RESEAL II: a large-scale in situ demonstration for repository sealing in an argillaceous host rock: phase II

Final ReportPreprin

Hurricanes and climate in the Caribbean during the past 3700 years BP

International audienceA multiproxy analysis of lacustrine sediments cored in Grand-Case Pond at Saint-Martin, north of the Lesser Antilles archipelago, reveals three distinct climatic periods for the last 3700 years. From 3700 to ~2500 yr cal. BP and from 1150 yr cal. BP to the present, carbonate mud deposition occurred in connection with pond lowstands. These periods were also punctuated by severe drought events, marked by gypsum laminae, and hurricane landfalls, leading to marine sand inputs into the pond. The intermediate time interval, from 2500 to 1150 yr cal. BP, is typified by black organic mud deposition, suggesting that hypoxic to anoxic conditions prevailed at the pond bottom. These were probably linked with a perennial pond highstand and reflect more uniform and wetter climatic conditions than today. The carbon isotopic composition of the ostracod Perissocytheridea bisulcata shows that the lowest δ13C values are recorded during the hypoxic periods, as a consequence of bacterial recycling of isotopically depleted organic matter. Such a climatic history agrees closely with that documented from other records in the Caribbean area, such as the Cariaco Basin, central coast of Belize or Barbados. By constrast, discrepancies seem to emerge from the comparison between hurricane activity recorded at Saint-Martin on the one hand and Vieques (Puerto Rico) on the other hand. We explain this apparent contradiction by a balance between two distinct storm paths in response to latitudinal shifts of the Intertropical Convergence Zone (ITCZ). Stronger storm activity over the Gulf coast and the inner Caribbean Sea is favoured by a southern position of the ITCZ in connection with dry climatic conditions. Plausible links with the North Atlantic Oscillation (NAO) are also suggested

Accurate masses and radii of normal stars: modern results and applications

This paper presents and discusses a critical compilation of accurate, fundamental determinations of stellar masses and radii. We have identified 95 detached binary systems containing 190 stars (94 eclipsing systems, and alpha Centauri) that satisfy our criterion that the mass and radius of both stars be known to 3% or better. To these we add interstellar reddening, effective temperature, metal abundance, rotational velocity and apsidal motion determinations when available, and we compute a number of other physical parameters, notably luminosity and distance. We discuss the use of this information for testing models of stellar evolution. The amount and quality of the data also allow us to analyse the tidal evolution of the systems in considerable depth, testing prescriptions of rotational synchronisation and orbital circularisation in greater detail than possible before. The new data also enable us to derive empirical calibrations of M and R for single (post-) main-sequence stars above 0.6 M(Sun). Simple, polynomial functions of T(eff), log g and [Fe/H] yield M and R with errors of 6% and 3%, respectively. Excellent agreement is found with independent determinations for host stars of transiting extrasolar planets, and good agreement with determinations of M and R from stellar models as constrained by trigonometric parallaxes and spectroscopic values of T(eff) and [Fe/H]. Finally, we list a set of 23 interferometric binaries with masses known to better than 3%, but without fundamental radius determinations (except alpha Aur). We discuss the prospects for improving these and other stellar parameters in the near future.Comment: 56 pages including figures and tables. To appear in The Astronomy and Astrophysics Review. Ascii versions of the tables will appear in the online version of the articl

Technical design and performance of the NEMO3 detector

The development of the NEMO3 detector, which is now running in the Frejus Underground Laboratory (L.S.M. Laboratoire Souterrain de Modane), was begun more than ten years ago. The NEMO3 detector uses a tracking-calorimeter technique in order to investigate double beta decay processes for several isotopes. The technical description of the detector is followed by the presentation of its performance.Comment: Preprint submitted to Nucl. Instrum. Methods A Corresponding author: Corinne Augier ([email protected]

Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade

Schistosomiasis is a tropical disease associated with high morbidity and mortality, currently affecting over 200 million people worldwide. Praziquantel is the only drug used to treat the disease, and with its increased use the probability of developing drug resistance has grown significantly. The Schistosoma parasites can survive for up to decades in the human host due in part to a unique set of antioxidant enzymes that continuously degrade the reactive oxygen species produced by the host's innate immune response. Two principal components of this defense system have been recently identified in S. mansoni as thioredoxin/glutathione reductase (TGR) and peroxiredoxin (Prx) and as such these enzymes present attractive new targets for anti-schistosomiasis drug development. Inhibition of TGR/Prx activity was screened in a dual-enzyme format with reducing equivalents being transferred from NADPH to glutathione via a TGR-catalyzed reaction and then to hydrogen peroxide via a Prx-catalyzed step. A fully automated quantitative high-throughput (qHTS) experiment was performed against a collection of 71,028 compounds tested as 7- to 15-point concentration series at 5 µL reaction volume in 1536-well plate format. In order to generate a robust data set and to minimize the effect of compound autofluorescence, apparent reaction rates derived from a kinetic read were utilized instead of end-point measurements. Actives identified from the screen, along with previously untested analogues, were subjected to confirmatory experiments using the screening assay and subsequently against the individual targets in secondary assays. Several novel active series were identified which inhibited TGR at a range of potencies, with IC50s ranging from micromolar to the assay response limit (∼25 nM). This is, to our knowledge, the first report of a large-scale HTS to identify lead compounds for a helminthic disease, and provides a paradigm that can be used to jump-start development of novel therapeutics for other neglected tropical diseases

Mechanics of the IL2RA Gene Activation Revealed by Modeling and Atomic Force Microscopy

Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static

Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies

Postlactational involution is the process following weaning during which the mammary gland undergoes massive cell death and tissue remodeling as it returns to the pre-pregnant state. Lobular involution is the process by which the breast epithelial tissue is gradually lost with aging of the mammary gland. While postlactational involution and lobular involution are distinct processes, recent studies have indicated that both are related to breast cancer development. Experiments using a variety of rodent models, as well as observations in human populations, suggest that deregulation of postlactational involution may act to facilitate tumor formation. By contrast, new human studies show that completion of lobular involution protects against subsequent breast cancer incidence

A CUPID Li2100MoO4scintillating bolometer tested in the CROSS underground facility

A scintillating bolometer based on a large cubic Li2100MoO4 crystal (45 mm side) and a Ge wafer (scintillation detector) has been operated in the CROSS cryogenic facility at the Canfranc underground laboratory in Spain. The dual-readout detector is a prototype of the technology that will be used in the next-generation 0¿2ß experiment CUPID . The measurements were performed at 18 and 12 mK temperature in a pulse tube dilution refrigerator. This setup utilizes the same technology as the CUORE cryostat that will host CUPID and so represents an accurate estimation of the expected performance. The Li2100MoO4 bolometer shows a high energy resolution of 6 keV FWHM at the 2615 keV ¿ line. The detection of scintillation light for each event triggered by the Li2100MoO4 bolometer allowed for a full separation (~8s) between ¿(ß) and a events above 2 MeV . The Li2100MoO4 crystal also shows a high internal radiopurity with 228Th and 226Ra activities of less than 3 and 8 µBq/kg, respectively. Taking also into account the advantage of a more compact and massive detector array, which can be made of cubic-shaped crystals (compared to the cylindrical ones), this test demonstrates the great potential of cubic Li2100MoO4 scintillating bolometers for high-sensitivity searches for the 100Mo 0¿2ß decay in CROSS and CUPID projects

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference