Model Of Negative Selection Research Articles

МОДЕЛЬ ОТРИЦАТЕЛЬНОГО ОТБОРА С МАСКИРОВАНИЕМ ДЕТЕКТОРОВ ДЛЯ РЕШЕНИЯ ЗАДАЧ ДИАГНОСТИРОВАНИЯ С ВЕЩЕСТВЕННЫМ ПРЕДСТАВЛЕНИЕМ ПРИЗНАКОВ

Решена актуальная задача автоматизации диагностирования объектов и систем, описанных вещественными признаками. Получил дальнейшее развитие метод обучения модели отрицательного отбора с маскированием, который модифицирован для работы с вещественным представлением детекторов. Решена задача неразрушающего диагностирования лопаток газотурбинных авиадвигателей. Библиогр.: 10 назв.Ключевые слова: диагностирование, вещественные признаки, отрицательный отбор, маскирование, детектор.

Genome Stability of Pandemic Influenza A (H1N1) 2009 Based on Analysis of Hemagglutinin and Neuraminidase Genes

Influenza A virus (H1N1), which arose in 2009, constituted the fourth pandemic after the cases of 1918, 1957, and 1968. This new variant was formed by a triple reassortment, with genomic segments from swine, avian, and human influenza origins. The objective of this study was to analyze sequences of hemagglutinin (n=2038) and neuraminidase (n=1273) genes, in order to assess the extent of diversity among circulating 2009-2010 strains, estimate if these genes evolved through positive, negative, or neutral selection models of evolution during the pandemic phase, and analyze the worldwide percentage of detection of important amino acid mutations that could enhance the viral performance, such as transmissibility or resistance to drugs. A continuous surveillance by public health authorities will be critical to monitor the appearance of new influenza variants, especially in animal reservoirs such as swine and birds, in order to prevent the potential animal-human transmission of viruses with pandemic potential.

THE DIAGNOSIS MODEL BUILDING ON THE BASIS OF NEGATIVE SELECTION PARADIGM USING THE PRINCIPLE OF DETECTOR ASKING

A new negative selection model using masked detectors with training method has been developed. Various stopping criteria for the training method have been investigated. The stopping criterion is proposed. It allows to terminate training procedure, to speedup training process and to reduce computational resources.

Impaired Thymic Selection and Abnormal Antigen-Specific T Cell Responses in Foxn1Δ/Δ Mutant Mice

Background Foxn1Δ/Δ mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from an atypical progenitor population. In the current study, we tested the effects of these defects on thymic selection.Methodology/Principal FindingsWe used Foxn1Δ/Δ; DO11 Tg and Foxn1Δ/Δ; OT1 Tg mice as positive selection and Foxn1Δ/Δ; MHCII I-E mice as negative selection models. We also used an in vivo system of antigen-specific reactivity to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection of both CD4 and CD8 SP thymocytes was reduced in Foxn1Δ/Δ mutants compared to Foxn1+/Δ control mice. These defects were associated with reduction of both MHC Class I and Class II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal in vitro, and were either hypersensitive or hyporesponsive to antigen-specific stimulation in vivo. These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output.Conclusions/SignificanceThese data show that a primary defect in the thymic microenvironment can cause both direct defects in selection which can in turn cause indirect effects on the periphery, exacerbating functional defects in T cells.

Kinase suppressor of Ras 1 is required for full ERK activation in thymocytes but not for thymocyte selection

The scaffold protein kinase suppressor of Ras 1 (KSR1) is critical for efficient activation of ERK in a number of cell types. Consistent with this, we observed a defect in ERK activation in thymocytes that lack KSR1. Interestingly, we found that the defect was much greater after PMA stimulation than by CD3 activation. Since ERK activation is believed to be important for thymocyte development, we analyzed thymocyte selection in KSR1-deficient (KSR1(-/-) ) mice. We found that positive selection in two different TCR transgenic models, HY and AND, was normal. On the other hand, negative selection in the HY model was slightly impaired in KSR1(-/-) mice. However, a defect in negative selection was not apparent in the AND TCR model system or in an endogenous superantigen-mediated model of negative selection. These results suggest that, despite a requirement for KSR1 for full ERK activation in thymocytes, full and efficient ERK activation is not essential for the majority of thymocyte selection events.

Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma–dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady–state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus.

Impaired thymic selection and abnormal antigen-specific T cell responses in Foxn1Δ/Δ mutant mice (36.36)

Abstract Foxn1Δ/Δ mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from a atypical progenitor. To test the effects of deficient TEC on thymic selection, we used Foxn1Δ/Δ;DO11 Tg and Foxn1Δ/Δ;OT1 Tg mice as positive selection and Foxn1Δ/Δ;MHCII I-E mice as negative selection models. An in vivo system of antigen-specific reactivity was used to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection was reduced in Foxn1Δ/Δ mutants compared to Foxn1+/Δ control mice. These defects were due in part to reduction of MHC I, II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal in vitro, and were either hypersensitive or hyporesponsive to antigen-specific stimulation in vivo. These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output, showing that a primary defect in the thymic microenvironment can cause indirect effects on the periphery that can in turn exacerbate functional defects in T cells.

