A “dock, lock, and latch” Structural Model for a Staphylococcal Adhesin Binding to Fibrinogen

AbstractGram-positive pathogens such as staphylococci contain multiple cell wall-anchored proteins that serve as an interface between the microbe and its environment. Some of these proteins act as adhesins and mediate bacterial attachment to host tissues. SdrG is a cell wall-anchored adhesin from Staphylococcus epidermidis that binds to the Bβ chain of human fibrinogen (Fg) and is necessary and sufficient for bacterial attachment to Fg-coated biomaterials. Here, we present the crystal structures of the ligand binding region of SdrG as an apoprotein and in complex with a synthetic peptide analogous to its binding site in Fg. Analysis of the crystal structures, along with mutational studies of both the protein and of the peptide, reveals that SdrG binds to its ligand with a dynamic “dock, lock, and latch” mechanism. We propose that this mechanism represents a general mode of ligand binding for structurally related cell wall-anchored proteins of gram-positive bacteria

Initial results from the Oman Drilling Project Multi-Borehole Observatory: Petrogenesis and ongoing alteration of mantle peridotite in the weathering horizon

International audienceThe Oman Drilling Project “Multi-Borehole Observatory” (MBO) samples an area of active weathering of tectonically exposed peridotite. This article reviews the geology of the MBO region, summarizes recent research, and provides new data constraining ongoing alteration. Host rocks are partially to completely serpentinized, residual mantle harzburgites, and replacive. Dunites show evidence for “reactive fractionation,” in which cooling, crystallizing magmas reacted with older residues of melting. Harzburgites and dunites are 65%–100% hydrated. Ferric to total iron ratios vary from 50% to 90%. In Hole BA1B, alteration extent decreases with depth. Gradients in water and core composition are correlated. Serpentine veins are intergrown with, and cut, carbonate veins with measurable 14C. Ongoing hydration is accompanied by SiO2 addition. Sulfur enrichment in Hole BA1B may result from oxidative leaching of sulfur from the upper 30 m, coupled with sulfate reduction and sulfide precipitation at 30–150 m. Oxygen fugacity deep in Holes BA3A, NSHQ14, and BA2A is fixed by the reaction 2H2O = 2H2 + O2 combined with oxidation of ferrous iron in serpentine, brucite, and olivine. fO2 deep in Holes BA1A, BA1D, and BA4A is 3–4 log units above the H2O-H2 limit, controlled by equilibria involving serpentine and brucite. Variations in alteration are correlated with texture, with reduced, low SiO2 assemblages in mesh cores recording very low water/rock ratios, juxtaposed with adjacent veins recording much higher ratios. The proportion of reduced mesh cores versus oxidized veins increases with depth, and the difference in fO2 recorded in cores and veins decreases with depth

Reversing Conventional Reactivity of Mixed Oxo/Alkyl Rare-Earth Complexes: Non-Redox Oxygen Atom Transfer

International audienceThe preferential substitution of oxo ligands over alkyl ones of rare-earth complexes is commonly considered as "impossible" due to the high oxophilicity of metal centers. Now, it has been shown that simply assembling mixed methyl/oxo rare-earth complexes to a rigid trinuclear cluster framework cannot only enhance the activity of the Ln-oxo bond, but also protect the highly reactive Ln-alkyl bond, thus providing a previously unrecognized opportunity to selectively manipulate the oxo ligand in the presence of numerous reactive functionalities. Such trimetallic cluster has proved to be a suitable platform for developing the unprecedented non-redox rare-earth-mediated oxygen atom transfer from ketones to CS2 and PhNCS. Controlled experiments and computational studies shed light on the driving force for these reactions, emphasizing the importance of the sterical accessibility and multimetallic effect of the cluster framework in promoting reversal of reactivity of rare-earth oxo complexes

Initial results from the Oman drilling project multi‐borehole observatory: petrogenesis and ongoing alteration of mantle peridotite in the weathering horizon

The Oman Drilling Project “Multi-Borehole Observatory” (MBO) samples an area of active weathering of tectonically exposed peridotite. This article reviews the geology of the MBO region, summarizes recent research, and provides new data constraining ongoing alteration. Host rocks are partially to completely serpentinized, residual mantle harzburgites, and replacive. Dunites show evidence for “reactive fractionation,” in which cooling, crystallizing magmas reacted with older residues of melting. Harzburgites and dunites are 65%–100% hydrated. Ferric to total iron ratios vary from 50% to 90%. In Hole BA1B, alteration extent decreases with depth. Gradients in water and core composition are correlated. Serpentine veins are intergrown with, and cut, carbonate veins with measurable 14C. Ongoing hydration is accompanied by SiO2 addition. Sulfur enrichment in Hole BA1B may result from oxidative leaching of sulfur from the upper 30 m, coupled with sulfate reduction and sulfide precipitation at 30–150 m. Oxygen fugacity deep in Holes BA3A, NSHQ14, and BA2A is fixed by the reaction 2H2O = 2H2 + O2 combined with oxidation of ferrous iron in serpentine, brucite, and olivine. fO2 deep in Holes BA1A, BA1D, and BA4A is 3–4 log units above the H2O-H2 limit, controlled by equilibria involving serpentine and brucite. Variations in alteration are correlated with texture, with reduced, low SiO2 assemblages in mesh cores recording very low water/rock ratios, juxtaposed with adjacent veins recording much higher ratios. The proportion of reduced mesh cores versus oxidized veins increases with depth, and the difference in fO2 recorded in cores and veins decreases with depth

Impact of CD4+ T Cell Responses on Clinical Outcome following Oral Administration of Wild-Type Enterotoxigenic Escherichia coli in Humans.

Enterotoxigenic Escherichia coli (ETEC) is a non-invasive enteric pathogen of considerable public health importance, being one of the most common attributable causes of diarrheal illness in infants and young children in developing countries and the most common cause of traveler's diarrhea. To enhance study-to-study consistency of our experimental challenge model of ETEC in volunteers, and to allow concomitant multi-site trials to evaluate anti-ETEC immunoprophylactic products, hundreds of vials, each containing a standardized inoculum of virulent wild-type (wt) ETEC strain H10407 (serotype O78:H11 expressing colonization factor antigen I and heat-labile and heat-stable enterotoxins), were prepared under current Good Manufacturing Practices (cGMP) and frozen. Following thawing, the contents of each vial can be used (diluted as necessary) to prepare consistent challenge inoculum, even at different study sites. A preliminary human experimental challenge study using this cGMP inoculum was conducted on a research isolation ward and the clinical and cell-mediated immune responses evaluated. Of the 6 healthy adult volunteers challenged 83% (5/6) developed diarrhea and 50% developed moderate-to-severe diarrhea (MSD). Moderate and severe diarrhea were defined as passage of ≥ 1 liter or ≥ 3 liters of diarrheal stool respectively. We compared the CD4+ T cell responses of volunteers who developed MSD against those who did not and identified significant differences in ETEC-specific cytokine production and gut homing potential. We furthermore demonstrated that increased expression of the gut-homing molecule integrin α4β7 by peripheral T follicular helper cells (pTfh) correlated with decreased stool volume and increased ETEC-specific IgA B memory cell (BM) development. Collectively, despite small numbers of volunteers, our results indicate a potential role for CD4+ T cells, in particular pTfh, in modulating disease outcome following exposure to wt ETEC in a volunteer experimental challenge model