Carbohydrate-Based Spiro-1,3-oxazolidine-2-thiones: Stereoselective Approaches Using Aziridines and Epoxides

International audienc

External validation of the MidiCAT variant of thrombography: Comparison with calibrated automated thrombography and study of the centrifugation scheme

International audienceIntroduction To perform Calibrated Automated Thrombography (CAT), the use of reduced plasma volumes (referred to as “MidiCAT”) makes it possible to more efficiently use limited volumes of valuable biobanked plasma samples and decreases expenses for reagents. It is, however, unclear whether the MidiCAT procedure is suitable when thrombin generation (TG) is studied in the presence of added thrombomodulin (TG-TM). Moreover, a simplified centrifugation scheme would facilitate biobanking, if appropriate, for more sensitive coagulation studies. We aimed to compare the results of “MidiCAT” (halved plasma and reagent volumes) with those from regular CAT, in the absence or presence of TM, as well as to study the impact of a single-centrifugation scheme for plasma preparation before freezing. Materials and methods Plasma samples were prepared from the citrated blood from 20 Geneva hospital diverse patients without gross coagulation abnormalities with a single- or double-centrifugation scheme. Samples were kept frozen at −80°C and thawed just before the TG assay in duplicate under two conditions: 1 pM tissue factor (TF) or 5 pM TF + TM. Results and discussion (1) We externally validated “MidiCAT” and also extended the validation to TG-TM. Whatever the method (CAT or MidiCAT), intra-assay (assessed with duplicates) CV was below 6% (1 pM TF) or below 10% (5 pM TF + TM) for ETP. Agreement between the MidiCAT and CAT results was satisfactory; the p coefficients were above 0.95 for ETP and above 0.90 for most other parameters; biases for ETP were +10.0% (1 pM FT) and +13.5% (5 pM + TM). (2) The centrifugation scheme markedly affected the results obtained in the presence of TM, whereas the bias and limit of agreement (difference plots) were low for the no TM condition. The bias in the presence of TM was obvious, more marked with plasma samples sensitive to TM when double centrifuged: the lower the ETP-TM, the greater the relative difference between the ETP-TM of plasma samples prepared with just single centrifugation and the reference plasma samples. Thus, a single-centrifugation procedure, as is often used for plasma biobanking, is suitable for TG study only if it is not performed in the presence of TM

A Software Tool for Atmospheric Correction and Surface Temperature Estimation of Landsat Infrared Thermal Data

International audienceLand surface temperature (LST) is an important variable involved in the Earth's surface energy and water budgets and a key component in many aspects of environmental research. The Landsat program, jointly carried out by NASA and the USGS, has been recording thermal infrared data for the past 40 years. Nevertheless, LST data products for Landsat remain unavailable. The atmospheric correction (AC) method commonly used for mono-window Landsat thermal data requires detailed information concerning the vertical structure (temperature, pressure) and the composition (water vapor, ozone) of the atmosphere. For a given coordinate, this information is generally obtained through either radio-sounding or atmospheric model simulations and is passed to the radiative transfer model (RTM) to estimate the local atmospheric correction parameters. Although this approach yields accurate LST data, results are relevant only near this given coordinate. To meet the scientific community's demand for high-resolution LST maps, we developed a new software tool dedicated to processing Landsat thermal data. The proposed tool improves on the commonly-used AC algorithm by incorporating spatial variations occurring in the Earth's atmosphere composition. The ERA-Interim dataset (ECMWFmeteorological organization) was used to retrieve vertical atmospheric conditions, which are available at a global scale with a resolution of 0.125 degrees and a temporal resolution of 6 h. A temporal and spatial linear interpolation of meteorological variables was performed to match the acquisition dates and coordinates of the Landsat images. The atmospheric correction parameters were then estimated on the basis of this reconstructed atmospheric grid using the commercial RTMsoftware MODTRAN. The needed surface emissivity was derived from the common vegetation index NDVI, obtained from the red and near-infrared (NIR) bands of the same Landsat image. This permitted an estimation of LST for the entire image without degradation in resolution. The software tool, named LANDARTs, which stands for Landsat automatic retrieval of surface temperatures, is fully automatic and coded in the programming language Python. In the present paper, LANDARTs was used for the local and spatial validation of surface temperature obtained from a Landsat dataset covering two climatically contrasting zones: southwestern France and central Tunisia. Long-term datasets of in situ surface temperature measurements for both locations were compared to corresponding Landsat LST data. This temporal comparison yielded RMSE values ranging from 1.84 • C–2.55 • C. Landsat surface temperature data obtained with LANDARTs were then spatially compared using the ASTER data products of kinetic surface temperatures (AST08) for both geographical zones. This comparison yielded a satisfactory RMSE of about 2.55 • C. Finally, a sensitivity analysis for the effect of spatial validation on the LST correction process showed a variability of up to 2 • C for an entire Landsat image, confirming that the proposed spatial approach improved the accuracy of Landsat LST estimations

Mammalian RAD52 Functions in Break-Induced Replication Repair of Collapsed DNA Replication Forks

Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks. To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed. RAD52, a gene dispensable for normal development in mice, was among the top hits. In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci. Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS. Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan. We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells

Isolation and identification of isocoumarin derivatives with specific inhibitory activity against Wnt pathway Lasiodiplodia venezuelensis and metabolome characterization of

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Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old