Mid- and Far-Infrared Marker Bands of the Metal Coordination Sites of the Histidine Side Chains in the Protein Cu,Zn-Superoxide Dismutase

International audienceVibrational spectroscopy gives important information on the properties of ligand and metal–ligand bonds in metalloenzymes. Infrared spectroscopy is appealing for the study of metal active sites that are not amenable to Raman spectroscopy. We present a combined experimental and theoretical approach to analyze the mid- and far-IR spectra of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) as a probe of the histidine ligands. This metalloenzyme provides a unique model to identify specific IR signatures of metal–histidine coordination and to study their alterations as a function of the metal (copper/zinc), the copper valence state (+I/+II), the histidine coordination mode (Nτ and Nπ) and the histidine protonation state. DFT calculations combined with normal mode descriptions from potential energy distribution calculations were performed on two slightly different cluster models. Differences in the constraints at the side chain of one histidine Cu ligand sensibly modify the geometric parameters and vibrational properties. Electrochemically induced FTIR difference spectroscopy provided mid- and far-IR fingerprint spectra of the Cu protein in aqueous media that are sensitive to the redox state of the Cu centre at the active site. Comparisons of the DFT predictions with the experimental IR modes of the histidine ligands at the Cu,Zn-SOD active site showed that useful mid-IR markers of histidine Nτ and Nπ coordination were predicted with good accuracy. The DFT analysis further demonstrated a link between the ν(C4–C5) mode frequency of His46 and the specific properties of the His46–Cu bond in Cu,Zn-SOD. A combined theoretical and experimental approach on samples in H2O and 2H2O or 15N-labelled samples identified the contributions from the histidine side chain modes in the 669–629 cm–1 region

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

The 13th Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-IV Survey Mapping Nearby Galaxies at Apache Point Observatory

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) began observations in July 2014. It pursues three core programs: APOGEE-2,MaNGA, and eBOSS. In addition, eBOSS contains two major subprograms: TDSS and SPIDERS. This paper describes the first data release from SDSS-IV, Data Release 13 (DR13), which contains new data, reanalysis of existing data sets and, like all SDSS data releases, is inclusive of previously released data. DR13 makes publicly available 1390 spatially resolved integral field unit observations of nearby galaxies from MaNGA,the first data released from this survey. It includes new observations from eBOSS, completing SEQUELS. In addition to targeting galaxies and quasars, SEQUELS also targeted variability-selected objects from TDSS and X-ray selected objects from SPIDERS. DR13 includes new reductions ofthe SDSS-III BOSS data, improving the spectrophotometric calibration and redshift classification. DR13 releases new reductions of the APOGEE-1data from SDSS-III, with abundances of elements not previously included and improved stellar parameters for dwarf stars and cooler stars. For the SDSS imaging data, DR13 provides new, more robust and precise photometric calibrations. Several value-added catalogs are being released in tandem with DR13, in particular target catalogs relevant for eBOSS, TDSS, and SPIDERS, and an updated red-clump catalog for APOGEE.This paper describes the location and format of the data now publicly available, as well as providing references to the important technical papers that describe the targeting, observing, and data reduction. The SDSS website, http://www.sdss.org, provides links to the data, tutorials and examples of data access, and extensive documentation of the reduction and analysis procedures. DR13 is the first of a scheduled set that will contain new data and analyses from the planned ~6-year operations of SDSS-IV.PostprintPeer reviewe

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

De MgO à CaO (modélisation expérimentale et théorique des sites basiques de surface)

MgO et CaO, isostructuraux, sont choisis comme solides modèles pour élucider le fonctionnement des sites basiques de surface, en déprotonation (adsorption de méthanol) et en catalyse (conversion du2-méthylbut-3-yn-2-ol [MBOH]). La modélisation dans le cadre de la DFT montre que l adsorption d oxoacides à la surface de MgO est gouvernée par la topologie des sites (concave ou convexe) et la coordinence des ions impliquées. Expérimentalement, seule une combinaison de techniques (microcalorimétrie et FTIR) permet de décrire complètement la déprotonation. Catalytiquement, l importance des espèces adsorbées (OH et carbonates) est pointée. Quantitativement, CaO est plus déprotonant et plus réactif que MgO mais dans les deux cas, les sites hydroxylés sont plus actifs que les déshydroxylés, pourtant plus déprotonants. Cette exaltation particulière de réactivité par hydroxylation est discutée en termes de stabilisation du MBOH déprotoné et de flexibilité des hydroxyles de surface.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Modeling Ammonia and Water Co-Adsorption in CuI-SSZ-13 Zeolite Using DFT Calculations

International audienceCu-SSZ-13 efficiently catalyzes the selective catalytic reduction (SCR) of NO by NH3 but the structure of the active site and, particularly, the redox state of the copper (+I or +II) is still debated. This paper focuses on the possible contribution of CuI species using quantum chemistry of adsorption and co-adsorption of NH3 and H2O on CuI species. The calculations show that CuI clearly migrates upon adsorption of NH3 and H2O. All the CuI complexes sit in the cage containing the 8 MR and interact with the zeolite framework through several H-bonds. In the experimental temperature and pressure domain of SCR conditions, calculated phase diagrams show that a coordination number of two is predicted for the co-adsorption of NH3 and H2O on CuI. Finally, the calculated phase diagrams of CuI-SSZ-13 are discussed together with those of CuII-SSZ-13 and recent experimental characterizations, providing a wider picture of the real catalyst in SCR conditions

Cooperative Cation Migrations upon CO Addition in CuI- and Alkali-Exchanged Faujasite: A DFT Study

International audienceCO adsorption in Al-rich faujasite zeolite containing copper and alkali cations has been investigated using DFT methods in order to determine how CO interacts and may modify the original position of the cations. Whether a cluster or a periodic model is used, addition of CO induces the formation of stable complexes labeled DI(CO) in which CO interacts by both its C-end and its O-end, resulting from a cooperative rearrangement of cations. In addition to a CuI migration from site II to the supercage, a migration of alkali from site III′ to site III may occur. DI(CO) also induces a downshift of the νCO mode in comparison with the complex containing CO interacting with a single cation, SI(CO). These results suggest a new assignment of the IR spectra of CO adsorbed in YCuI and YNa+: for YCuI, the upshifted signal at ca. 2160 cm-1 in comparison with νCOgas at 2143 cm-1 could be assigned to a SI(CO) structure, whereas the downshifted signal at ca. 2140 cm-1 could be assigned to a DI(CO) complex. For YNa+, the upshifted signal at ca. 2170 cm-1 could be assigned to SI(CO) NaSII · · ·CO and/or to DI(CO) NaSII · · ·OC· · · NaSIII′, whereas the downshifted signal at ca. 2122 cm-1 could be assigned to DI(CO) complex NaSII · · ·CO· · ·NaSIII′. This study shows that the DI(CO) interaction is a key ingredient for understanding the metal-exchanged zeolite properties

The French Conference on Catalysis-FCCat 1

International audienc