Gadd45β-induced prolonged activation of p38 kinase defines a novel pathway mediating negative selection of thymocytes

The clonal deletion of thymocytes by negative selection is an important process to ensure immunologic tolerance, even though the underlying molecular mechanisms are poorly understood. Here, we show that Gadd45β, a regulator of mitogen-activated protein kinases, is critically involved in triggering negative selection. Gadd45β expression was inducible in different models of negative selection. Strikingly, only TCR-ligating peptides resulting in negative selection, but not positively selecting ligands or dexamethasone, a TCR-independent apoptosis agonist, induced Gadd45β expression. Expression of Gadd45β maintained a sustained activation of p38 kinase and thereby promoted TCR-mediated apoptosis. In contrast, inhibition of Gadd45β expression or p38 activity impaired cell death. Moreover, thymocytes from Gadd45β-deficient mice revealed only transient p38 activation, reduced caspase activation and cell death. Thus, we provide evidence that Gadd45β and a resulting persistent activation of p38 constitute a novel apoptotic pathway involved in negative selection.

During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain

Apoptosis accompanying negative selection is a central but poorly understood event in T cell development. The Nur77 nuclear steroid receptor and Bim, a proapoptotic BH3-only member of the Bcl-2 family, are two molecules implicated in this process. However, how they relate to each other and how Nur77 induces apoptosis remain unclear. In thymocytes, Nur77 has been shown to induce cell death through a transcriptional-dependent pathway, but in cancer cell lines, Nur77 was reported to induce apoptosis through conversion of Bcl-2 into a killer protein at the mitochondria. Whether this Nur77 transcriptional-independent pathway actually occurs in vivo remains controversial. Using an optimized fractionation protocol for thymocytes, here we report that stimulation of CD4+CD8+ thymocytes results in translocation of Nur77 and its family member Nor-1 to the mitochondria, leading to their association with Bcl-2 and exposure of the Bcl-2 proapoptotic BH3 domain. In two T cell receptor transgenic models of negative selection, F5 and HY, a conformational change of the Bcl-2 molecule in the negatively selected T cell population was similarly observed. Thus, the Nur77 family and Bim pathways converge at mitochondria to mediate negative selection.

No requirement for TRAIL in intrathymic negative selection

The contribution of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway to intrathymic negative selection is a controversial subject with two studies suggesting a key role for TRAIL, while others demonstrated normal negative selection, in TRAIL- and TRAIL receptor-deficient mice. The basis of these discrepancies is unclear and may in part reflect differences in the negative selection models under investigation. Considering the importance of the negative selection process in the establishment of a competent immune system, it is essential that these discrepancies be fully resolved. In this study, we failed to identify a role for TRAIL in an acute model of peptide antigen-specific negative selection using a TCR transgenic system as well as antibody-mediated TCR/CD3 ligation in vitro and in vivo. Moreover, thymic dendritic cells, the main cellular mediators of negative selection in the thymus, did not constitutively express TRAIL, and TRAIL receptor (DR5) expression was negative or extremely low on thymocytes. Furthermore, in vitro thymocyte deletion was normal in C57BL/6 TRAIL(-/-) gld mice, suggesting that TRAIL and FasL do not function cooperatively to induce negative selection. These results, combined with the fact that aged C57BL/6 TRAIL(-/-) mice showed no signs of spontaneous autoimmunity, strongly indicate that intrathymic negative selection occurs normally in the absence of TRAIL signaling.

A hardware/software partitioning algorithm based on artificial immune principles

Hardware/software codesign is the main approach to designing the embedded systems. One of the primary steps of the hardware/software codesign is the hardware/software partitioning. A good partitioning scheme is a tradeoff of some constraints, such as power, size, performance, and so on. Inspired by both negative selection model and evolutionary mechanism of the biological immune system, an evolutionary negative selection algorithm for hardware/software partitioning, namely ENSA-HSP, is proposed in this paper. This ENSA-HSP algorithm is proved to be convergent, and its ability to escape from the local optimum is also analyzed. The experimental results demonstrate that ENSA-HSP is more efficient than traditional evolutionary algorithm.

