WorldWideScience

Sample records for accelerated foxp2 evolution

  1. Accelerated FoxP2 evolution in echolocating bats.

    Directory of Open Access Journals (Sweden)

    Gang Li

    Full Text Available FOXP2 is a transcription factor implicated in the development and neural control of orofacial coordination, particularly with respect to vocalisation. Observations that orthologues show almost no variation across vertebrates yet differ by two amino acids between humans and chimpanzees have led to speculation that recent evolutionary changes might relate to the emergence of language. Echolocating bats face especially challenging sensorimotor demands, using vocal signals for orientation and often for prey capture. To determine whether mutations in the FoxP2 gene could be associated with echolocation, we sequenced FoxP2 from echolocating and non-echolocating bats as well as a range of other mammal species. We found that contrary to previous reports, FoxP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats. We detected divergent selection (a change in selective pressure at FoxP2 between bats with contrasting sonar systems, suggesting the intriguing possibility of a role for FoxP2 in the evolution and development of echolocation. We speculate that observed accelerated evolution of FoxP2 in bats supports a previously proposed function in sensorimotor coordination.

  2. Evo-devo, deep homology and FoxP2: implications for the evolution of speech and language

    Science.gov (United States)

    Scharff, Constance; Petri, Jana

    2011-01-01

    The evolution of novel morphological features, such as feathers, involves the modification of developmental processes regulated by gene networks. The fact that genetic novelty operates within developmental constraints is the central tenet of the ‘evo-devo’ conceptual framework. It is supported by findings that certain molecular regulatory pathways act in a similar manner in the development of morphological adaptations, which are not directly related by common ancestry but evolved convergently. The Pax6 gene, important for vision in molluscs, insects and vertebrates, and Hox genes, important for tetrapod limbs and fish fins, exemplify this ‘deep homology’. Recently, ‘evo-devo’ has expanded to the molecular analysis of behavioural traits, including social behaviour, learning and memory. Here, we apply this approach to the evolution of human language. Human speech is a form of auditory-guided, learned vocal motor behaviour that also evolved in certain species of birds, bats and ocean mammals. Genes relevant for language, including the transcription factor FOXP2, have been identified. We review evidence that FoxP2 and its regulatory gene network shapes neural plasticity in cortico-basal ganglia circuits underlying the sensory-guided motor learning in animal models. The emerging picture can help us understand how complex cognitive traits can ‘descend with modification’. PMID:21690130

  3. Analysis list: Foxp2 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Foxp2 Liver,Pancreas + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Fo...xp2.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Foxp2.5.tsv http://dbarchive.biosciencedbc.j...p/kyushu-u/mm9/target/Foxp2.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Foxp2.Liver.tsv,http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Foxp2.Pancreas.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Liver.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Pancreas.gml ...

  4. FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it

    Energy Technology Data Exchange (ETDEWEB)

    Tanabe, Yuko [Division of Development and Differentiation, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigasi, Kodaira 187-8511 (Japan); Fujita, Eriko [Division of Development and Differentiation, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigasi, Kodaira 187-8511 (Japan); Department of Pediatrics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498 (Japan); Momoi, Takashi, E-mail: momoi@iuhw.ac.jp [Division of Development and Differentiation, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigasi, Kodaira 187-8511 (Japan); Center for Medical Science, International University of Health and Welfare, 2600-1 Kitakanamaru, Otawara, Tochigi 324-8501 (Japan)

    2011-07-08

    Highlights: {yields} We isolated protection of telomeres 1 (POT1) as a FOXP2-associated protein by a yeast two-hybrid. {yields} FOXP2 associated and co-localized with POT1 in the nuclei. {yields} FOXP2(R553H) also co-localized with POT1 in both the cytoplasm and nuclei. {yields} FOXP2(R553H) partially prevented the nuclear translocation of POT1. {yields} FOXP2(R553H) mutation may be associated with the pathogenesis of speech-language disorder. -- Abstract: FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein with a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech-language disorder with FOXP2(R553H) mutation.

  5. FOXP2 promotes the nuclear translocation of POT1, but FOXP2(R553H), mutation related to speech-language disorder, partially prevents it

    International Nuclear Information System (INIS)

    Tanabe, Yuko; Fujita, Eriko; Momoi, Takashi

    2011-01-01

    Highlights: → We isolated protection of telomeres 1 (POT1) as a FOXP2-associated protein by a yeast two-hybrid. → FOXP2 associated and co-localized with POT1 in the nuclei. → FOXP2(R553H) also co-localized with POT1 in both the cytoplasm and nuclei. → FOXP2(R553H) partially prevented the nuclear translocation of POT1. → FOXP2(R553H) mutation may be associated with the pathogenesis of speech-language disorder. -- Abstract: FOXP2 is a forkhead box-containing transcription factor with several recognizable sequence motifs. However, little is known about the FOXP2-associated proteins except for C-terminal binding protein (CtBP). In the present study, we attempted to isolate the FOXP2-associated protein with a yeast two-hybrid system using the C-terminal region, including the forkhead domain, as a bait probe, and identified protection of telomeres 1 (POT1) as a FOXP2-associated protein. Immunoprecipitation assay confirmed the association with FOXP2 and POT1. POT1 alone localized in the cytoplasm but co-localized with FOXP2 and the forkhead domain of FOXP2 in nuclei. However, both FOXP2 with mutated nuclear localization signals and (R553H) mutated forkhead, which is associated with speech-language disorder, prevented the nuclear translocation of POT1. These results suggest that FOXP2 is a binding partner for the nuclear translocation of POT1. As loss of POT1 function induces the cell arrest, the impaired nuclear translocation of POT1 in the developing neuronal cells may be associated with the pathogenesis of speech-language disorder with FOXP2(R553H) mutation.

  6. Intracellular distribution of a speech/language disorder associated FOXP2 mutant

    International Nuclear Information System (INIS)

    Mizutani, Akifumi; Matsuzaki, Ayumi; Momoi, Mariko Y.; Fujita, Eriko; Tanabe, Yuko; Momoi, Takashi

    2007-01-01

    Although a mutation (R553H) in the forkhead box (FOX)P2 gene is associated with speech/language disorder, little is known about the function of FOXP2 or its relevance to this disorder. In the present study, we identify the forkhead nuclear localization domains that contribute to the cellular distribution of FOXP2. Nuclear localization of FOXP2 depended on two distally separated nuclear localization signals in the forkhead domain. A truncated version of FOXP2 lacking the leu-zip, Zn 2+ finger, and forkhead domains that was observed in another patient with speech abnormalities demonstrated an aggregated cytoplasmic localization. Furthermore, FOXP2 (R553H) mainly exhibited a cytoplasmic localization despite retaining interactions with nuclear transport proteins (importin α and β). Interestingly, wild type FOXP2 promoted the transport of FOXP2 (R553H) into the nucleus. Mutant and wild type FOXP2 heterodimers in the nucleus or FOXP2 R553H in the cytoplasm may underlie the pathogenesis of the autosomal dominant speech/language disorder

  7. Generation of mice with a conditional Foxp2 null allele

    OpenAIRE

    French, C.; Groszer, M.; Preece, C.; Coupe, A.; Rajewsky, K.; Fisher, S.

