Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides

Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2.04 Å resolution. CteB has the (β/α)6-TIM barrel fold that is characteristic of radical SAM enzymes, as well as a C-terminal SPASM domain that contains two auxiliary [4Fe-4S] clusters. Importantly, one [4Fe-4S] cluster in the SPASM domain exhibits an open coordination site in absence of peptide substrate, which is coordinated by a peptidyl-cysteine residue in the bound state. The crystal structure of CteB also reveals an accessory N-terminal domain that has high structural similarity to a recently discovered motif present in several enzymes that act on ribosomally synthesized and post-translationally modified peptides (RiPPs), known as a RiPP precursor peptide recognition element (RRE). This crystal structure is the first of a sactionine bond forming enzyme and sheds light on structures and mechanisms of other members of this class such as AlbA or ThnB

The On-orbit Calibrations for the Fermi Large Area Telescope

The Large Area Telescope (LAT) on--board the Fermi Gamma ray Space Telescope began its on--orbit operations on June 23, 2008. Calibrations, defined in a generic sense, correspond to synchronization of trigger signals, optimization of delays for latching data, determination of detector thresholds, gains and responses, evaluation of the perimeter of the South Atlantic Anomaly (SAA), measurements of live time, of absolute time, and internal and spacecraft boresight alignments. Here we describe on orbit calibration results obtained using known astrophysical sources, galactic cosmic rays, and charge injection into the front-end electronics of each detector. Instrument response functions will be described in a separate publication. This paper demonstrates the stability of calibrations and describes minor changes observed since launch. These results have been used to calibrate the LAT datasets to be publicly released in August 2009.Comment: 60 pages, 34 figures, submitted to Astroparticle Physic

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475,000 Individuals

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up

The spectral energy distribution of fermi bright blazars

We have conducted a detailed investigation of the broadband spectral properties of the γ-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated Fermi γ-ray spectra with Swift, radio, infra-red, optical, and other hard X-ray/γ-ray data, collected within 3 months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous spectral energy distributions (SED) for 48 LBAS blazars. The SED of these γ-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual log ν-log ν Fν representation, the typical broadband spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SED to characterize the peak intensity of both the low- and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broadband colors (i.e., the radio to optical, αro, and optical to X-ray, αox, spectral slopes) and from the γ-ray spectral index. Our data show that the synchrotron peak frequency (νSpeak) is positioned between 1012.5 and 1014.5 Hz in broad-lined flat spectrum radio quasars (FSRQs) and between 10 13 and 1017 Hz in featureless BL Lacertae objects. We find that the γ-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron-inverse Compton scenarios. However, simple homogeneous, one-zone, synchrotron self-Compton (SSC) models cannot explain most of our SED, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. More complex models involving external Compton radiation or multiple SSC components are required to reproduce the overall SED and the observed spectral variability. While more than 50% of known radio bright high energy peaked (HBL) BL Lacs are detected in the LBAS sample, only less than 13% of known bright FSRQs and LBL BL Lacs are included. This suggests that the latter sources, as a class, may be much fainter γ-ray emitters than LBAS blazars, and could in fact radiate close to the expectations of simple SSC models. We categorized all our sources according to a new physical classification scheme based on the generally accepted paradigm for Active Galactic Nuclei and on the results of this SED study. Since the LAT detector is more sensitive to flat spectrum γ-ray sources, the correlation between νSpeak and γ-ray spectral index strongly favors the detection of high energy peaked blazars, thus explaining the Fermi overabundance of this type of sources compared to radio and EGRET samples. This selection effect is similar to that experienced in the soft X-ray band where HBL BL Lacs are the dominant type of blazars. © 2010 The American Astronomical Society

Harzburgite melting with and without H₂O: Experimental data and predictive modeling

The effect of H2O on harzburgite-saturated melts has been quantified with a series of hydrous and anhydrous melting experiments using a piston-cylinder device. Experimental conditions were 1.2–2.2 GPa and 1175–1500°C. Melt H2O contents range from 0 to 10 wt %. The effects of temperature, pressure, and bulk composition (including H2O) on the SiO2 content of the experimental melts have been evaluated using SiO2 activity coefficients. The results suggest a two-lattice-type model for the melt phase in which H2O mixes nearly ideally with other network modifiers (MgO, FeO, etc.) but does not mix on the network-forming lattice site and so has little effect on SiO2 activity coefficients. The effect of H2O on SiO2 activity is too small to produce the high SiO2 contents observed in mafic andesite magmas. It is proposed that the SiO2-rich character of hydrous, subduction-related magmas is the result of the low temperatures at which hydrous melting occurs relative to anhydrous melting. Partition coefficients for MgO and FeO increase at lower temperatures, while the partition coefficient for SiO2 is nearly constant and is buffered by olivine-orthopyroxene equilibria. Therefore the SiO2/(MgO + FeO) ratios of harzburgite saturated melts increase as temperature falls in both hydrous and anhydrous systems. The results suggest that H2O contents of andesitic magmas may be far higher (>7 wt %) than is generally accepted. Experimentally measured mineral/melt partition coefficients (this study and literature data) have been parameterized in terms of pressure, temperature, and melt H2O content. These expressions have been used to construct a Gibbs-Duhem-based numerical model that predicts the compositions of hydrous and anhydrous olivine-orthopyroxene-saturated melts. Comparisons with experimental data not included in the model indicate that it is the most accurate model available for predicting the compositions of high-degree mantle melts, with or without H2O

Melting of the primitive martian mantle at 0.5-2.2 GPa and the origin of basalts and alkaline rocks on Mars

International audienceWe have performed piston–cylinder experiments on a primitive martian mantle composition between 0.5 and 2.2 GPa and 1160 to 1550 °C. The composition of melts and residual minerals constrain the possible melting processes on Mars at 50 to 200 km depth under nominally anhydrous conditions. Silicate melts produced by low degrees of melting (<10 wt.%) were analyzed in layers of vitreous carbon spheres or in micro-cracks inside the graphite capsule. The total range of melt fractions investigated extends from 5 to 50 wt.%, and the liquids produced display variable SiO2 (43.7–59.0 wt.%), MgO (5.3–18.6 wt.%) and Na2O + K2O (1.0–6.5 wt.%) contents. We provide a new equation to estimate the solidus temperature of the martian mantle: , which places the solidus 50 °C below that of fertile terrestrial peridotites. Low- and high-degree melts are compared to martian alkaline rocks and basalts, respectively. We suggest that the parental melt of Adirondack-class basalts was produced by ∼25 wt.% melting of the primitive martian mantle at 1.5 GPa (∼135 km) and ∼1400 °C. Despite its brecciated nature, NWA 7034/7533 might be composed of material that initially crystallized from a primary melt produced by ∼10–30 wt.% melting at the same pressure. Other igneous rocks from Mars require mantle reservoirs with different CaO/Al2O3 and FeO/MgO ratios or the action of fractional crystallization. Alkaline rocks can be derived from mantle sources with alkali contents (∼0.5 wt.%) similar to the primitive mantle

The origin of high-Mg magmas in Mt Shasta and Medicine Lake volcanoes, Cascade Arc (California): higher and lower than mantle oxygen isotope signatures attributed to current and past subduction

International audienc