surveys by the Lunar Prospector (Jolliff et al., 2011) and Diviner Lunar Radiometer Experiment (Glotch et al., 2010; Jolliff et al., 2011) indicating the global significance of evolved igneous rocks suggest that the formation of these granites removed water from some mantle source regions, helping to explain the existence of mare basalts with <10 ppm water, but must have left regions of the interior relatively wet as seen by the water content in volcanic glass and melt inclusions. Although these early-formed evolved melts were water-rich, their petrogenesis supports the conclusion that the Moon's mantle had <100 ppm water for most of its history

Volatiles in lunar felsite clasts: Impact-related delivery of hydrous material to an ancient dry lunar crust

In this detailed geochemical, petrological, and microstructural study of felsite clast materials contained in Apollo breccia samples 12013, 14321, and 15405, little evidence was found for relatively enriched reservoirs of endogenic lunar volatiles. NanoSIMS measurements have revealed very low volatile abundances (≤2–18 ppm hydrogen) in nominally anhydrous minerals (NAMS) plagioclase, potassic alkali feldspar, and SiO2 that make up a majority of these felsic lithologies. Yet these mineral assemblages and clast geochemistries on Earth would normally yield relatively high volatiles contents in their NAMS (∼20 to ≥80 ppm hydrogen). This difference is particularly notable in felsite 14321,1062 that exhibits extremely low volatile abundances (≤2 ppm hydrogen) and a relatively low amount of microstructural evidence for shock metamorphism given that it is a clast of the most evolved (∼74 wt.% SiO2) rock-type returned from the Moon. If taken at face value, ‘wet’ felsic magmas (∼1.2–1.7 wt.% water) are implied by the relatively high hydrogen contents of feldspar in felsite clasts in Apollo samples 12013 and 15405, but these results are likely misleading. These felsic clasts have microstructural features indicative of significantly higher shock stress than 14321,1062. These crustal lithologies likely obtained no more water from the lunar interior than the magma body producing 14321,1062. Rather, we suggest hydrogen was enriched in samples 12013 and 15405 by impact induced exchange, and/or partial assimilation of volatiles added to the surface of the Moon by a hydrated impactor (asteroid or comet) or the solar wind. Thus, the best estimate for magmatic water contents of felsic lunar magmas comes from 14321,1062 that leads to a calculated magmatic water content of ≤0.2 wt.%. This dry felsic magma has a slightly greater, but comparable water content to the ancient mafic magmas implied by the other lithologies that we have studied. Based on this and expanding evidence for a significantly dry ancient or early degassed Moon it is likely that some recent estimates (100's ppm) of the water abundances in the lunar parental magma ocean have been overestimated

Discovery of a first-in-class potent small molecule antagonist against the adrenomedullin-2 receptor

The hormone adrenomedullin has both physiological and pathological roles in biology. As a potent vasodilator, adrenomedullin is critically important in regulation of blood pressure, but it also has several roles in disease, of which its actions in cancer are becoming recognized to have clinical importance. Reduced circulating adrenomedullin causes increased blood pressure but also reduces tumour progression, so drugs blocking all effects of adrenomedullin would be unacceptable clinically. However, there are two distinct receptors for adrenomedullin, each comprising the same orphan G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR), together with a different accessory protein known as a receptor activity-modifying protein (RAMP). CLR with RAMP2 forms an adrenomedullin-1 receptor and CLR with RAMP3 forms an adrenomedullin-2receptor. Recent research suggests that selective blockade of adrenomedullin-2 receptors would be valuable therapeutically. Here we describe the design, synthesis and characterization of potent small molecule adrenomedullin-2 receptor antagonists with 1,000-foldselectivity over the adrenomedullin-1 receptor. These molecules have clear effects on markers of pancreatic cancer progression in vitro, drug-like pharmacokinetic properties and inhibit xenograft tumour growth and extend life in a mouse model of pancreatic cancer. Taken together, our data support the promise of a new class of anti-cancer therapeutics as well as improved understanding of the pharmacology of the adrenomedullin receptors and other GPCR/RAMP heteromers

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

The Majorana Neutrinoless Double-Beta Decay Experiment

The proposed Majorana double-beta decay experiment is based on an array of segmented intrinsic Ge detectors with a total mass of 500 kg of Ge isotopically enriched to 86% in 76Ge. A discussion is given of background reduction by: material selection, detector segmentation, pulse shape analysis, and electro-formation of copper parts and granularity. Predictions of the experimental sensitivity are given. For an experimental running time of 10 years over the construction and operation of Majorana, a half-life sensitivity of ~4x10^27 y (neutrinoless) is predicted. This corresponds to an effective Majorana mass of the electron neutrino of ~0.03-0.04 eV, according to recent QRPA and RQRPA matrix element calculations.Comment: 10 pages, 7 figure

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Design and construction of the MicroBooNE detector

This paper describes the design and construction of the MicroBooNE liquid argon time projection chamber and associated systems. MicroBooNE is the first phase of the Short Baseline Neutrino program, located at Fermilab, and will utilize the capabilities of liquid argon detectors to examine a rich assortment of physics topics. In this document details of design specifications, assembly procedures, and acceptance tests are reported

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Mapping geographical inequalities in childhood diarrhoeal morbidity and mortality in low-income and middle-income countries, 2000–17 : analysis for the Global Burden of Disease Study 2017

Background Across low-income and middle-income countries (LMICs), one in ten deaths in children younger than 5 years is attributable to diarrhoea. The substantial between-country variation in both diarrhoea incidence and mortality is attributable to interventions that protect children, prevent infection, and treat disease. Identifying subnational regions with the highest burden and mapping associated risk factors can aid in reducing preventable childhood diarrhoea. Methods We used Bayesian model-based geostatistics and a geolocated dataset comprising 15 072 746 children younger than 5 years from 466 surveys in 94 LMICs, in combination with findings of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, to estimate posterior distributions of diarrhoea prevalence, incidence, and mortality from 2000 to 2017. From these data, we estimated the burden of diarrhoea at varying subnational levels (termed units) by spatially aggregating draws, and we investigated the drivers of subnational patterns by creating aggregated risk factor estimates. Findings The greatest declines in diarrhoeal mortality were seen in south and southeast Asia and South America, where 54·0% (95% uncertainty interval [UI] 38·1–65·8), 17·4% (7·7–28·4), and 59·5% (34·2–86·9) of units, respectively, recorded decreases in deaths from diarrhoea greater than 10%. Although children in much of Africa remain at high risk of death due to diarrhoea, regions with the most deaths were outside Africa, with the highest mortality units located in Pakistan. Indonesia showed the greatest within-country geographical inequality; some regions had mortality rates nearly four times the average country rate. Reductions in mortality were correlated to improvements in water, sanitation, and hygiene (WASH) or reductions in child growth failure (CGF). Similarly, most high-risk areas had poor WASH, high CGF, or low oral rehydration therapy coverage. Interpretation By co-analysing geospatial trends in diarrhoeal burden and its key risk factors, we could assess candidate drivers of subnational death reduction. Further, by doing a counterfactual analysis of the remaining disease burden using key risk factors, we identified potential intervention strategies for vulnerable populations. In view of the demands for limited resources in LMICs, accurately quantifying the burden of diarrhoea and its drivers is important for precision public health