    2007-01-01

    Disruptions of the human FOXP2 gene cause problems with articulation of complex speech sounds, accompanied by impairment in many aspects of language ability. The FOXP2/Foxp2 transcription factor is highly similar in humans and mice, and shows a complex conserved expression pattern, with high levels in neuronal subpopulations of the cortex, striatum, thalamus, and cerebellum. In the present study we generated mice in which loxP sites flank exons 12?14 of Foxp2; these exons encode the DNA-bindi...

  8. Expression analysis of the speech-related genes FoxP1 and FoxP2 and their relation to singing behavior in two songbird species

    Science.gov (United States)

    Chen, Qianqian; Heston, Jonathan B.; Burkett, Zachary D.; White, Stephanie A.

    2013-01-01

    SUMMARY Humans and songbirds are among the rare animal groups that exhibit socially learned vocalizations: speech and song, respectively. These vocal-learning capacities share a reliance on audition and cortico-basal ganglia circuitry, as well as neurogenetic mechanisms. Notably, the transcription factors Forkhead box proteins 1 and 2 (FoxP1, FoxP2) exhibit similar expression patterns in the cortex and basal ganglia of humans and the zebra finch species of songbird, among other brain regions. Mutations in either gene are associated with language disorders in humans. Experimental knock-down of FoxP2 in the basal ganglia song control region Area X during song development leads to imprecise copying of tutor songs. Moreover, FoxP2 levels decrease naturally within Area X when zebra finches sing. Here, we examined neural expression patterns of FoxP1 and FoxP2 mRNA in adult Bengalese finches, a songbird species whose songs exhibit greater sequence complexity and increased reliance on audition for maintaining their quality. We found that FoxP1 and FoxP2 expression in Bengalese finches is similar to that in zebra finches, including strong mRNA signals for both factors in multiple song control nuclei and enhancement of FoxP1 in these regions relative to surrounding brain tissue. As with zebra finches, when Bengalese finches sing, FoxP2 is behaviorally downregulated within basal ganglia Area X over a similar time course, and expression negatively correlates with the amount of singing. This study confirms that in multiple songbird species, FoxP1 expression highlights song control regions, and regulation of FoxP2 is associated with motor control of song. PMID:24006346

  9. Segregating polymorphisms of FOXP2 are associated with measures of inner speech, speech fluency and strength of handedness in a healthy population.

    Science.gov (United States)

    Crespi, Bernard; Read, Silven; Hurd, Peter

    2017-10-01

    We genotyped a healthy population for three haplotype-tagging FOXP2 SNPs, and tested for associations of these SNPs with strength of handedness and questionnaire-based metrics of inner speech characteristics (ISP) and speech fluency (FLU), as derived from the Schizotypal Personality Questionnaire-BR. Levels of mixed-handedness were positively correlated with ISP and FLU, supporting prior work on these two domains. Genotype for rs7799109, a SNP previously linked with lateralization of left frontal regions underlying language, was associated with degree of mixed handedness and with scores for ISP and FLU phenotypes. Genotype of rs1456031, which has previously been linked with auditory hallucinations, was also associated with ISP phenotypes. These results provide evidence that FOXP2 SNPs influence aspects of human inner speech and fluency that are related to lateralized phenotypes, and suggest that the evolution of human language, as mediated by the adaptive evolution of FOXP2, involved features of inner speech. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2.

    Science.gov (United States)

    Zuo, Tao; Liu, Runhua; Zhang, Huiming; Chang, Xing; Liu, Yan; Wang, Lizhong; Zheng, Pan; Liu, Yang

    2007-12-01

    S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpress ERBB2/HER2, additional FOXP3 targets may be involved in its tumor suppressor activity. Here, we show that mammary carcinomas from mice heterozygous for a Foxp3 mutation exhibited increased Skp2 expression. Ectopic expression of FOXP3 in mouse mammary cancer cells repressed SKP2 expression with a corresponding increase in p27 and polyploidy. Conversely, siRNA silencing of the FOXP3 gene in human mammary epithelial cells increased SKP2 expression. We also show that Foxp3 directly interacted with and repressed the Skp2 promoter. Moreover, the analysis of over 200 primary breast cancer samples revealed an inverse correlation between FOXP3 and SKP2 levels. Finally, we demonstrated that downregulation of SKP2 was critical for FOXP3-mediated growth inhibition in breast cancer cells that do not overexpress ERBB2/HER2. Our data provide genetic, biochemical, and functional evidence that FOXP3 is a novel transcriptional repressor for the oncogene SKP2.

  11. circ-SHKBP1 Regulates the Angiogenesis of U87 Glioma-Exposed Endothelial Cells through miR-544a/FOXP1 and miR-379/FOXP2 Pathways

    Directory of Open Access Journals (Sweden)

    Qianru He

    2018-03-01

    Full Text Available Circular RNAs (circRNAs are a type of endogenous non-coding RNAs, which have been considered to mediate diverse tumorigenesis including angiogenesis. The present study aims to elucidate the potential role and molecular mechanism of circ-SHKBP1 in regulating the angiogenesis of U87 glioma-exposed endothelial cells (GECs. The expression of circ-SHKBP1, but not linear SHKBP1, was significantly upregulated in GECs compared with astrocyte-exposed endothelial cells (AECs. circ-SHKBP1 knockdown inhibited the viability, migration, and tube formation of GECs dramatically. The expressions of miR-379/miR-544a were downregulated in GECs, and circ-SHKBP1 functionally targeted miR-544a/miR-379 in an RNA-induced silencing complex (RISC manner. Dual-luciferase reporter assay demonstrated that forkhead box P1/P2 (FOXP1/FOXP2 were targets of miR-544a/miR-379. The expressions of FOXP1/FOXP2 were upregulated in GECs, and silencing of FOXP1/FOXP2 inhibited the viability, migration, and tube formation of GECs. Meanwhile, FOXP1/FOXP2 promoted angiogenic factor with G patch and FHA domains 1 (AGGF1 expression at the transcriptional level. Furthermore, knockdown of AGGF1 suppressed the viability, migration, and tube formation of GECs via phosphatidylinositol 3-kinase (PI3K/AKT and extracellular signal-regulated kinase (ERK1/2 pathways. Taken together, the present study demonstrated that circ-SHKBP1 regulated the angiogenesis of GECs through miR-544a/FOXP1 and miR-379/FOXP2 pathways, and these findings might provide a potential target and effective strategy for combined therapy of gliomas.

  12. Sobre el significado del descubrimiento del gen FOXP2

    OpenAIRE

    Longa Martínez, Víctor Manuel

    2006-01-01

    El reciente descubrimiento del gen FOXP2 ha ofrecido la primera evidencia clara de la base genética del lenguaje, mostrando una correlación inequívoca desde la perspectiva genética entre una versión mutada de F0XP2 y los trastornos lingüísticos de diferente tipo sufridos por una familia inglesa, conocida como KE. El objetivo central del presente trabajo es discutir diferentes aspectos relacionados con tal descubrimiento; especialmente, la discusión del significado de FOXP2 con ...

  13. Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

    Directory of Open Access Journals (Sweden)

    Lea J. Hachigian

    2017-12-01

    Full Text Available Summary: Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington’s disease (HD. The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT. Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD. : Hachigian et al. demonstrate that manipulating levels of the striatum-enriched transcription factor Foxp2 can either rescue or mimic HD-associated behaviors in vivo. They link Foxp2 to the post-developmental regulation of the structure and function of the corticostriatal synapse. Keywords: Huntington’s disease, Foxp2, striatum, corticostriatal synapse

  14. FOXP2-positive diffuse large B-cell lymphomas exhibit a poor response to R-CHOP therapy and distinct biological signatures

    DEFF Research Database (Denmark)

    Wong, Kah Keng; Gascoyne, Duncan M; Soilleux, Elizabeth J

    2016-01-01

    frequency of FOXP2 expression significantly correlated with FOXP1-positivity (P = 0.0187), and FOXP1 co-immunoprecipitated FOXP2 from ABC-DLBCL cells indicating that these proteins can co-localize in a multi-protein complex. FOXP2-positive DLBCL had reduced expression of HIP1R (P = 0.0348), which...

  15. Phonological working memory and FOXP2.

    Science.gov (United States)

    Schulze, Katrin; Vargha-Khadem, Faraneh; Mishkin, Mortimer

    2018-01-08

    The discovery and description of the affected members of the KE family (aKE) initiated research on how genes enable the unique human trait of speech and language. Many aspects of this genetic influence on speech-related cognitive mechanisms are still elusive, e.g. if and how cognitive processes not directly involved in speech production are affected. In the current study we investigated the effect of the FOXP2 mutation on Working Memory (WM). Half the members of the multigenerational KE family have an inherited speech-language disorder, characterised as a verbal and orofacial dyspraxia caused by a mutation of the FOXP2 gene. The core phenotype of the affected KE members (aKE) is a deficiency in repeating words, especially complex non-words, and in coordinating oromotor sequences generally. Execution of oromotor sequences and repetition of phonological sequences both require WM, but to date the aKE's memory ability in this domain has not been examined in detail. To do so we used a test series based on the Baddeley and Hitch WM model, which posits that the central executive (CE), important for planning and manipulating information, works in conjunction with two modality-specific components: The phonological loop (PL), specialized for processing speech-based information; and the visuospatial sketchpad (VSSP), dedicated to processing visual and spatial information. We compared WM performance related to CE, PL, and VSSP function in five aKE and 15 healthy controls (including three unaffected members of the KE family who do not have the FOXP2 mutation). The aKE scored significantly below this control group on the PL component, but not on the VSSP or CE components. Further, the aKE were impaired relative to the controls not only in motor (i.e. articulatory) output but also on the recognition-based PL subtest (word-list matching), which does not require speech production. These results suggest that the aKE's impaired phonological WM may be due to a defect in subvocal

  16. FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells.

    Science.gov (United States)

    Liu, Shuo; Zhang, Cun; Zhang, Kuo; Gao, Yuan; Wang, Zhaowei; Li, Xiaoju; Cheng, Guang; Wang, Shuning; Xue, Xiaochang; Li, Weina; Zhang, Wei; Zhang, Yingqi; Xing, Xianghui; Li, Meng; Hao, Qiang

    2017-07-04

    Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFκB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFκB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells.

  17. Ultrasonic vocalizations of adult male Foxp2-mutant mice: behavioral contexts of arousal and emotion.

    Science.gov (United States)

    Gaub, S; Fisher, S E; Ehret, G

    2016-02-01

    Adult mouse ultrasonic vocalizations (USVs) occur in multiple behavioral and stimulus contexts associated with various levels of arousal, emotion and social interaction. Here, in three experiments of increasing stimulus intensity (water; female urine; male interacting with adult female), we tested the hypothesis that USVs of adult males express the strength of arousal and emotion via different USV parameters (18 parameters analyzed). Furthermore, we analyzed two mouse lines with heterozygous Foxp2 mutations (R552H missense, S321X nonsense), known to produce severe speech and language disorders in humans. These experiments allowed us to test whether intact Foxp2 function is necessary for developing full adult USV repertoires, and whether mutations of this gene influence instinctive vocal expressions based on arousal and emotion. The results suggest that USV calling rate characterizes the arousal level, while sound pressure and spectrotemporal call complexity (overtones/harmonics, type of frequency jumps) may provide indices of levels of positive emotion. The presence of Foxp2 mutations did not qualitatively affect the USVs; all USV types that were found in wild-type animals also occurred in heterozygous mutants. However, mice with Foxp2 mutations displayed quantitative differences in USVs as compared to wild-types, and these changes were context dependent. Compared to wild-type animals, heterozygous mutants emitted mainly longer and louder USVs at higher minimum frequencies with a higher occurrence rate of overtones/harmonics and complex frequency jump types. We discuss possible hypotheses about Foxp2 influence on emotional vocal expressions, which can be investigated in future experiments using selective knockdown of Foxp2 in specific brain circuits. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  18. Interaction between MAOA and FOXP2 in association with autism and verbal communication in a Korean population.

    Science.gov (United States)

    Park, YoungJoon; Won, SeongSik; Nam, Min; Chung, Joo-Ho; Kwack, KyuBum

    2014-12-01

    Expression levels of monoamine oxidase A (MAOA), the enzyme that related to monoamine neurotransmitters metabolism such as serotonin, are related to schizophrenia and autism spectrum disorder. Forkhead box protein P2 (FOXP2), a transcription factor, is associated with abnormal language development and is expressed in several areas of the central nervous system in response to serotonin. For this reason, we undertook interaction analysis between MAOA and FOXP2 in autism spectrum disorder, including testing the verbal communication score of the childhood autism rating scale. In interaction analysis, the FOXP2-TCGC (rs12531289-rs1350135-rs10230087-rs2061183) diplotype and MAOA-TCG (rs6323-rs1801291-rs3027407) haplotype were significantly associated with autism spectrum disorder in males. However, when the interaction term was omitted, neither MAOA nor FOXP2 was associated with autism spectrum disorder or verbal communication. These results indicate that language and speech ability is affected by an interaction between FOXP2 and MAOA, but not by either gene separately. © The Author(s) 2013.

  19. Interleukin 4 promotes the development of ex-Foxp3 Th2 cells during immunity to intestinal helminths

    Science.gov (United States)

    Coomes, Stephanie M.; Kannan, Yashaswini; Entwistle, Lewis J.; Perez-Lloret, Jimena; Czieso, Stephanie

    2017-01-01

    Immunity to intestinal helminth infections requires the rapid activation of T helper 2 cells (Th2 cells). However, simultaneous expansion of CD4+Foxp3+ regulatory T cells (T reg cells) impedes protective responses, resulting in chronic infections. The ratio between T reg and effector T cells can therefore determine the outcome of infection. The redifferentiation of T reg cells into Th cells has been identified in hyperinflammatory diseases. In this study, we asked whether ex–T reg Th2 cells develop and contribute to type-2 immunity. Using multigene reporter and fate-reporter systems, we demonstrate that a significant proportion of Th2 cells derive from Foxp3+ cells after Heligmosomoides polygyrus infection and airway allergy. Ex-Foxp3 Th2 cells exhibit characteristic Th2 effector functions and provide immunity to H. polygyrus. Through selective deletion of Il4ra on Foxp3+ cells, we further demonstrate IL-4 is required for the development of ex-Foxp3 Th2 cells. Collectively, our findings indicate that converting T reg cells into Th2 cells could concomitantly enhance Th2 cells and limit T reg cell–mediated suppression. PMID:28507062

  20. The plateau zokors' learning and memory ability is related to the high expression levels of foxP2 in the brain.

    Science.gov (United States)

    Ma, Ben-Yuan; Wei, Lian; Sun, Sheng-Zhen; Wang, Duo-Wei; Wei, Deng-Bang

    2014-04-25

    Plateau zokor (Myospalax baileyi) is a subterranean mammal. Plateau zokor has high learning and memory ability, and can determine the location of blocking obstacles in their tunnels. Forkhead box p2 (FOXP2) is a transcription factor implicated in the neural control of orofacial coordination and sensory-motor integration, particularly with respect to learning, memory and vocalization. To explore the association of foxP2 with the high learning and memory ability of plateau zokor, the cDNA of foxP2 of plateau zokor was sequenced; by using plateau pika as control, the expression levels of foxP2 mRNA and FOXP2 protein in brain of plateau zokor were determined by real-time PCR and Western blot, respectively; and the location of FOXP2 protein in the brain of plateau zokor was determined by immunohistochemistry. The result showed that the cDNA sequence of plateau zokor foxP2 was similar to that of other mammals and the amino acid sequences showed a relatively high degree of conservation, with the exception of two particular amino acid substitutions [a Gln (Q)-to-His (H) change at position 231 and a Ser (S)-to-Ile (I) change at position 235]. Higher expression levels of foxP2 mRNA (3-fold higher) and FOXP2 protein (>2-fold higher) were detected in plateau zokor brain relative to plateau pika brain. In plateau zokor brain, FOXP2 protein was highly expressed in the cerebral cortex, thalamus and the striatum (a basal ganglia brain region). The results suggest that the high learning and memory ability of plateau zokor is related to the high expression levels of foxP2 in the brain.

  1. Activation-dependent mitochondrial translocation of Foxp3 in human hepatocytes

    International Nuclear Information System (INIS)

    Rojas, Joselyn; Teran-Angel, Guillermo; Barbosa, Luisa; Peterson, Darrell L.; Berrueta, Lisbeth; Salmen, Siham

    2016-01-01

    Foxp3 is considered to be the master regulator for the development and function of regulatory T cells (Treg). Recently Foxp3, has been detected in extra lymphoid tissue, and in hepatocytes and has been associated with hepatocellular carcinoma (HCC), although its role has not been defined. Since it is expected that there is a relationship between protein localization, activity and cellular function, the aim of this study was to explore the subcellular localization of Foxp3 in resting and stimulated human hepatocytes. Foxp3 expression was measured by flow cytometry, subcellular fractioning, and immunofluorescence, and this data was used to track the shuttling of Foxp3 in different subcellular compartments in hepatocytes (HepG2 cell line), stimulated by using the PKC activators (PMA), core and preS1/2 antigen from hepatitis B virus (HBV). Our data shows that besides the nuclear location, mitochondrial translocation was detected after stimulation with PMA and at to a lesser extent, with preS1/2. In addition, Foxp3 is localizes at outer mitochondrial membrane. These results suggest a non-canonical role of Foxp3 in the mitochondrial compartment in human hepatocytes, and opens a new field about their role in liver damages during HBV infection. - Highlights: • The expression and subcellular distribution of Foxp3, is modulated by PMA and preS1/2. • PMA and preS1/2 increase Foxp3 expression on HepG2. • PMA and preS1/2 induce foxp3 enrichment at mitochondrial, microsomal and nuclear compartments. • Results suggest a non-canonical function of Foxp3 or a mitochondrial transcriptional activity.

