Ankylosing Spondylitis: a trade Off of HLA-B27, ERAP, and pathogen interconnections? Focus on Sardinia

The frequency of HLA-B27 in patients with Ankylosing Spondylitis (AS) is over 85%. There are more than 170 recognized HLA-B27 alleles but the majority of them is not sufficiently represented for genetic association studies. So far only two alleles, the HLA-B*2706 in Asia and the HLA-B*2709 in Sardinia, have not been found to be associated with AS. The highly homogenous genetic structure of the Sardinian population has favored the search of relevant variants for disease-association studies. Moreover, malaria, once endemic in the island, has been shown to have contributed to shape the native population genome affecting the relative allele frequency of relevant genes. In Sardinia, the prevalence of HLA-B*2709, which differs from the strongly AS-associated B*2705 prototype for one amino acid (His/Asp116) in the F pocket of the peptide binding groove, is around 20% of all HLA-B27 alleles. We have previously hypothesized that malaria could have contributed to the establishment of this allele in Sardinia. Based on our recent findings, in this perspective article we speculate that the Endoplasmic Reticulum Amino Peptidases, ERAP1 and 2, associated with AS and involved in antigen presentation, underwent co-selection by malaria. These genes, besides shaping the immunopeptidome of HLA-class I molecules, have other biological functions that could also be involved in the immunosurveillance against malaria

Modelling the atmosphere of the carbon-rich Mira RU Vir

Context. We study the atmosphere of the carbon-rich Mira RU Vir using the mid-infrared high spatial resolution interferometric observations from VLTI/MIDI. Aims. The aim of this work is to analyse the atmosphere of the carbon-rich Mira RU Vir, with state of the art models, in this way deepening the knowledge of the dynamic processes at work in carbon-rich Miras. Methods. We compare spectro-photometric and interferometric measurements of this carbon-rich Mira AGB star, with the predictions of different kinds of modelling approaches (hydrostatic model atmospheres plus MOD-More Of Dusty, self-consistent dynamic model atmospheres). A geometric model fitting tool is used for a first interpretation of the interferometric data. Results. The results show that a joint use of different kind of observations (photometry, spectroscopy, interferometry) is essential to shed light on the structure of the atmosphere of a carbon-rich Mira. The dynamic model atmospheres fit well the ISO spectrum in the wavelength range {\lambda} = [2.9, 25.0] {\mu}m. Nevertheless, a discrepancy is noticeable both in the SED (visible), and in the visibilities (shape and level). A possible explanation are intra-/inter-cycle variations in the dynamic model atmospheres as well as in the observations. The presence of a companion star and/or a disk or a decrease of mass loss within the last few hundred years cannot be excluded but are considered unlikely.Comment: 15 pages. Accepted in A&

An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes

The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly influences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1. We therefore show here for the first time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specific therapeutic approaches

The MIPSGAL View of Supernova Remnants in the Galactic Plane

We report the detection of Galactic supernova remnants (SNRs) in the mid-infrared (at 24 and 70 μm), in the coordinate ranges 10° < l < 65° and 285° < l < 350°, |b| < 1°, using MIPS aboard the Spitzer Space Telescope. We search for infrared counterparts to SNRs in Green's catalog and identify 39 out of 121, i.e., a detection rate of about 32%. Such a relatively low detection fraction is mainly due to confusion with nearby foreground/background sources and diffuse emission. The SNRs in our sample show a linear trend in [F_8/F_(24)] versus [F_(70)/F_(24)]. We compare their infrared fluxes with their corresponding radio flux at 1.4 GHz and find that most remnants have a ratio of 70 μm to 1.4 GHz which is similar to those found in previous studies of SNRs (with the exception of a few that have ratios closer to those of H II regions). Furthermore, we retrieve a slope close to unity when correlating infrared (24 and 70 μm) with 1.4 GHz emission. Our survey is more successful in detecting remnants with bright X-ray emission, which we find is well correlated with the 24 μm morphology. Moreover, by comparing the power emitted in the X-ray, infrared, and radio, we conclude that the energy released in the infrared is comparable to the cooling in the X-ray range

Tracing the energetics and evolution of dust with Spitzer : a chapter in the history of the Eagle Nebula

