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

Topological signature of deterministic chaos in short nonstationary signals from an optical parametric oscillator

Although deterministic chaos has been predicted to occur in the triply resonant optical parametric oscillator (TROPO) fifteen years ago, experimental evidence of chaotic behavior in this system has been lacking so far, in marked contrast with most nonlinear systems, where chaos has been actively tracked and found. This situation is probably linked to the high sensitivity of the TROPO to perturbations, which adversely affects stationary operation at high power. We report the experimental observation in this system of a burst of irregular behavior of duration 80 microseconds. Although the system is highly nonstationary over this time interval, a topological analysis allows us to extract a clearcut signature of deterministic chaos from a time series segment of only 9 base cycles (3 microseconds). This result suggests that nonstationarity is not necessarily an obstacle to the characterization of chaos

Should We Assess Pituitary Function in Children After a Mild Traumatic Brain Injury? A Prospective Study

The aim of this study was to evaluate the frequency of hypopituitarism following TBI in a cohort of children who had been hospitalized for mild TBI and to identify the predictive factors for this deficiency. A prospective study was conducted on children between 2 and 16 years of age who had been hospitalized for mild TBI according to the Glasgow Coma Scale between September 2009 and June 2013. Clinical parameters, basal pituitary hormone assessment at 0, 6, and 12 months, as well as a dynamic testing (insulin tolerance test) 12 months after TBI were performed. The study included 109 children, the median age was 8.5 years. Patients were examined 6 months ( = 99) and 12 months ( = 96) after TBI. Somatotropic deficiency (defined by a GH peak &lt;20 mUI/l in two tests, an IGF-1 &lt;-1SDS and a delta height &lt;0SDS) were confirmed in 2 cases. One case of gonadotrophic deficiency occurred 1 year after TBI among 13 pubertal children. No cases of precocious puberty, 5 cases of low prolactin level, no cases of corticotropic insufficiency (cortisol peak &lt;500 nmol/l) and no cases diabetes insipidus were recorded. Pituitary insufficiency was present 1year after mild TBI in about 7% of children. Based on our results, we suggest testing children after mild TBI in case of clinical abnormalities. i.e., for GH axis, IGF-1, which should be assessed in children with a delta height &lt;0 SDS, 6 to 12 months after TBI, and a dynamic GH testing (preferentially by an ITT) should be performed in case of IGF-1 &lt;-1SDS, with a GH threshold at 20 mUI/L. However, if a systematic pituitary assessment is not required for mild TBI, physicians should monitor children 1 year after mild TBI with particular attention to growth and weight gain

Comprehensive annotation and evolutionary insights into the canine (Canis lupus familiaris) antigen receptor loci

Dogs are an excellent model for human disease. For example, the treatment of canine lymphoma has been predictive of the human response to that treatment. However, an incomplete picture of canine (Canis lupus familiaris) immunoglobulin (IG) and T cell receptor (TR) - or antigen receptor (AR) - gene loci has restricted their utility. This work advances the annotation of the canine AR loci and looks into breed-specific features of the loci. Bioinformatic analysis of unbiased RNA sequence data was used to complete the annotation of the canine AR genes. This annotation was used to query 107 whole genome sequences from 19 breeds and identified over 5,500 alleles across the 550 genes of the seven AR loci: the IG heavy, kappa, and lambda loci; and the TR alpha, beta, gamma, and delta loci. Of note was the discovery that half of the IGK variable (V) genes were located downstream of, and inverted with respect to, the rest of the locus. Analysis of the germline sequences of all the AR V genes identified greater conservation between dog and human than mouse with either. This work brings our understanding of the genetic diversity and expression of AR in dogs to the same completeness as that of mice and men, making it the third species to have all AR loci comprehensively and accurately annotated. The large number of germline sequences serves as a reference for future studies, and has allowed statistically powerful conclusions to be drawn on the pressures that have shaped these loci.This work was supported by funding from the BBSRC and the Wellcome Trust

Logarithmic periodicities in the bifurcations of type-I intermittent chaos

The critical relations for statistical properties on saddle-node bifurcations are shown to display undulating fine structure, in addition to their known smooth dependence on the control parameter. A piecewise linear map with the type-I intermittency is studied and a log-periodic dependence is numerically obtained for the average time between laminar events, the Lyapunov exponent and attractor moments. The origin of the oscillations is built in the natural probabilistic measure of the map and can be traced back to the existence of logarithmically distributed discrete values of the control parameter giving Markov partition. Reinjection and noise effect dependences are discussed and indications are given on how the oscillations are potentially applicable to complement predictions made with the usual critical exponents, taken from data in critical phenomena.Comment: 4 pages, 6 figures, accepted for publication in PRL (2004

HIV infection and aging: enhanced Interferon- and Tumor Necrosis Factor-alpha production by the CD8(+) CD28(-) T subset

BACKGROUND: T cells from HIV(+) and aged individuals show parallels in terms of suppressed proliferative activity and interleukin-2 (I1-2) production and an increased number of CD8(+) CD28(-) T cells. In order to compare cytokine production from T cells from these two states, CD4(+) and CD8(+) T cells from HIV(+) aged, and normal young donors (controls) were monitored for cytokine production by flow cytometry, quantitative PCR and ELISA upon activation by PMA and anti-CD3. In addition, the CD8(+) T cell subsets CD28(+) and CD28(-) from the HIV(+) and the aged groups were evaluated for cytokine production by flow cytometry, and compared with those from young controls. RESULTS: Flow cytometric analysis indicated that CD8(+) T cells from both HIV(+) and aged donors showed an increase of approximately 2–3 fold over controls in percentage of cells producing inflammatory cytokines IFN-γ and TNF-α. Similar analysis also revealed that the production of interleukins-4,6 and 10, production was very low (1–2% of cells) and unchanged in these cells. Quantitative PCR also showed a substantial increase (4–5 fold) in IFN-γ and TNF-α mRNA from HIV(+) and aged CD8(+) T cells, as did ELISA for secreted IFN-γ and TNF-α (2.3–4 fold). Flow cytometric analysis showed that the CD8(+) CD28(-) T cell subset accounts for approximately 80–86% of the IFN-γ and TNF-α production from the CD8(+) subset in the aged and HIV(+) states. The CD4(+) T cell, while not significantly changed in the HIV(+) or aged states in terms of IFN-γ production, showed a small but significant increase in TNF-α production in both states. CONCLUSIONS: Our data appear compatible with physiologic conditions existing in HIV(+) and aged individuals, i.e. elevated serum levels and elevated CD8(+) T cell production of IFN-γ and TNF-α. Thus, the capacity for increased production of cytokines IFN-γ and TNF-α in the aged individual by the dominant CD8(+) CD28(-) subset may have a profound influence on the clinical state by aggravating inflammatory pathologies such as rheumatoid arthritis, and possibly Alzheimer's disease and Crohn's disease. In AIDS, these cytokines may contribute to wasting and cachexia. We theorize that the predominant phenotypic change to the cytotoxic CD8(+) CD28(-) T cell subsets in both the HIV(+) and the aged states may reflect a natural "endpoint" in CD8(+) T cell differentiation induced after a lifetime of immune activity (toward viruses, etc) in the aged, and after a massive accelerated response to HIV in the HIV-positive individual

Profiling the T Cell Receptor Alpha/Delta Locus in Salmonids

In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (family Salmonidae) include two key teleost species for aquaculture, rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar) which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified in Salmo, the majority with a close counterpart in Oncorhynchus. Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets

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