  2. Activation-dependent mitochondrial translocation of Foxp3 in human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, Joselyn; Teran-Angel, Guillermo; Barbosa, Luisa [Instituto de Inmunología Clínica, Facultad de Medicina, Universidad de Los Andes, Merida (Venezuela, Bolivarian Republic of); Peterson, Darrell L. [Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA (United States); Berrueta, Lisbeth, E-mail: lberruet@ula.ve [Instituto de Inmunología Clínica, Facultad de Medicina, Universidad de Los Andes, Merida (Venezuela, Bolivarian Republic of); Division of Preventive Medicine, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States); Salmen, Siham, E-mail: sihamsa@ula.ve [Instituto de Inmunología Clínica, Facultad de Medicina, Universidad de Los Andes, Merida (Venezuela, Bolivarian Republic of)

    2016-05-01

    Foxp3 is considered to be the master regulator for the development and function of regulatory T cells (Treg). Recently Foxp3, has been detected in extra lymphoid tissue, and in hepatocytes and has been associated with hepatocellular carcinoma (HCC), although its role has not been defined. Since it is expected that there is a relationship between protein localization, activity and cellular function, the aim of this study was to explore the subcellular localization of Foxp3 in resting and stimulated human hepatocytes. Foxp3 expression was measured by flow cytometry, subcellular fractioning, and immunofluorescence, and this data was used to track the shuttling of Foxp3 in different subcellular compartments in hepatocytes (HepG2 cell line), stimulated by using the PKC activators (PMA), core and preS1/2 antigen from hepatitis B virus (HBV). Our data shows that besides the nuclear location, mitochondrial translocation was detected after stimulation with PMA and at to a lesser extent, with preS1/2. In addition, Foxp3 is localizes at outer mitochondrial membrane. These results suggest a non-canonical role of Foxp3 in the mitochondrial compartment in human hepatocytes, and opens a new field about their role in liver damages during HBV infection. - Highlights: • The expression and subcellular distribution of Foxp3, is modulated by PMA and preS1/2. • PMA and preS1/2 increase Foxp3 expression on HepG2. • PMA and preS1/2 induce foxp3 enrichment at mitochondrial, microsomal and nuclear compartments. • Results suggest a non-canonical function of Foxp3 or a mitochondrial transcriptional activity.

  3. Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria.

    Science.gov (United States)

    Turner, Samantha J; Hildebrand, Michael S; Block, Susan; Damiano, John; Fahey, Michael; Reilly, Sheena; Bahlo, Melanie; Scheffer, Ingrid E; Morgan, Angela T

    2013-09-01

    Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems. Copyright © 2013 Wiley Periodicals, Inc.

  4. FOXP3-specific immunity

    DEFF Research Database (Denmark)

    Andersen, Mads Hald

    2013-01-01

    Forkhead box P3 (FOXP3)-specific cytotoxic CD8(+) T cells are present among human peripheral blood mononuclear cells (PBMCs), especially in cancer patients. Such T lymphocytes are able not only to specifically recognize dendritic cells (DCs) that have been exposed to recombinant FOXP3 and regulat...... and regulatory T cells, but also to kill FOXP3(+) malignant T cells. The natural occurrence of FOXP3-specific cytotoxic T lymphocytes among human PBMCs suggests a general role for these cells in the complex network of immune regulation....

  5. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2

    OpenAIRE

    Zuo, Tao; Liu, Runhua; Zhang, Huiming; Chang, Xing; Liu, Yan; Wang, Lizhong; Zheng, Pan; Liu, Yang

    2007-01-01

    S-phase kinase-associated protein 2 (SKP2) is a component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex. Overexpression of SKP2 results in cell cycle dysregulation and carcinogenesis; however, the genetic lesions that cause this upregulation are poorly understood. We recently demonstrated that forkhead box P3 (FOXP3) is an X-linked breast cancer suppressor and an important repressor of the oncogene ERBB2/HER2. Since FOXP3 suppresses tumor growth regardless of whether the tumors overexpres...

  6. A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering.

    Science.gov (United States)

    Han, Tae-Un; Park, John; Domingues, Carlos F; Moretti-Ferreira, Danilo; Paris, Emily; Sainz, Eduardo; Gutierrez, Joanne; Drayna, Dennis

    2014-09-01

    A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of

  7. β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.

    Science.gov (United States)

    Johnson, Mark C; Garland, Alaina L; Nicolson, Sarah C; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

    2013-11-01

    Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.

  8. FOXP3 Expression in GARP-Transduced Helper T Cells Is Not Associated with FOXP3 TSDR Demethylation.

    Science.gov (United States)

    Kehrmann, Jan; Zeschnigk, Michael; Buer, Jan; Probst-Kepper, Michael

    2011-10-01

    AIM: Glycoprotein A repetitions predominant (GARP or LRRC32) represents a human regulatory CD4+ CD25(hi) FOXP3+ T (T(reg)) cell-specific receptor that controls FOXP3. Ectopic expression of GARP in helper T (T(h)) cells has been shown to be sufficient for the induction of FOXP3 and generation of a stable regulatory phenotype. Since expression of FOXP3 in Treg cells is epigenetically controlled by a conserved motif, the so-called T(reg)-specific demethylated region (TSDR), we asked whether GARP-mediated upregulation of FOXP3 in Th cells is similarly accompanied by demethylation of the TSDR. METHODS: DNA methylation of the FOXP3 TSDR was analyzed by direct sequencing of polymerase chain reaction (PCR) products from bisulfite-treated genomic DNA. RESULTS: Although GARP-transduced T(h) cells exhibit constitutive FOXP3 expression and a regulatory phenotype, the FOXP3 TSDR is completely methylated as in naive T(h) cells. GARP-mediated FOXP3 upregulation in T(h) cells is not associated with T(reg)-specific demethylation of the FOXP3 TSDR. CONCLUSION: Although GARP-engineered T(h) cells exhibit stable FOXP3 expression and a phenotypic reprogramming towards T(reg) cells in vitro, these cells do not completely mimic the epigenotype of natural T(reg) cells. Thus, concepts based on the genetic modification of T(h) cells as cellular therapies to treat autoimmune diseases or to control transplantation tolerance should be critically tested before any clinical application.

  9. Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain.

    Science.gov (United States)

    Blane, Ashleigh; Fanucchi, Sylvia

    2015-06-30

    Forkhead box P2 (FOXP2) is a transcription factor expressed in cardiovascular, intestinal, and neural tissues during embryonic development and is implicated in language development. FOXP2 like other FOX proteins contains a DNA binding domain known as the forkhead domain (FHD). The FHD interacts with DNA by inserting helix 3 into the major groove. One of these DNA-protein interactions is a direct hydrogen bond that is formed with His554. FOXP2 is localized in the nuclear compartment that has a pH of 7.5. Histidine contains an imidazole side chain in which the amino group typically has a pKa of ~6.5. It seems possible that pH fluctuations around 6.5 may result in changes in the protonation state of His554 and thus the ability of the FOXP2 FHD to bind DNA. To investigate the effect of pH on the FHD, both the structure and the binding affinity were studied in the pH range of 5-9. This was done in the presence and absence of DNA. The structure was assessed using size exclusion chromatography, far-UV circular dichroism, and intrinsic and extrinsic fluorescence. The results indicated that while pH did not affect the secondary structure in the presence or absence of DNA, the tertiary structure was pH sensitive and the protein was less compact at low pH. Furthermore, the presence of DNA caused the protein to become more compact at low pH and also had the potential to increase the dimerization propensity. Fluorescence anisotropy was used to investigate the effect of pH on the FOXP2 FHD DNA binding affinity. It was found that pH had a direct effect on binding affinity. This was attributed to the altered hydrogen bonding patterns upon protonation or deprotonation of His554. These results could implicate pH as a means of regulating transcription by the FOXP2 FHD, which may also have repercussions for the behavior of this protein in cancer cells.

