An Architectural Model for Component Groupware

This paper proposes an architectural model to facilitate the design of component-based groupware systems. This architectural model has been defined based on (1) three pre-defined component types, (2) a refinement strategy that relies on these component types, (3) the identification of layers of collaboration concerns, and (4) rules for the coupling and distribution of the components that implement these concerns. Our architectural model is beneficial for controlling the complexity of the development process, since it gives concrete guidance on the concerns to be considered and decomposition disciplines to be applied in each development step. The paper illustrates the application of this architectural model with an example of an electronic voting system

Performance of Optically Readout GEM-based TPC with a 55Fe source

Optical readout of large Time Projection Chambers (TPCs) with multiple Gas Electron Multipliers (GEMs) amplification stages has shown to provide very interesting performances for high energy particle tracking. Proposed applications for low-energy and rare event studies, such as Dark Matter search, ask for demanding performance in the keV energy range. The performance of such a readout was studied in details as a function of the electric field configuration and GEM gain by using a $^{55}$Fe source within a 7 litre sensitive volume detector developed as a part of the R\&D for the CYGNUS project. Results reported in this paper show that the low noise level of the sensor allows to operate with a 2~keV threshold while keeping a rate of fake-events lesser than 10 per year. In this configuration, a detection efficiency well above 95\% along with an energy resolution ($\sigma$) of 18\% is obtained for the 5.9 keV photons, demonstrating the very promising capabilities of this technique

Vitamin D responsive elements within the HLA-DRB1 promoter region in Sardinian multiple sclerosis associated alleles

Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15:01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15:01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04:05, *03:01, *13:01 and *15:01 and non-MS-associated *16:01, *01, *11, *07:01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15:01, *16:01, *11 and in 45/73 *03:01 and in heterozygous state in 28/73 *03:01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13:03, *04:05 and *07:01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04:05 and *03:01 alleles carrying the new mutated VDRE, while the *16:01 and *03:01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16:01 and in the *15:01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients

First evidence of luminescence in a He/CF4_4 gas mixture induced by non-ionizing electrons

Optical readout of Gas Electron Multipliers (GEM) provides very interesting performances and has been proposed for different applications in particle physics. In particular, thanks to its good efficiency in the keV energy range, it is being developed for low-energy and rare event studies, such as Dark Matter search. So far, the optical approach exploits the light produced during the avalanche processes in GEM channels. Further luminescence in the gas can be induced by electrons accelerated by a suitable electric field. The CYGNO collaboration studied this process with a combined use of a triple-GEM structure and a grid in an He/CF$_4$ (60/40) gas mixture at atmospheric pressure. Results reported in this paper allow to conclude that with an electric field of about 11~kV/cm a photon production mean free path of about 1.0~cm was found

CYGNO: a gaseous TPC with optical readout for dark matter directional search

The CYGNO project has the goal to use a gaseous TPC with optical readout to detect dark matter and solar neutrinos with low energy threshold and directionality. The CYGNO demonstrator will consist of 1 m 3 volume filled with He:CF 4 gas mixture at atmospheric pressure. Optical readout with high granularity CMOS sensors, combined with fast light detectors, will provide a detailed reconstruction of the event topology. This will allow to discriminate the nuclear recoil signal from the background, mainly represented by low energy electron recoils induced by radioactivity. Thanks to the high reconstruction efficiency, CYGNO will be sensitive to low mass dark matter, and will have the potential to overcome the neutrino floor, that ultimately limits non-directional dark matter searches

Performance of an Optically Read-Out Time Projection Chamber with ultra-relativistic electrons

The Time Projection Chamber (TPC) is an ideal candidate to finely study the charged particle ionization in a gaseous medium. Large volumes TPCs can be readout with a suitable number of channels offering a complete 3D reconstruction of an ultra-relativistic charged particle track, that is the sequence of its energy releases in the TPC gas volume. Moreover, He-based TPCs are very promising to study keV energy particles as nuclear recoils, opening the possibility for directional searches of Dark Matter (DM) and the study of Solar Neutrinos (SN). In this paper we report the analysis of the data acquired with a small TPC prototype (named LEMOn) built by the CYGNO collaboration that was exposed to a beam of 450 MeV electrons at the Beam Test Facility of National Laboratories of Frascati. LEMOn is operated with a He-CF4 mixture at atmospheric pressure and is based on a Gas Electron Multipliers amplification stage that produces visible light collected by a sub-millimeter position resolution scientific CMOS camera. This type of readout - in conjunction with a fast light detection - allows a 3D reconstruction of the electrons tracks. The electrons are leaving a trail of segments of ionizations corresponding to a few keV energy release each. Their study leads to predict a keV energy threshold and 1-10 mm longitudinal and 0.1-0.3 mm transverse position resolution for nuclear recoils, very promising for the application of optically readout TPC to DM searches and SN measurements

Y-Chromosome Based Evidence for Pre-Neolithic Origin of the Genetically Homogeneous but Diverse Sardinian Population: Inference for Association Scans

The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0–25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8–22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms

The Immune Response to Melanoma Is Limited by Thymic Selection of Self-Antigens

The expression of melanoma-associated antigens (MAA) being limited to normal melanocytes and melanomas, MAAs are ideal targets for immunotherapy and melanoma vaccines. As MAAs are derived from self, immune responses to these may be limited by thymic tolerance. The extent to which self-tolerance prevents efficient immune responses to MAAs remains unknown. The autoimmune regulator (AIRE) controls the expression of tissue-specific self-antigens in thymic epithelial cells (TECs). The level of antigens expressed in the TECs determines the fate of auto-reactive thymocytes. Deficiency in AIRE leads in both humans (APECED patients) and mice to enlarged autoreactive immune repertoires. Here we show increased IgG levels to melanoma cells in APECED patients correlating with autoimmune skin features. Similarly, the enlarged T cell repertoire in AIRE−/− mice enables them to mount anti-MAA and anti-melanoma responses as shown by increased anti-melanoma antibodies, and enhanced CD4+ and MAA-specific CD8+ T cell responses after melanoma challenge. We show that thymic expression of gp100 is under the control of AIRE, leading to increased gp100-specific CD8+ T cell frequencies in AIRE−/− mice. TRP-2 (tyrosinase-related protein), on the other hand, is absent from TECs and consequently TRP-2 specific CD8+ T cells were found in both AIRE−/− and AIRE+/+ mice. This study emphasizes the importance of investigating thymic expression of self-antigens prior to their inclusion in vaccination and immunotherapy strategies

The Development of Mouse APECED Models Provides New Insight into the Role of AIRE in Immune Regulation

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed