IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis

IMGT/V-QUEST is the highly customized and integrated system for the standardized analysis of the immunoglobulin (IG) and T cell receptor (TR) rearranged nucleotide sequences. IMGT/V-QUEST identifies the variable (V), diversity (D) and joining (J) genes and alleles by alignment with the germline IG and TR gene and allele sequences of the IMGT reference directory. New functionalities were added through a complete rewrite in Java. IMGT/V-QUEST analyses batches of sequences (up to 50) in a single run. IMGT/V-QUEST describes the V-REGION mutations and identifies the hot spot positions in the closest germline V gene. IMGT/V-QUEST can detect insertions and deletions in the submitted sequences by reference to the IMGT unique numbering. IMGT/V-QUEST integrates IMGT/JunctionAnalysis for a detailed analysis of the V-J and V-D-J junctions, and IMGT/Automat for a full V-J- and V-D-J-REGION annotation. IMGT/V-QUEST displays, in ‘Detailed view’, the results and alignments for each submitted sequence individually and, in ‘Synthesis view’, the alignments of the sequences that, in a given run, express the same V gene and allele. The ‘Advanced parameters’ allow to modify default parameters used by IMGT/V-QUEST and IMGT/JunctionAnalysis according to the users’ interest. IMGT/V-QUEST is freely available for academic research at http://imgt.cines.f

Recovering probabilities for nucleotide trimming processes for T cell receptor TRA and TRG V-J junctions analyzed with IMGT tools

<p>Abstract</p> <p>Background</p> <p>Nucleotides are trimmed from the ends of variable (V), diversity (D) and joining (J) genes during immunoglobulin (IG) and T cell receptor (TR) rearrangements in B cells and T cells of the immune system. This trimming is followed by addition of nucleotides at random, forming the N regions (N for nucleotides) of the V-J and V-D-J junctions. These processes are crucial for creating diversity in the immune response since the number of trimmed nucleotides and the number of added nucleotides vary in each B or T cell. IMGT^®sequence analysis tools, IMGT/V-QUEST and IMGT/JunctionAnalysis, are able to provide detailed and accurate analysis of the final observed junction nucleotide sequences (tool "output"). However, as trimmed nucleotides can potentially be replaced by identical N region nucleotides during the process, the observed "output" represents a <it>biased </it>estimate of the "true trimming process."</p> <p>Results</p> <p>A probabilistic approach based on an analysis of the standardized tool "output" is proposed to infer the probability distribution of the "true trimmming process" and to provide plausible biological hypotheses explaining this process. We collated a benchmark dataset of TR alpha (TRA) and TR gamma (TRG) V-J rearranged sequences and junctions analysed with IMGT/V-QUEST and IMGT/JunctionAnalysis, the nucleotide sequence analysis tools from IMGT^®, the international ImMunoGeneTics information system^®, <url>http://imgt.cines.fr</url>. The standardized description of the tool output is based on the IMGT-ONTOLOGY axioms and concepts. We propose a simple first-order model that attempts to transform the observed "output" probability distribution into an estimate closer to the "true trimming process" probability distribution. We use this estimate to test the hypothesis that Poisson processes are involved in trimming. This hypothesis was not rejected at standard confidence levels for three of the four trimming processes: TRAV, TRAJ and TRGV.</p> <p>Conclusion</p> <p>By using trimming of rearranged TR genes as a benchmark, we show that a probabilistic approach, applied to IMGT^®standardized tool "outputs" opens the way to plausible hypotheses on the events involved in the "true trimming process" and eventually to an exact quantification of trimming itself. With increasing high-throughput of standardized immunogenetics data, similar probabilistic approaches will improve understanding of processes so far only characterized by the "output" of standardized tools.</p

IMGT®, the international ImMunoGeneTics information system®

IMGT®, the international ImMunoGeneTics information system® (http://www.imgt.org), was created in 1989 by Marie-Paule Lefranc, Laboratoire d'ImmunoGénétique Moléculaire LIGM (Université Montpellier 2 and CNRS) at Montpellier, France, in order to standardize and manage the complexity of immunogenetics data. The building of a unique ontology, IMGT-ONTOLOGY, has made IMGT® the global reference in immunogenetics and immunoinformatics. IMGT® is a high-quality integrated knowledge resource specialized in the immunoglobulins or antibodies, T cell receptors, major histocompatibility complex, of human and other vertebrate species, proteins of the IgSF and MhcSF, and related proteins of the immune systems of any species. IMGT® provides a common access to standardized data from genome, proteome, genetics and 3D structures. IMGT® consists of five databases (IMGT/LIGM-DB, IMGT/GENE-DB, IMGT/3Dstructure-DB, etc.), fifteen interactive online tools for sequence, genome and 3D structure analysis, and more than 10 000 HTML pages of synthesis and knowledge. IMGT® is used in medical research (autoimmune diseases, infectious diseases, AIDS, leukemias, lymphomas and myelomas), veterinary research, biotechnology related to antibody engineering (phage displays, combinatorial libraries, chimeric, humanized and human antibodies), diagnostics (clonalities, detection and follow-up of residual diseases) and therapeutical approaches (graft, immunotherapy, vaccinology). IMGT is freely available at http://www.imgt.org

Prospects for annihilating dark matter in the inner galactic halo by the Cherenkov Telescope Array

We compute the sensitivity to dark matter annihilations for the forthcoming large Cherenkov Telescope Array (CTA) in several primary channels and over a range of dark matter masses from 50 GeV up to 80 TeV. For all channels, we include inverse Compton scattering of e± by dark matter annihilations on the ambient photon background, which yields substantial contributions to the overall γ-ray flux. We improve the analysis over previous work by: (i) implementing a spectral and morphological analysis of the γ-ray emission; (ii) taking into account the most up-to-date cosmic ray background obtained from a full CTA Monte Carlo simulation and a description of the diffuse astrophysical emission; and (iii) including the systematic uncertainties in the rich observational CTA data sets. We find that our spectral and morphological analysis improves the CTA sensitivity by roughly a factor 2. For the hadronic channels, CTA will be able to probe thermal dark matter candidates over a broad range of masses if the systematic uncertainties in the data sets will be controlled better than the percent level. For the leptonic modes, the CTA sensitivity will be well below the thermal value of the annihilation cross-section. In this case, even with larger systematics, thermal dark matter candidates up to masses of a few TeV will be easily studied

Appeal No. 0714: Gary Harris & Group Maintenance v. Division of Mineral Resources Management

Chief\u27s Order 2003-1

A major electronics upgrade for the H.E.S.S. Cherenkov telescopes 1-4

The High Energy Stereoscopic System (H.E.S.S.) is an array of imaging atmospheric Cherenkov telescopes (IACTs) located in the Khomas Highland in Namibia. It consists of four 12-m telescopes (CT1-4), which started operations in 2003, and a 28-m diameter one (CT5), which was brought online in 2012. It is the only IACT system featuring telescopes of different sizes, which provides sensitivity for gamma rays across a very wide energy range, from ~30 GeV up to ~100 TeV. Since the camera electronics of CT1-4 are much older than the one of CT5, an upgrade is being carried out; first deployment was in 2015, full operation is planned for 2016. The goals of this upgrade are threefold: reducing the dead time of the cameras, improving the overall performance of the array and reducing the system failure rate related to aging. Upon completion, the upgrade will assure the continuous operation of H.E.S.S. at its full sensitivity until and possibly beyond the advent of CTA. In the design of the new components, several CTA concepts and technologies were used and are thus being evaluated in the field: The upgraded read-out electronics is based on the NECTAR readout chips; the new camera front- and back-end control subsystems are based on an FPGA and an embedded ARM computer; the communication between subsystems is based on standard Ethernet technologies. These hardware solutions offer good performance, robustness and flexibility. The design of the new cameras is reported here.Comment: Proceedings of the 34th International Cosmic Ray Conference, 30 July- 6 August, 2015, The Hague, The Netherland

Serological proteome analysis reveals new specific biases in the IgM and IgG autoantibody repertoires in autoimmune polyendocrine syndrome type 1

Objective: Autoimmune polyendocrine syndrome type 1 (APS 1) is caused by mutations in the AIRE gene that induce intrathymic T-cell tolerance breakdown, which results in tissue-specific autoimmune diseases. Design: To evaluate the effect of a well-defined T-cell repertoire impairment on humoral self-reactive fingerprints, comparative serum self-IgG and self-IgM reactivities were analyzed using both one- and two-dimensional western blotting approaches against a broad spectrum of peripheral tissue antigens. Methods: Autoantibody patterns of APS 1 patients were compared with those of subjects affected by other autoimmune endocrinopathies (OAE) and healthy controls. Results: Using a Chi-square test, significant changes in the Ab repertoire were found when intergroup patterns were compared. A singular distortion of both serum self-IgG and self-IgM repertoires was noted in APS 1 patients. The molecular characterization of these antigenic targets was conducted using a proteomic approach. In this context, autoantibodies recognized more significantly either tissue-specific antigens, such as pancreatic amylase, pancreatic triacylglycerol lipase and pancreatic regenerating protein 1α, or widely distributed antigens, such as peroxiredoxin-2, heat shock cognate 71-kDa protein and aldose reductase. As expected, a well-defined self-reactive T-cell repertoire impairment, as described in APS 1 patients, affected the tissue-specific self-IgG repertoire. Interestingly, discriminant IgM reactivities targeting both tissue-specific and more widely expressed antigens were also specifically observed in APS 1 patients. Using recombinant targets, we observed that post translational modifications of these specific antigens impacted upon their recognition. Conclusions: The data suggest that T-cell-dependent but also T-cell-independent mechanisms are involved in the dynamic evolution of autoimmunity in APS 1