  10. The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest.

    Science.gov (United States)

    Gascoyne, Duncan M; Spearman, Hayley; Lyne, Linden; Puliyadi, Rathi; Perez-Alcantara, Marta; Coulton, Les; Fisher, Simon E; Croucher, Peter I; Banham, Alison H

    2015-01-01

    Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up-regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology.

  11. Prospective investigation of FOXP1 syndrome.

    Science.gov (United States)

    Siper, Paige M; De Rubeis, Silvia; Trelles, Maria Del Pilar; Durkin, Allison; Di Marino, Daniele; Muratet, François; Frank, Yitzchak; Lozano, Reymundo; Eichler, Evan E; Kelly, Morgan; Beighley, Jennifer; Gerdts, Jennifer; Wallace, Arianne S; Mefford, Heather C; Bernier, Raphael A; Kolevzon, Alexander; Buxbaum, Joseph D

    2017-01-01

    Haploinsufficiency of the forkhead-box protein P1 ( FOXP1 ) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1 . Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early

  12. Immunologic targeting of FOXP3 in inflammatory breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Smita Nair

    Full Text Available The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC cells, SUM149 (triple negative, ErbB1-activated and SUM190 (ErbB2-overexpressing. Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149 derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.

  13. The importance of Foxp3 antibody and fixation/permeabilization buffer combinations in identifying CD4+CD25+Foxp3+ regulatory T cells.

    Science.gov (United States)

    Law, Jacqueline P; Hirschkorn, Dale F; Owen, Rachel E; Biswas, Hope H; Norris, Philip J; Lanteri, Marion C

    2009-12-01

    Foxp3 is a key marker for CD4(+) regulatory T cells (T(regs)) and was used in developing a multiparameter flow cytometric panel to identify T(regs). Achieving reproducible staining and analysis first required optimization of Foxp3 staining. We present a comparative study of PCH101, 236A/E7, 3G3, 206D, 150D, and 259D/C7 clones of anti-human-Foxp3 antibodies used in combination with five different fixation/permeabilization buffers. Staining for CD25, CD152, and CD127 was also compared between fixation/permeabilization treatments. Promising antibody/buffer combinations were tested in a panel of peripheral blood mononuclear cells from 10 individuals, and then on fresh versus frozen cells from four individuals. Finally, different fluorochromes coupled to two representative antibodies were compared to optimize separation of Foxp3(+) from Foxp3(-) events. Foxp3 gates were set using two gating strategies based on CD127(+)CD25(-) "non-T(regs)" or based on isotype controls. For Foxp3 staining, the best conditions for fixation/permeabilization were obtained using the eBioscience Foxp3, Imgenex, BioLegend, and BD Foxp3 buffers. Comparing results from 10 subjects, 259D/C7, PCH101, 236A/E7, and 206D antibodies yielded statistically higher levels of Foxp3 cells than those by 150D and 3G3 antibodies (mean = 6.9, 5.1, 4.7, and 3.7% compared with 1.7, and 0.3% of CD25(+)Foxp3(+) events within CD4(+) cells, respectively). Importantly, the "nonspecificity" of some antibodies observed with a Foxp3 gate based on isotype controls could be eliminated by setting the Foxp3 gate on "non-T(regs)". Better separation of Foxp3(+) and Foxp3(-) populations was observed using the PCH101 clone coupled to Alexa647 compared with FITC or the 259D/C7 clone coupled to PE compared with Alexa488 fluorochrome. Foxp3 staining can be highly variable and depends on the choice of antibody/buffer pair and the fluorochrome used. Selecting the correct population for setting the Foxp3 gate is critical to avoid

  14. Foxp3 expression in human cancer cells

    Directory of Open Access Journals (Sweden)

    Gourgoulianis Konstantinos I

    2008-04-01

    Full Text Available Abstract Objective Transcription factor forkhead box protein 3 (Foxp3 specifically characterizes the thymically derived naturally occurring regulatory T cells (Tregs. Limited evidence indicates that it is also expressed, albeit to a lesser extent, in tissues other than thymus and spleen, while, very recently, it was shown that Foxp3 is expressed by pancreatic carcinoma. This study was scheduled to investigate whether expression of Foxp3 transcripts and mature protein occurs constitutively in various tumor types. Materials and methods Twenty five tumor cell lines of different tissue origins (lung cancer, colon cancer, breast cancer, melanoma, erythroid leukemia, acute T-cell leukemia were studied. Detection of Foxp3 mRNA was performed using both conventional RT-PCR and quantitative real-time PCR while protein expression was assessed by immunocytochemistry and flow cytometry, using different antibody clones. Results Foxp3 mRNA as well as Foxp3 protein was detected in all tumor cell lines, albeit in variable levels, not related to the tissue of origin. This expression correlated with the expression levels of IL-10 and TGFb1. Conclusion We offer evidence that Foxp3 expression, characterizes tumor cells of various tissue origins. The biological significance of these findings warrants further investigation in the context of tumor immune escape, and especially under the light of current anti-cancer efforts interfering with Foxp3 expression.

  15. FOXP2 and the neuroanatomy of speech and language.

    Science.gov (United States)

    Vargha-Khadem, Faraneh; Gadian, David G; Copp, Andrew; Mishkin, Mortimer

    2005-02-01

    That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech.

  16. Cosmological evolution of vacuum and cosmic acceleration

    International Nuclear Information System (INIS)

    Kaya, Ali

    2010-01-01

    It is known that the unregularized expressions for the stress-energy tensor components corresponding to subhorizon and superhorizon vacuum fluctuations of a massless scalar field in a Friedmann-Robertson-Walker background are characterized by the equation of state parameters ω = 1/3 and ω = -1/3, which are not sufficient to produce cosmological acceleration. However, the form of the adiabatically regularized finite stress-energy tensor turns out to be completely different. By using the fact that vacuum subhorizon modes evolve nearly adiabatically and superhorizon modes have ω = -1/3, we approximately determine the regularized stress-energy tensor, whose conservation is utilized to fix the time dependence of the vacuum energy density. We then show that vacuum energy density grows from zero up to H 4 in about one Hubble time, vacuum fluctuations give positive acceleration of the order of H 4 /M 2 p and they can completely alter the cosmic evolution of the universe dominated otherwise by the cosmological constant, radiation or pressureless dust. Although the magnitude of the acceleration is tiny to explain the observed value today, our findings indicate that the cosmological backreaction of vacuum fluctuations must be taken into account in early stages of cosmic evolution.

