Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes

High magnetic anisotropy of Fe+ ions in KTaO3 and SrCl2

The zero-field splitting constant, D, and the gyromagnetic tensor of the off-center system KTaO3:Fe+ and SrCl2:Fe+ have been explored by means of calculations based on the density-functional theory at the C4v local equilibrium geometry. The calculated D values for KTaO3:Fe+ (9?cm?1) and SrCl2:Fe+ (53 cm?1) are found to be much higher than typical figures measured for insulating compounds containing common 3d Kramers ions with a spin S>1/2 in the ground state. This result together with the calculated g? and g? values concur with available experimental information. The high magnetic anisotropy derived for Fe+ in KTaO3 and SrCl2 is shown to be strongly related to the existence of a 4E excited state lying only at about 3000 and 600?cm?1, respectively, above the ground state. Implications of present findings in the search of new molecular magnets with high values of the magnetic anisotropy are discussed in some detail.The support by the Spanish Ministerio de Ciencia y Tecnología under Projects No. FIS2006-02261 and No. FIS2009-07083 is acknowledged.The support by the Spanish Ministerio de Ciencia y Tecnología under Projects No. FIS2006-02261 and No. FIS2009-07083 is acknowledged

Reshaping Silica Particles: Mesoporous Nanodiscs for Bimodal Delivery and Improved Cellular Uptake

The role played by the shape of mesoporous silica nanoparticles has been investigated for intra- and extracellular delivery. Specifically, we have developed the bottom-up synthesis of flat disc-shaped mesoporous silica nanoparticles, the Nanodiscs (NDs). Due to their peculiar shape and large porous system, NDs present a higher cellular uptake than commonly investigated spherical mesoporous nanoparticles. Moreover, NDs are able to efficiently perform exhaustive delivery of their therapeutic cargo when loaded with the anticancer drug Doxorubicin and administered in vitro to cancerous HeLa cells. Thanks to their aspect ratio, NDs can also be readily assembled into well-organized monolayers to be employed in HeLa cells adhesion experiments upon preliminary functionalization with a specific targeting ligand. In these conditions NDs are able to deliver a hydrophobic dye to adhered cells via the highly accessible vertically aligned pores and their flat surface that ensures optimal cell contact. This initial investigation on the performance of NDs in both intra- and extracellular delivery activities suggests the great potential of these particles.This work was financially supported by the European Research Council (ERC) Advanced Grant “MAGIC” (grant N° 247365), the Marie Skłodowska-Curie fellowship (MSCA-IEF) “POP-SILICA” (grant N° 627788) and the SACS Project (grant N° 310651), the Foundation ARC through the project “Thera-HCC” (grant N° IHU201301187), the Région Alsace, and the Département du Bas-Rhin. LDC especially acknowledges AXA Research funds. PHS and SVA acknowledge the Max Planck Society for generous funding

SAVASA project @ TRECVid 2013: semantic indexing and interactive surveillance event detection

In this paper we describe our participation in the semantic indexing (SIN) and interactive surveillance event detection (SED) tasks at TRECVid 2013 [11]. Our work was motivated by the goals of the EU SAVASA project (Standards-based Approach to Video Archive Search and Analysis) which supports search over multiple video archives. Our aims were: to assess a standard object detection methodology (SIN); evaluate contrasting runs in automatic event detection (SED) and deploy a distributed, cloud-based search interface for the interactive component of the SED task. Results from the SIN task, underlying retrospective classifiers for the surveillance event detection and a discussion of the contrasting aims of the SAVASA user interface compared with the TRECVid task requirements are presented

Lattice models and Landau theory for type II incommensurate crystals

Ground state properties and phonon dispersion curves of a classical linear chain model describing a crystal with an incommensurate phase are studied. This model is the DIFFOUR (discrete frustrated phi4) model with an extra fourth-order term added to it. The incommensurability in these models may arise if there is frustration between nearest-neighbor and next-nearest-neighbor interactions. We discuss the effect of the additional term on the phonon branches and phase diagram of the DIFFOUR model. We find some features not present in the DIFFOUR model such as the renormalization of the nearest-neighbor coupling. Furthermore the ratio between the slopes of the soft phonon mode in the ferroelectric and paraelectric phase can take on values different from -2. Temperature dependences of the parameters in the model are different above and below the paraelectric transition, in contrast with the assumptions made in Landau theory. In the continuum limit this model reduces to the Landau free energy expansion for type II incommensurate crystals and it can be seen as the lowest-order generalization of the simplest Lifshitz-point model. Part of the numerical calculations have been done by an adaption of the Effective Potential Method, orginally used for models with nearest-neighbor interaction, to models with also next-nearest-neighbor interactions.Comment: 33 pages, 7 figures, RevTex, submitted to Phys. Rev.