Context. The Spitzer GLIMPSE and MIPSGAL surveys have revealed a wealth of details about the Galactic plane in the infrared (IR)with orders of magnitude higher sensitivity, higher resolution, and wider coverage than previous IR observations. The structure of the interstellar medium (ISM) is tightly connected to the countless star-forming regions. We use these surveys to study the energetics and dust properties of the Eagle Nebula (M16), one of the best known star-forming regions. Aims. We present MIPSGAL observations of M16 at 24 and 70 μm and combine them with previous IR data. The mid-IR image shows a shell inside the well-known molecular borders of the nebula, as in the ISO and MSX observations from 15 to 21 μm. The morphologies at 24 and 70 μm are quite different, and its color ratio is unusually warm. The far-IR image resembles the one at 8 μm that enhances the structure of the molecular cloud and the "pillars of creation". We use this set of IR data to analyze the dust energetics and properties within this template for Galactic star-forming regions. Methods. We measure IR spectral energy distributions (SEDs) across the entire nebula, both within the inner shell and the photodissociation regions (PDRs).We use the DUSTEM model to fit these SEDs and constrain the dust temperature, the dust-size distribution, and the radiation field intensity relative to that provided by the star cluster NGC 6611 (χ/χ0). Results. Within the PDRs, the inferred dust temperature (~35 K), the dust-size distribution, and the radiation field intensity (χ/χ0 < 1) are consistent with expectations. Within the inner shell, the dust is hotter (~70 K). Moreover, the radiation field required to fit the SED is larger than that provided by NGC 6611 (χ/χ0 > 1). We quantify two solutions to this problem: (1) The size distribution of the dust in the shell is not that of interstellar dust. There is a significant enhancement of the carbon dust-mass in stochastically heated very small grains. (2) The dust emission arises from a hot (~10^6 K) plasma where both UV and collisions with electrons contribute to the heating. Within this hypothesis, the shell SED may be fit for a plasma pressure p/k ~ 5 × 10^7 K cm^(−3). Conclusions. We suggest two interpretations for the M16 inner shell: (1) The shell matter is supplied by photo-evaporative flows arising from dense gas exposed to ionized radiation. The flows renew the shell matter as it is pushed out by the pressure from stellar winds. Within this scenario, we conclude that massive-star forming regions such as M16 have a major impact on the carbon dustsize distribution. The grinding of the carbon dust could result from shattering in grain-grain collisions within shocks driven by the dynamical interaction between the stellar winds and the shell. (2) We also consider a more speculative scenario where the shell is a supernova remnant. In this case, we would be witnessing a specific time in the evolution of the remnant where the plasma pressure and temperature would enable the remnant to cool through dust emission

AIF-1 gene does not confer susceptibility to Behçet's disease: Analysis of extended haplotypes in Sardinian population

Background BehcEet's disease (BD) is a polygenic immune-mediated disorder characterized by a close association with the HLA-B∗51 allele. The HLA region has a strong linkage disequilibrium (LD) and carries several genetic variants (e.g. MIC-A, TNF-α genes) identified as associated to BD because of their LD with HLA-B∗51. In fact, the HLA-B∗51 is inherited as part of extended HLA haplotypes which are well preserved in patients with BD. Sardinian population is highly differentiated from other Mediterranean populations because of a distinctive genetic structure with very highly preserved HLA haplotypes. Patients and methods In order to identify other genes of susceptibility to BD within the HLA region we investigated the distribution of human Allograft Inflammatory Factor-1 (AIF-1) gene variants among BD patients and healthy controls from Sardinia. Six (rs2736182; rs2259571; rs2269475; rs2857597; rs13195276; rs4711274) AIF-1 single nucleotide polymorphisms (SNPs) and related extended haplotypes have been investigated as well as their LD within the HLA region and with HLA-B∗51. Overall, 64 BD patients, 43 HLA-B∗51 positive healthy controls (HC) and 70 random HC were enrolled in the study. Results HLA-B∗51 was the only allele with significantly higher frequency (pc = 0.0021) in BD patients (40.6%) than in HC (9.8%). The rs2259571TAIF-1 variant had a significantly reduced phenotypic, but not allelic frequency in BD patients (72.1%; pc = 0.014) compared to healthy population (91.3%). That was likely due to the LD between HLA-B∗51 and rs2259571G(pc= 9E-5), even though the rs2259571Gdistribution did not significantly differ between BD patients and HC. Conclusion No significant difference in distribution of AIF-1 SNPs haplotypes was observed between BD patients and HC and between HLA-B∗51 positive BD patients and HLA-B∗51 positive HC. Taken together, these results suggest that AIF-1 gene is not associated with susceptibility to BD in Sardinia

Application of a NMDA Receptor Conductance in Rat Midbrain Dopaminergic Neurons Using the Dynamic Clamp Technique

Neuroscientists study the function of the brain by investigating how neurons in the brain communicate. Many investigators look at changes in the electrical activity of one or more neurons in response to an experimentally-controlled input. The electrical activity of neurons can be recorded in isolated brain slices using patch clamp techniques with glass micropipettes. Traditionally, experimenters can mimic neuronal input by direct injection of current through the pipette, electrical stimulation of the other cells or remaining axonal connections in the slice, or pharmacological manipulation by receptors located on the neuronal membrane of the recorded cell