Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease

Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA–gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA–gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD

Atmospheric Acetaldehyde: Importance of Air-Sea Exchange and a Missing Source in the Remote Troposphere.

We report airborne measurements of acetaldehyde (CH3CHO) during the first and second deployments of the National Aeronautics and Space Administration (NASA) Atmospheric Tomography Mission (ATom). The budget of CH3CHO is examined using the Community Atmospheric Model with chemistry (CAM-chem), with a newly-developed online air-sea exchange module. The upper limit of the global ocean net emission of CH3CHO is estimated to be 34 Tg a-1 (42 Tg a-1 if considering bubble-mediated transfer), and the ocean impacts on tropospheric CH3CHO are mostly confined to the marine boundary layer. Our analysis suggests that there is an unaccounted CH3CHO source in the remote troposphere and that organic aerosols can only provide a fraction of this missing source. We propose that peroxyacetic acid (PAA) is an ideal indicator of the rapid CH3CHO production in the remote troposphere. The higher-than-expected CH3CHO measurements represent a missing sink of hydroxyl radicals (and halogen radical) in current chemistry-climate models

Structural and Functional Insights into the Malaria Parasite Moving Junction Complex

Members of the phylum Apicomplexa, which include the malaria parasite Plasmodium, share many features in their invasion mechanism in spite of their diverse host cell specificities and life cycle characteristics. The formation of a moving junction (MJ) between the membranes of the invading apicomplexan parasite and the host cell is common to these intracellular pathogens. The MJ contains two key parasite components: the surface protein Apical Membrane Antigen 1 (AMA1) and its receptor, the Rhoptry Neck Protein (RON) complex, which is targeted to the host cell membrane during invasion. In particular, RON2, a transmembrane component of the RON complex, interacts directly with AMA1. Here, we report the crystal structure of AMA1 from Plasmodium falciparum in complex with a peptide derived from the extracellular region of PfRON2, highlighting clear specificities of the P. falciparum RON2-AMA1 interaction. The receptor-binding site of PfAMA1 comprises the hydrophobic groove and a region that becomes exposed by displacement of the flexible Domain II loop. Mutations of key contact residues of PfRON2 and PfAMA1 abrogate binding between the recombinant proteins. Although PfRON2 contacts some polymorphic residues, binding studies with PfAMA1 from different strains show that these have little effect on affinity. Moreover, we demonstrate that the PfRON2 peptide inhibits erythrocyte invasion by P. falciparum merozoites and that this strong inhibitory potency is not affected by AMA1 polymorphisms. In parallel, we have determined the crystal structure of PfAMA1 in complex with the invasion-inhibitory peptide R1 derived by phage display, revealing an unexpected structural mimicry of the PfRON2 peptide. These results identify the key residues governing the interactions between AMA1 and RON2 in P. falciparum and suggest novel approaches to antimalarial therapeutics

Heterogeneity and chemical reactivity of the remote troposphere defined by aircraft measurements

The NASA Atmospheric Tomography (ATom) mission built a photochemical climatology of air parcels based on in situ measurements with the NASA DC-8 aircraft along objectively planned profiling transects through the middle of the Pacific and Atlantic oceans. In this paper we present and analyze a data set of 10 s (2 km) merged and gap-filled observations of the key reactive species driving the chemical budgets of O3 and CH4 (O3, CH4, CO, H2O, HCHO, H2O2, CH3OOH, C2H6, higher alkanes, alkenes, aromatics, NOx, HNO3, HNO4, peroxyacetyl nitrate, other organic nitrates), consisting of 146,494 distinct air parcels from ATom deployments 1 through 4. Six models calculated the O3 and CH4 photochemical tendencies from this modeling data stream for ATom 1. We find that 80 %&ndash;90 % of the total reactivity lies in the top 50 % of the parcels; and 25 %&ndash;35 %, in the top 10 %, supporting previous model-only studies that tropospheric chemistry is driven by a fraction of all the air. In other words, accurate simulation of the least reactive 50 % of the troposphere is unimportant for global budgets. Surprisingly, the probability densities of species and reactivities averaged on a model scale (100 km) differ only slightly from the 2 km ATom data, indicating that much of the heterogeneity in tropospheric chemistry can be captured with current global chemistry models. Comparing the ATom reactivities over the tropical oceans with climatological statistics from six global chemistry models, we find generally good agreement with the reactivity rates for O3 and CH4. In the Pacific but not Atlantic, however, models distinctly underestimate O3 production below 2 km, and this can be traced lower NOX levels than observed. Attaching photochemical reactivities to measurements of chemical species allows for a richer, yet more constrained-to-what-matters, set of metrics for model evaluation.</p

An ill-posed mechanical problem with friction

International audienceMany models involve the Coulomb's law in order to describe dynamical properties of friction phenomena. In order to generalize this Coulomb's law and to deal with its correct mathematical expression, we study a nonlinear equation where we take into account a maximal monotone graph. In the particular case of Coulomb's law, existence and uniqueness are proved. But in the general case, only existence persists. A counter-example to uniqueness is given

Study of some rheological models with a finite number of degrees of freedom

International audienceA large number of rheological models can be covered by the existence and uniqueness theory for maximal monotone operators. Numerical simulations display hysteresis cycles when the forcing is periodic. A given shape of hysteresis cycle in an appropriate class of polygonal cycles can always be realized by adjusting the physical parameters of the rheological model

A stochastic differential equation from friction mechanics. Une équation différentielle stochastique en mécanique du frottement.

International audienceThe existence and uniqueness of solutions to multivalued stochastic differential equations of the second order on Riemannian manifolds are proved. The class of problem is motivated by rigid body and multibody dynamics with friction and an application to the spherical pendulum with friction is presented. On démontre l'existence et l'unicité de la solution d'un système d'équations stochastiques multivoques du deuxième ordre sur une variété riemannienne. L'étude de cette classe de problèmes est motivée par la dynamique du corps rigide, et plus généralement des problèmes multicorps. On présente une application au pendule sphérique avec frottement

Study of an elastoplastic model with an infinite number of internal degrees of freedom

International audienceWe treat the dynamical behavior of the continuous elastoplastic model of Masing, consisting of an infinite number of springs and dry-friction elements. Using the theory of differential inclusions we prove existence and uniqueness result. Moreover, we prove that the continuous model is the limit of the discrete Masing model when the number of degrees of freedom tends to infinity. Starting from known results of numerical analysis, we build an implicit Euler-like numerical scheme of order one