169 research outputs found

    Age constraints on the dispersal of dinosaurs in the Late Triassic from magnetochronology of the Los Colorados Formation (Argentina)

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    A measured magnetozone sequence defined by 24 sampling sites with normal polarity and 28 sites with reverse polarity characteristic magnetizations was established for the heretofore poorly age-constrained Los Colorados Formation and its dinosaur-bearing vertebrate fauna in the Ischigualasto–Villa Union continental rift basin of Argentina. The polarity pattern in this ∼600-m-thick red-bed section can be correlated to Chrons E7r to E15n of the Newark astrochronological polarity time scale. This represents a time interval from 227 to 213 Ma, indicating that the Los Colorados Formation is predominantly Norian in age, ending more than 11 My before the onset of the Jurassic. The magnetochronology confirms that the underlying Ischigualasto Formation and its vertebrate assemblages including some of the earliest known dinosaurs are of Carnian age. The oldest dated occurrences of vertebrate assemblages with dinosaurs in North America (Chinle Formation) are younger (Norian), and thus the rise of dinosaurs was diachronous across the Americas. Paleogeography of the Ischigualasto and Los Colorados Formations indicates prolonged residence in the austral temperate humid belt where a provincial vertebrate fauna with early dinosaurs may have incubated. Faunal dispersal across the Pangean supercontinent in the development of more cosmopolitan vertebrate assemblages later in the Norian may have been in response to reduced contrasts between climate zones and lowered barriers resulting from decreasing atmospheric pCO2 levels

    The Hydrogen Epoch of Reionization Array Dish II: Characterization of Spectral Structure with Electromagnetic Simulations and its science Implications

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    We use time-domain electromagnetic simulations to determine the spectral characteristics of the Hydrogen Epoch of Reionization Arrays (HERA) antenna. These simulations are part of a multi-faceted campaign to determine the effectiveness of the dish's design for obtaining a detection of redshifted 21 cm emission from the epoch of reionization. Our simulations show the existence of reflections between HERA's suspended feed and its parabolic dish reflector that fall below -40 dB at 150 ns and, for reasonable impedance matches, have a negligible impact on HERA's ability to constrain EoR parameters. It follows that despite the reflections they introduce, dishes are effective for increasing the sensitivity of EoR experiments at relatively low cost. We find that electromagnetic resonances in the HERA feed's cylindrical skirt, which is intended to reduce cross coupling and beam ellipticity, introduces significant power at large delays (40-40 dB at 200 ns) which can lead to some loss of measurable Fourier modes and a modest reduction in sensitivity. Even in the presence of this structure, we find that the spectral response of the antenna is sufficiently smooth for delay filtering to contain foreground emission at line-of-sight wave numbers below k0.2k_\parallel \lesssim 0.2 hhMpc1^{-1}, in the region where the current PAPER experiment operates. Incorporating these results into a Fisher Matrix analysis, we find that the spectral structure observed in our simulations has only a small effect on the tight constraints HERA can achieve on parameters associated with the astrophysics of reionization.Comment: Accepted to ApJ, 18 pages, 17 Figures. Replacement matches accepted manuscrip

    The Hydrogen Epoch of Reionization Array Dish I: Beam Pattern Measurements and Science Implications

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    The Hydrogen Epoch of Reionization Array (HERA) is a radio interferometer aiming to detect the power spectrum of 21 cm fluctuations from neutral hydrogen from the Epoch of Reionization (EOR). Drawing on lessons from the Murchison Widefield Array (MWA) and the Precision Array for Probing the Epoch of Reionization (PAPER), HERA is a hexagonal array of large (14 m diameter) dishes with suspended dipole feeds. Not only does the dish determine overall sensitivity, it affects the observed frequency structure of foregrounds in the interferometer. This is the first of a series of four papers characterizing the frequency and angular response of the dish with simulations and measurements. We focus in this paper on the angular response (i.e., power pattern), which sets the relative weighting between sky regions of high and low delay, and thus, apparent source frequency structure. We measure the angular response at 137 MHz using the ORBCOMM beam mapping system of Neben et al. We measure a collecting area of 93 m^2 in the optimal dish/feed configuration, implying HERA-320 should detect the EOR power spectrum at z~9 with a signal-to-noise ratio of 12.7 using a foreground avoidance approach with a single season of observations, and 74.3 using a foreground subtraction approach. Lastly we study the impact of these beam measurements on the distribution of foregrounds in Fourier space.Comment: 13 pages, 9 figures. Replaced to match accepted ApJ versio

    Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

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    Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

    The long term vaccine-induced anti-SARS-CoV-2 immune response is impaired in quantity and quality under TNFα blockade

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    The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor-α (TNF-α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti-TNF-α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease-modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS-CoV-2-specific B- and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti-SARS-CoV-2 IgG levels, IgG avidity and anti-pre-VOC NA titres were significantly reduced in anti-TNF-α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti-TNF-α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS-CoV-2-specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti-BA.2 NA titres compared to both other groups. We show a reduced SARS-CoV-2 neutralizing capacity in patients under TNF-α blockade. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced

    Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

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    Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors

    Tumor Necrosis Factor Receptor Associated Factor 6 Is Not Required for Atherogenesis in Mice and Does Not Associate with Atherosclerosis in Humans

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    BACKGROUND: Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF alpha, and IL1beta. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease. METHODOLOGY/PRINCIPAL FINDINGS: Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6(+/+)/LDLR(-/-)) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6(+/-)/LDLR(-/-) mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034+/-0.0021, N = 178), acute coronary heart disease (0.029+/-0.0027, N = 70), and those without coronary heart disease (0.032+/-0.0016, N = 77) as assessed by angiography. CONCLUSION: Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis
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