Stoichiometry of HLA Class II-Invariant Chain Oligomers

BACKGROUND: The HLA gene complex encodes three class II isotypes, DR, DQ, and DP. HLA class II molecules are peptide receptors that present antigens for recognition by T lymphocytes. In antigen presenting cells, the assembly of matched α and β subunits to heterodimers is chaperoned by invariant chain (Ii). Ii forms a homotrimer with three binding sites for class II heterodimers. The current model of class II and Ii structure states that three αβ heterodimers bind to an Ii trimer. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] We have now analyzed the composition and size of the complexes of class II and Ii using epitope tagged class II subunits and density gradient experiments. We show here that class II-Ii oligomers consist of one class II heterodimer associated with one Ii trimer, such that the DR, DQ and DP isotypes are contained within separate complexes with Ii. CONCLUSION/SIGNIFICANCE: We propose a structural model of the class II-Ii oligomer and speculate that the pentameric class II-Ii complex is bent towards the cell membrane, inhibiting the binding of additional class II heterodimers to Ii

A Genetic Basis of Susceptibility to Acute Pyelonephritis

For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring

Thrombosis in vasculitis: from pathogenesis to treatment

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients

Emissions Trading, CDM, JI, and More - The Climate Strategy of the EU

The objective of this paper is to assess the likely allocation effects of the current cli-mate protection strategy as it is laid out in the National Allocation Plans (NAPs) for the European Emissions Trading Scheme (ETS). The multi-regional, multi-sectoral CGE-model DART is used to simulate the effects of the current policies in the year 2012 when the Kyoto targets need to be met. Different scenarios are simulated in or-der to highlight the effects of the grandfathering of permits to energy-intensive instal-lations, the use of the project-based mechanisms (CDM and JI), and the restriction imposed by the supplementarity criterion

The biochemistry of antigen presentation

This thesis describes studies on the binding of peptides to the murine major histocompatibility complex (MHC) class I molecule H-2Db (Db). The expression of the recombinant soluble Db molecule in Chinese hamster ovary cells and its subsequent purification by nickel affinity chromatography, gel filtration, and preparative native isoelectric focusing are reported. The product is the correct molecule, homogeneous, a dimer of dimers, and free of endogenous peptide. A novel binding assay based on the enhancement of natural tryptophan fluorescence by the binding of peptide is introduced. This assay is used to determine melting curves of the empty and peptide-loaded protein, and to measure association rate constants by stopped-flow fluorescence spectroscopy. Radioligand binding measurements of equilibrium as well as association and dissociation rate constants and their temperature dependence are reported. In agreement with earlier observations, the ratio of association and dissociation rate constants is much larger than the equilibrium association constant. Fluorescence anisotropy decay spectroscopy gives evidence for conformational alterations in the Db molecule upon peptide binding. The data, possible errors and ways to avoid them, and mathematical models of binding are discussed to obtain an overall picture of the binding process.</p

Efficient Bayesian inference for large chaotic dynamical systems

Abstract Estimating parameters of chaotic geophysical models is challenging due to their inherent unpredictability. These models cannot be calibrated with standard least squares or filtering methods if observations are temporally sparse. Obvious remedies, such as averaging over temporal and spatial data to characterize the mean behavior, do not capture the subtleties of the underlying dynamics. We perform Bayesian inference of parameters in high-dimensional and computationally demanding chaotic dynamical systems by combining two approaches: (i) measuring model–data mismatch by comparing chaotic attractors and (ii) mitigating the computational cost of inference by using surrogate models. Specifically, we construct a likelihood function suited to chaotic models by evaluating a distribution over distances between points in the phase space; this distribution defines a summary statistic that depends on the geometry of the attractor, rather than on pointwise matching of trajectories. This statistic is computationally expensive to simulate, compounding the usual challenges of Bayesian computation with physical models. Thus, we develop an inexpensive surrogate for the log likelihood with the local approximation Markov chain Monte Carlo method, which in our simulations reduces the time required for accurate inference by orders of magnitude. We investigate the behavior of the resulting algorithm with two smaller-scale problems and then use a quasi-geostrophic model to demonstrate its large-scale application

The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation

The monomorphic antigen-presenting molecule major histocompatibility complex-I-related protein 1 (MR1) presents small-molecule metabolites to mucosal-associated invariant T (MAIT) cells. The MR1-MAIT cell axis has been implicated in a variety of infectious and noncommunicable diseases, and recent studies have begun to develop an understanding of the molecular mechanisms underlying this specialized antigen presentation pathway. However, proteins regulating MR1 folding, loading, stability, and surface expression remain to be identified. Here, we performed a gene trap screen to discover novel modulators of MR1 surface expression through insertional mutagenesis of an MR1-overexpressing clone derived from the near-haploid human cell line HAP1 (HAP1.MR1). The most significant positive regulators identified included β(2)-microglobulin, a known regulator of MR1 surface expression, and ATP13A1, a P5-type ATPase in the endoplasmic reticulum (ER) not previously known to be associated with MR1-mediated antigen presentation. CRISPR/Cas9-mediated knockout of ATP13A1 in both HAP1.MR1 and THP-1 cell lines revealed a profound reduction in MR1 protein levels and a concomitant functional defect specific to MR1-mediated antigen presentation. Collectively, these data are consistent with the ER-resident ATP13A1 being a key posttranscriptional determinant of MR1 surface expression

Hierarchical Bayesian propulsion power models:a simplified example with cruise ships

Abstract Mathematical models for ships’ consumption are in a central role in assessing the CO₂ emissions of marine traffic. Moreover, such models are needed when optimizing the ways the vessels are operated (e.g. routing). Nowadays, many ships are equipped with data collection systems, enabling data-based calibration of the models. Typically this calibration is done independently for each ship. In this paper, we demonstrate a hierarchical Bayesian approach, where we fit a single model over many vessels, with the assumption that the parameters of vessels of similar characteristics are likely close to each other. The benefits of such an approach are two-fold; (1) we can borrow information about parameters that are not well informed by the vessel-specific data using data from similar ships, and (2) we can use the hierarchical model to predict the behavior of a vessel from which we have no data, based only on its characteristics. In this paper, we discuss the basic concept and present a simple version of the model using cruise vessels. We apply the Stan modeling tool for the fitting and use real data from 64 ships collected via the commercial Eniram platform. The prediction accuracy of the model is compared to an existing data-free method. We demonstrate that the accuracy of such an approach can improve upon the classical resistance calculation-based methods