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants

Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

<p>Abstract</p> <p>Background</p> <p>The transcription factor NFAT5/TonEBP regulates the response of mammalian cells to hypertonicity. However, little is known about the physiopathologic tonicity thresholds that trigger its transcriptional activity in primary cells. Wilkins et al. recently developed a transgenic mouse carrying a luciferase reporter (9xNFAT-Luc) driven by a cluster of NFAT sites, that was activated by calcineurin-dependent NFATc proteins. Since the NFAT site of this reporter was very similar to an optimal NFAT5 site, we tested whether this reporter could detect the activation of NFAT5 in transgenic cells.</p> <p>Results</p> <p>The 9xNFAT-Luc reporter was activated by hypertonicity in an NFAT5-dependent manner in different types of non-transformed transgenic cells: lymphocytes, macrophages and fibroblasts. Activation of this reporter by the phorbol ester PMA plus ionomycin was independent of NFAT5 and mediated by NFATc proteins. Transcriptional activation of NFAT5 in T lymphocytes was detected at hypertonic conditions of 360–380 mOsm/kg (isotonic conditions being 300 mOsm/kg) and strongly induced at 400 mOsm/kg. Such levels have been recorded in plasma in patients with osmoregulatory disorders and in mice deficient in aquaporins and vasopressin receptor. The hypertonicity threshold required to activate NFAT5 was higher in bone marrow-derived macrophages (430 mOsm/kg) and embryonic fibroblasts (480 mOsm/kg). Activation of the 9xNFAT-Luc reporter by hypertonicity in lymphocytes was insensitive to the ERK inhibitor PD98059, partially inhibited by the PI3-kinase inhibitor wortmannin (0.5 μM) and the PKA inhibitor H89, and substantially downregulated by p38 inhibitors (SB203580 and SB202190) and by inhibition of PI3-kinase-related kinases with 25 μM LY294002. Sensitivity of the reporter to FK506 varied among cell types and was greater in primary T cells than in fibroblasts and macrophages.</p> <p>Conclusion</p> <p>Our results indicate that NFAT5 is a sensitive responder to pathologic increases in extracellular tonicity in T lymphocytes. Activation of NFAT5 by hypertonicity in lymphocytes was mediated by a combination of signaling pathways that differed from those required in other cell types. We propose that the 9xNFAT-Luc transgenic mouse model might be useful to study the physiopathological regulation of both NFAT5 and NFATc factors in primary cells.</p

Towards Harmonisation in Landscape Unit Delineation: An Analysis of Spanish Case Studies

[EN] The European Landscape Convention has encouraged member states to develop tools for landscape planning and management. Landscape character assessment is the most widespread approach. The aim of this paper is to identify the main trends in landscape unit delineation in Spain. For this purpose, 29 works are analysed by the Multiple Correspondence technique (MCA). Each work is characterised by a category of the variables: scale, type of extent, geomorphology, land matrix and visual boundaries. Results show that there is an implicit hierarchy in the way Spanish professionals are mapping landscape units. It is more apparent in variables related to geomorphology and less evident in variables related to land matrix. Regarding visual boundaries, they are not usually used at small scales and are more frequent at intermediate and large scales. The definition of clear criteria that allow comparable classifications and the increased consideration of cultural and perceptual factors is encouraged for future landscape character classifications.This work was supported by DGI and FEDER grant n8 AGL–2004-03263/AGR. We would like to thank Paz Aramburu, Rafael Escribano, Jordi Puig, the enterprise P&G and Florencio Zoido and Valencia Regional Department of Environment for the data provided for this research and also the R&D&I Linguistic Assistance Office at the Universidad Polite´cnica de Valencia for their help in revising and correcting this paper.Vallés-Planells, M.; Galiana, F.; Bru García, R. (2012). Towards Harmonisation in Landscape Unit Delineation: An Analysis of Spanish Case Studies. Landscape Research. 38(3):329-346. https://doi.org/10.1080/01426397.2011.647896S32934638

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data