  17. Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells

    Science.gov (United States)

    Patzelt, Thomas; Keppler, Selina J.; Gorka, Oliver; Thoene, Silvia; Wartewig, Tim; Reth, Michael; Förster, Irmgard; Lang, Roland; Buchner, Maike; Ruland, Jürgen

    2018-01-01

    The transcription factor Foxp1 is critical for early B cell development. Despite frequent deregulation of Foxp1 in B cell lymphoma, the physiological functions of Foxp1 in mature B cells remain unknown. Here, we used conditional gene targeting in the B cell lineage and report that Foxp1 disruption in developing and mature B cells results in reduced numbers and frequencies of follicular and B-1 B cells and in impaired antibody production upon T cell-independent immunization in vivo. Moreover, Foxp1-deficient B cells are impaired in survival even though they exhibit an increased capacity to proliferate. Transcriptional analysis identified defective expression of the prosurvival Bcl-2 family gene Bcl2l1 encoding Bcl-xl in Foxp1-deficient B cells, and we identified Foxp1 binding in the regulatory region of Bcl2l1. Transgenic overexpression of Bcl2 rescued the survival defect in Foxp1-deficient mature B cells in vivo and restored peripheral B cell numbers. Thus, our results identify Foxp1 as a physiological regulator of mature B cell survival mediated in part via the control of Bcl-xl expression and imply that this pathway might contribute to the pathogenic function of aberrant Foxp1 expression in lymphoma. PMID:29507226

  18. Fast accelerator driven subcritical system for energy production: nuclear fuel evolution

    International Nuclear Information System (INIS)

    Barros, Graiciany de P.; Pereira, Claubia; Veloso, Maria A.F.; Costa, Antonella L.

    2011-01-01

    Accelerators Driven Systems (ADS) are an innovative type of nuclear system, which is useful for long-lived fission product transmutation and fuel regeneration. The ADS consist of a coupling of a sub-critical nuclear core reactor and a proton beam produced by a particle accelerator. These particles are injected into a target for the neutrons production by spallation reactions. The neutrons are then used to maintain the fission chain in the sub-critical core. The aim of this study is to investigate the nuclear fuel evolution of a lead cooled accelerator driven system used for energy production. The fuel studied is a mixture based upon "2"3"2Th and "2"3"3U. Since thorium is an abundant fertile material, there is hope for the thorium-cycle fuels for an accelerator driven sub-critical system. The target is a lead spallation target and the core is filled with a hexagonal lattice. High energy neutrons are used to reduce the negative reactivity caused by the presence of protoactinium, since this effect is most pronounced in the thermal range of the neutron spectrum. For that reason, such material is not added moderator to the system. In this work is used the Monte Carlo code MCNPX 2.6.0, that presents the the depletion/ burnup capability. The k_e_f_f evolution, the neutron energy spectrum in the core and the nuclear fuel evolution using ADS source (SDEF) and kcode-mode are evaluated during the burnup. (author)

  19. FOXP1 forkhead transcription factor is associated with the pathogenesis of endometrial cancer

    Directory of Open Access Journals (Sweden)

    Makito Mizunuma

    2016-05-01

    Full Text Available Endometrial cancers are mostly estrogen-dependent. FOXP1 is a P subfamily of forkhead box (FOX, and known as an estrogen-responsive transcription factor. The aims of this study were to examine histological location of FOXP1 in normal and malignant endometrium, and to investigate a possible association between FOXP1 and other factors considered to be involved in pathogenesis of endometrial cancer. The levels of FOXP1, estrogen receptor (ERα, and ERβ expression were examined immunohistochemically in normal and malignant endometrium obtained from 75 women (8 normal, 8 atypical endometrial hyperplasia, and 59 endometrial cancers from grade 1 to 3. The effects of estrogen on ERα, FOXP1, KRAS, and PTEN expression were analyzed in telomerase-immortalized human endometrial stromal cells (T HESCs by Western blotting. Western blotting was also used to examine the effect of FOXP1 plasmid DNA or siRNA transfection on KRAS and PTEN expression in Ishikawa cells (well differentiated endometrioid adenocarcinoma, HEC-50B cells (poorly differentiated endometrioid adenocarcinoma, and T HESCs, respectively. FOXP1 was expressed in normal and malignant endometrium, but the rate of expression was different depending upon menstrual cycle and pathological grade of malignancy. FOXP1 expression in nucleus and cytoplasm of grade 3 endometrioid cancers was significantly lower than that of grade 1 and 2 ones. Estradiol increased levels of FOXP1 and KRAS expression in a dose- and time-dependent manner in T HESCs cells, and FOXP1 transfection or knockdown led to increase or decrease of KRAS expression but not PTEN. KRAS expression level was significantly related to FOXP1 and ERα levels in cancer tissues. Estradiol did not affect KRAS expression in T HESCs cells transfected with FOXP1 siRNA. These results suggest that FOXP1 is involved in estrogen dependent endometrial cancers through KRAS pathway.

  20. Genetic polymorphism in FOXP3 gene: imbalance in regulatory T ...

    Indian Academy of Sciences (India)

    2013-04-02

    Apr 2, 2013 ... In contrast, high Treg levels have been reported in peripheral blood, lymph ... patients with different types of cancer. ... Therefore, in the present study, the relationship between genetic ... (amino acids 240–261) and a carboxy-terminal forkhead ... FOXP3 in tumour cells indicates that FOXP3-targeted drugs.

  1. Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: clinical report and review.

    Science.gov (United States)

    Lennon, P A; Cooper, M L; Peiffer, D A; Gunderson, K L; Patel, A; Peters, Sarika; Cheung, S W; Bacino, C A

    2007-04-15

    We report on a young male with moderate mental retardation, dysmorphic features, and language delay who is deleted for 7q31.1-7q31.31. His full karyotype is 46,XY,der(7)del(7)(q31.1q31.31)ins(10;7)(q24.3;q31.1q31.31)mat. This child had language impairment, including developmental verbal dyspraxia, but did not meet criteria for autism according to standardized ADOS testing. Our patient's deletion, which is the smallest reported deletion including FOXP2, adds to the body of evidence that supports the role of FOXP2 in speech and language impairment, but not in autism. A reported association between autism and deletions of WNT2, a gene also deleted in our patient, is likewise not supported by our case. Previously, fine mapping with microsatellites markers within in a large three-generation family, in which half the members had severe specific language impairment, aided the localization of the SPCH1 locus to 7q31 within markers D7S2459 (107.1 Mb) and D7S643 (120.5 Mb). Additionally, chromosome rearrangement of 7q31 and mutational analyses have supported the growing evidence that FOXP2, a gene within the SPCH1 region, is involved with speech and language development. It is unclear however whether the AUTS1 (autistic spectrum 1) locus, highly linked to 7q31, overlaps with the SPCH1 and FOXP2. Copyright 2007 Wiley-Liss, Inc.