The coexistence of hybrid and parentalDaphnia: the role of parasites

Parasite driven time-lagged negative frequency-dependent selection of hosts has been studied in natural populations by following changes in host genotype frequencies over time. However, such dynamics have not been considered at higher taxonomic levels, for example, between parental species and their hybrids. In a field study on a Daphnia hybrid system, we observed that one Daphnia taxon first was relatively under-infected, but became over-infected after a strong increase in frequency. This finding is consistent with the idea of parasite evolution towards the most frequent host taxon. In two experiments, we investigated whether the assumptions made by a model of negative frequency-dependent selection apply to our host taxa system. First, we showed that the parasite can change the outcome of taxa competition and secondly, we confirmed that the over-infection of one host taxon observed in the field has a genetic basis. Our results indicate that the incorporation of host-parasite interactions at the species level may allow us to gain a more complete picture of forces driving dynamic taxa coexistence in Daphnia hybrid systems. More generally, we suggest that if hybrids coexist in sympatry with parental taxa, the infection patterns as observed under natural conditions may be rather temporal and unstable.

Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation

HDAC7, a class II histone deacetylase that is highly expressed in thymocytes, inhibits both transcription of the orphan steroid nuclear receptor Nur77 and induction of apoptosis in response to activation of the T-cell receptor (TCR). Here, we report that HDAC7 is exported to the cytoplasm by a calcium-independent signaling pathway after TCR activation. Protein kinase D1 (PKD1) was activated after TCR engagement, interacted with HDAC7, and phosphorylated three serines (Ser155, Ser318, and Ser448) at its N terminus, leading to its export from the nucleus. Mutation of Ser155, Ser318, and Ser448 blocked the nucleocytoplasmic shuttling of HDAC7 in response to TCR activation, as did overexpression of a kinase-inactive form of PKD1. Consistent with the regulatory role of HDAC7 in Nur77 expression, PKD1 activation led to the transcriptional activation of Nur77 via myocyte enhancer factor 2-binding sites in its promoter. In a mouse model of negative selection, PKD1 was activated during thymocyte activation. These observations indicate that PKD1 regulates the expression of Nur77 during thymocyte activation at least in part by phosphorylating HDAC7.

Evidence that positive selection drives Y-chromosome degeneration in Drosophila miranda.

Why does the Y chromosome harbor so few functional loci? Evolutionary theory predicts that Y chromosomes degenerate because they lack genetic recombination. Both positive and negative selection models have been invoked to explain this degeneration, as both can result in the recurrent fixation of linked deleterious mutations on a nonrecombining Y chromosome. To distinguish between these models, I investigated patterns of nucleotide variability along 37 kb of the recently formed neo-Y chromosome in Drosophila miranda. Levels of nucleotide variability on this chromosome are 30 times lower than in highly recombining portions of the genome. Both positive and negative selection models can result in reduced variability levels, but their effects on the frequency spectrum of mutations differ. Using coalescent simulations, I show that the patterns of nucleotide variability on the neo-Y chromosome are unlikely under deleterious mutation models (including background selection and Muller's ratchet) but are expected under recent positive selection. These results implicate positive selection as an important force driving the degeneration of Y chromosomes; adaptation at a few loci, possibly increasing male fitness, occurs at the cost of most other genes on this chromosome.

Polymorphic signals of harassed female odonates and the males that learn them support a novel frequency-dependent model

For mate-searching species, the learned mate recognition (LMR) hypothesis assumes that sexual harassment favours signal variation among females, which exploits the receiver ability of males. The model predicts that coevolving males have responded to the female sexual foil by learning to recognize female variants as potential mates. I translate the LMR hypothesis into the language of signal detection theory to explain its novelty as a dynamic, coevolutionary, negative frequency-dependent selection model. Due to gene–environment interactions, males cueing to the morph detected most often should generate positive but often asymmetrical, detection-dependent harassment towards females. Females are expected to sort to an ideal free distribution where harassment costs are equal. At equilibrium, morph fitness, but not necessarily morph frequency, is predicted to be equal. The LMR hypothesis is consistent with recent experimental data and the distribution of colour polymorphisms in the Odonata, predicts general conditions favouring variation in sexual signals, and provides a novel mechanism for speciation via sexual signalling.

Calcineurin B1 Is Essential for Positive but Not Negative Selection during Thymocyte Development

During development, discrete cell fates often result from variation in the intensity of a particular signal. The mechanisms underlying these seemingly analog-to-digital switches are not understood. In developing T lymphocytes, low-intensity signals through the antigen receptor result in positive selection while more intense signals give rise to negative selection. By deleting the genetic locus encoding the regulatory B1 subunit of calcineurin specifically in thymocytes, we found an absolute requirement for calcineurin in positive selection. In contrast, calcineurin activity was dispensable in several models of negative selection. Unexpectedly, we found that removal of calcineurin activity from thymocytes results in inefficient ERK activation at the double-positive stage of thymocyte development, when selection occurs. These studies clarify the mechanism by which graded signals are converted to discrete outcomes in T cell development and further indicate that the developmental roles of calcineurin likely contribute to immunosuppression by calcineurin inhibitors.

