The Integrin Receptor in Biologically Relevant Bilayers: Insights from Molecular Dynamics Simulations

Integrins are heterodimeric (αβ) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2–F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive. In this study an integrin/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics. The results of this study demonstrate the dynamic nature of the integrin receptor and suggest that the presence of the integrin receptor alters the lipid organization between the two leaflets of the bilayer. In particular, our results suggest elevated density of cholesterol and of phosphatidylserine lipids around the integrin/talin complex and a slowing down of lipids in an annulus of ~30 Å around the protein due to interactions between the lipids and the integrin/talin F2–F3 complex. This may in part regulate the interactions of integrins with other related proteins or integrin clustering thus facilitating signal transduction across cell membranes

Intravenous radiocontrast induced anaphylactoid reaction: a rare cause of death

Anaphylactoid reaction after the injection of iodinated contrast media can be life threatening. A 23-year-old woman presented to the emergency room with abdominal pain and fever, for couple of days duration. After completion of a computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast, the patient complained of feeling hot and shortness of breath. She became unresponsive, cyanotic, and developed asystole. The patient was successfully intubated without any laryngeal oedema or bronchial spasm. Despite all resuscitation efforts the patient died. The patient had undergone CT scans with contrast three times in the past. An autopsy could not reveal any obvious cause and the serum tryptase concentration was 211 ng/ml (normal <9 ng/ml)

Fissile mass quantification in radioactive waste packages using photofission delayed gamma rays

International audienceThis paper reports a feasibility study, performed by numerical simulation with MCNPX, of fissile mass characterization in dense, large volume, long-lived and medium activity radioactive waste packages, using photofission delayed gamma rays. High-energy photon interrogation with a 15 MeV LINAC has been modelled for a 1.18 m3 cemented waste package, coupled to high resolution spectroscopy with a HP Ge detector. The study was carried out by assessing the passive and active backgrounds respectively due to the waste package gamma emission, and to material activation during irradiation, in view to determine the detection limits for the main delayed gamma rays of interest. The obtained detection limits are lower than the expected uranium mass in the waste package. On the other hand, as the photofission signal results from both fissile 235U and fertile 238U isotopes, a method for uranium isotopes discrimination based on gamma-ray ratios has been evaluated, showing that photofission delayed gamma rays could be used to assess the fissile mass as well as the total uranium mass

Passive neutron coincidence counting with plastic scintillators for the characterization of radioactive waste drums

International audienceThis paper reports a feasibility study, performed by numerical simulation with MCNPX-PoliMi v2.0, for plutonium quantitative assessment in radioactive waste packages by passive neutron coincidence counting with plastic scintillators. Owing to their low cost and good detection efficiency for fast neutrons, plastic scintillators could indeed constitute a good alternative to 3He proportional counters, which have become too costly because of 3He global shortage. However, their high-sensitivity to gamma rays and crosstalk are well-known drawbacks that need to be carefully studied. A measurement system for 118 L drums filled either with metallic or organic technological wastes have been modeled with MCNPX-PoliMi, and output data have been processed with ROOT. A 5-cm-thick lead shield is used in front of the detectors to attenuate plutonium and americium gamma radiation. In the studied cases, triple coincidences due to 240Pu spontaneous fissions represent more than 85 percent of the total signal when using crosstalk rejection algorithms, the 15 percent remaining coincidences being due to parasitic coincidences caused by ( αn) reactions or Am and Pu gamma rays. Although crosstalk rejection significantly reduces counting statistics, a few thousand triple coincidences are still recorded for 1 g of Pu homogeneously distributed in both metallic and organic matrices in a 25 min acquisition. For higher masses of Pu, a linear evolution of the number of coincidences with the mass is observed up to about 10 g. In addition, a study of Pu localization effects has shown that the triple coincidence difference is smaller than 20 percent between a point-like fission source and the homogeneous distribution in the drum

Modeling and molecular dynamics of HPA-1a and -1b polymorphisms: effects on the structure of the β3 subunit of the αIIbβ3 integrin.

The HPA-1 alloimmune system carried by the platelet integrin αIIbβ3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the β3 subunit. Although the structure of αIIbβ3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions.A complete 3D model of the L33-β3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 β3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 β3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains.These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the β3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and β3 structure that suggest possible effects on the alloimmune response and platelet function

Local structure and <i>N_eq</i> analyses.

<p><i>N_eq</i> values (average number of PBs weighted by their frequencies, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047304#s2" target="_blank">Materials and Methods</a>) of residues from the PSI, I-EGF-1, and I-EGF-2 domains were computed for L33 (blue lines) and P33 (red lines) β3 forms. For each domain, the absolute value of <i>N_eq</i> L33 and <i>N_eq</i> P33 differences (Δ<i>N_eq</i>) is also plotted (black lines). The sequence of the C26–C38 loop in the PSI domain is highlighted (pink-shaded area). The horizontal gray lines indicate an <i>N_eq</i> value of 1. A <i>N_eq</i> value of 1 indicates strong structure rigidity since only one PB is adopted by the residue; above 1, flexibility is proportional to the <i>N_eq</i> value. <i>N_eq</i> analyses demonstrated that the three domain structures are highly flexible, in particular, PSI has four small interspersed rigid areas. L33 and P33 (indicated by an arrow), belong to a rigid stretch (residues 33 to 35). Residues whose Δ<i>N_eq</i> was significantly modified (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047304#s2" target="_blank">Materials and Methods</a>) by the L33P substitution are identified by a vertical dotted line.</p