Different requirements for CD40-DC154 interaction during thymic negative selection of CD4+ T cells

Rationale Self-reactive T cells are normally deleted in the thymus through negative selection. In addition to TCR engagement, negative selection is regulated by signals from co-stimulatory molecules, particularly CD154. Previous research has demonstrated negative selection to endogenously expressed antigens is dependent on CD40-CD154 interactions while negative selection to exogenously administered antigen is independent of CD154. Methods Transgenic animals from two different models of thymic negative selection were injected with mAb to CD154 or control antibody. Following treatment, cell populations were analyzed by flow cytometry. Results In this study we found differential effects of CD154 blockade on two different models of CD4+ T cell negative selection to endogenously expressed self-antigens. Treatment with anti-CD154 mAb resulted in accumulation of large numbers of functional auto-reactive T cells in the thymus of ANDxRO Tg animals. However, these animals had few transgenic cells in the periphery and the remaining few cells had been rendered anergic. In another model of negative selection, Act-mOVAxOTII Tg animals showed normal deletion of transgenic CD4+ T cells despite the presence of anti-CD154 mAb. Conclusions There are differing requirement for CD40-CD154 interaction in negative selection of CD4+ thymocytes.

Characterization of transcriptional regulation during negative selection in vivo.

Negative selection is the process whereby immature thymocytes expressing TCRs with high affinity for self-peptide:MHC complexes are induced to undergo apoptosis. The transcriptional events that occur as a result of TCR signaling during negative selection are not well-characterized. Using oligonucleotide arrays, we have identified 33 genes that exhibit changes in RNA levels in CD4(+)CD8(+) thymocytes during negative selection in vivo. Of 18 genes that have been further characterized, 13 are regulated in response to stimulation with Ag or anti-CD3 and anti-CD28 Abs ex vivo, indicating that these genes are regulated independently of activation of the peripheral immune system. These data also support the idea that anti-CD3/CD28-mediated thymocyte apoptosis is a valid model for negative selection in vivo. A detailed examination of the regulation of many of the identified genes in response to treatment with dexamethasone or gamma-radiation or in response to anti-CD3/anti-CD28 stimulation in the presence of pharmacological inhibitors of mitogen-activated protein kinase kinase kinase 1, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, calcineurin, and cyclin-dependent kinase 2 has facilitated the elucidation of a map of the transcriptional events that occur downstream of the TCR. These studies support a model whereby similar signal transduction pathways are activated by stimuli that induce positive and negative selection and are consistent with the idea that the balance between opposing proapoptotic and antiapoptotic pathways determines cell fate. The data presented in this study also suggest that calcineurin functions to amplify TCR signals by promoting sustained increases in the levels of specific transcripts.

Realization of a self-recognition algorithm based on the biological immune system

As the use of the computer is popularized, the damage from computer viruses and hacking by malicious users is increasing rapidly. To block the hacking that is an intrusion into a person's computer, and the viruses that destroy data, a study into an intrusion detection and virus detection system based on the biological immune system is in progress. In this article, we describe a model of positive and negative selection for self-recognition, which has a similar function to the cytotoxic T cells that play an important role in the biological immune system. We propose a self/nonself discrimination algorithm for a computer system, which will the important when we detect data infected by a computer virus, of data modified by an intrusion from outside. We also show the validity and effectiveness of the proposed self-recognition algorithm by a computer simulation of some infected data obtained from cell changes and string changes in the self-file.

Without peripheral interference, thymic deletion is mediated in a cohort of double-positive cells without classical activation.

Peripheral activation can cause bystander thymocyte death by eliciting a "cytokine storm." This event complicates in vivo studies using exogenous ligand-induced models of negative selection. A stable transgenic model that selectively eliminates peripheral CD4 cells has allowed us to analyze negative selection as direct cognate events in two T cell receptor transgenic mice, OT-II and DO11. Whereas cognate peptide induced a massive deletion in double-positive (DP) cells in mice with peripheral CD4 cells, this DP deletion was modest in mice lacking peripheral CD4 cells. Using BrdUrd and annexin V staining, we found that negative selection primarily occurs in a cohort of DP cells and the absence of single-positive (SP) cells is largely caused by reduction in the cohort of DP precursors. Moreover, the fates of DP cells and SP cells after antigen exposure were vastly different. Whereas SP cells up-regulated uniformly their CD69 and CD44 levels, increased their cell size, and survived after antigen exposure, DP cells had less CD69 and CD44 up-regulation, no size change, and promptly died. Thus, negative selection represents an "abortive" activation different from activation-induced cell death of mature T cells.