  2. Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T cells is independent of direct TCR stimulation and requires IL-2, IL-10 and TGFbeta.

    Directory of Open Access Journals (Sweden)

    Anja Scholzen

    2009-08-01

    Full Text Available CD4(+CD25(+Foxp3(+ regulatory T cells (Tregs regulate disease-associated immunity and excessive inflammatory responses, and numbers of CD4(+CD25(+Foxp3(+ Tregs are increased during malaria infection. The mechanisms governing their generation, however, remain to be elucidated. In this study we investigated the role of commonly accepted factors for Foxp3 induction, TCR stimulation and cytokines such as IL-2, TGFbeta and IL-10, in the generation of human CD4(+CD25(+Foxp3(+ T cells by the malaria parasite Plasmodium falciparum. Using a co-culture system of malaria-infected red blood cells (iRBCs and peripheral blood mononuclear cells from healthy individuals, we found that two populations of Foxp3(hi and Foxp3(int CD4(+CD25(hi T cells with a typical Treg phenotype (CTLA-4(+, CD127(low, CD39(+, ICOS(+, TNFRII(+ were induced. Pro-inflammatory cytokine production was confined to the Foxp3(int subset (IFNgamma, IL-4 and IL-17 and inversely correlated with high relative levels of Foxp3(hi cells, consistent with Foxp3(hi CD4 T cell-mediated inhibition of parasite-induced effector cytokine T cell responses. Both Foxp3(hi and Foxp3(int cells were derived primarily from proliferating CD4(+CD25(- T cells with a further significant contribution from CD25(+Foxp3(+ natural Treg cells to the generation of the Foxp3(hi subset. Generation of Foxp3(hi, but not Foxp3(int, cells specifically required TGFbeta1 and IL-10. Add-back experiments showed that monocytes expressing increased levels of co-stimulatory molecules were sufficient for iRBC-mediated induction of Foxp3 in CD4 T cells. Foxp3 induction was driven by IL-2 from CD4 T cells stimulated in an MHC class II-dependent manner. However, transwell separation experiments showed that direct contact of monocytes with the cells that acquire Foxp3 expression was not required. This novel TCR-independent and therefore antigen-non specific mechanism for by-stander CD4(+CD25(hiFoxp3(+ cell induction is likely to reflect a

  3. A Foxp2 mutation implicated in human speech deficits alters sequencing of ultrasonic vocalizations in adult male mice

    Directory of Open Access Journals (Sweden)

    Jonathan Chabout

    2016-10-01

    Full Text Available Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here we performed a systematic study of ultrasonic vocalizations (USVs of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans.

  4. Extinction Events Can Accelerate Evolution

    DEFF Research Database (Denmark)

    Lehman, Joel; Miikkulainen, Risto

    2015-01-01

    Extinction events impact the trajectory of biological evolution significantly. They are often viewed as upheavals to the evolutionary process. In contrast, this paper supports the hypothesis that although they are unpredictably destructive, extinction events may in the long term accelerate...... evolution by increasing evolvability. In particular, if extinction events extinguish indiscriminately many ways of life, indirectly they may select for the ability to expand rapidly through vacated niches. Lineages with such an ability are more likely to persist through multiple extinctions. Lending...... computational support for this hypothesis, this paper shows how increased evolvability will result from simulated extinction events in two computational models of evolved behavior. The conclusion is that although they are destructive in the short term, extinction events may make evolution more prolific...

  5. Foxp3 (-/ATT polymorphism contributes to the susceptibility of preeclampsia.

    Directory of Open Access Journals (Sweden)

    Ximing Chen

    Full Text Available OBJECTIVE: To evaluate the potential influence of Foxp3 polymorphism on preeclampsia (PE susceptibility, we conducted a case-control study in Han Chinese women. METHODS: Foxp3 genotyping was determined by polymerase chain reaction with sequence-specific primers (PCR-SSP in 156 PE patients and 252 age-frequency matched controls. Immunohistochemical staining was used to detect the expression of Foxp3 specific transcription factor in 30 PE and 30 normal pregnant women. RESULTS: The positive rate of Foxp3 expression in PE (26.67% was significant difference from that in normal control (63.33%, P<0.05. The frequency of Foxp3-6054 TT genotype was significantly lower in PE patient than that in control. No significant difference was found in Foxp3-3279 genotypes between PE and control, as well as for the variant allele. The frequency of Foxp3-6054A/-3279C haplotype in PE was significantly higher than that in control (P<0.01, while the frequency of Foxp3 6054T/-3279C haplotype was significantly lower in PE patient than that in control (P<0.01. CONCLUSION: Our findings suggest that the immune suppression function in PE patients is weakened, which may result in the occurrence of PE. Foxp3 polymorphism (rs5902434 may be a potential contributor for the development of PE in Han Chinese women.

  6. The Forkhead Transcription Factor, FOXP3, Is Required for Normal Pituitary Gonadotropin Expression in Mice1

    Science.gov (United States)

    Jung, Deborah O.; Jasurda, Jake S.; Egashira, Noboru; Ellsworth, Buffy S.

    2012-01-01

    autoimmune cells. We find that Foxp3sf/Y mice have elevated expression of thyroid-stimulating hormone beta (Tshb), suggesting that they may suffer from thyroiditis as well. Expression of the pituitary transcription factors, Pitx1, Pitx2, Lhx3, and Egr1, is normal; however, expression of Foxl2 and Gata2 is elevated. These data are the first to demonstrate a defect at the pituitary level in the absence of FOXP3, which contributes to the infertility observed in mice with Foxp3 loss of function mutations. PMID:22357547

  7. Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP.

    Science.gov (United States)

    Elkord, Eyad; Abd Al Samid, May; Chaudhary, Belal

    2015-08-21

    Regulatory T cells (Tregs) are key players of immune regulation/dysregulation both in physiological and pathophysiological settings. Despite significant advances in understanding Treg function, there is still a pressing need to define reliable and specific markers that can distinguish different Treg subpopulations. Herein we show for the first time that markers of activated Tregs [latency associated peptide (LAP) and glycoprotein A repetitions predominant (GARP, or LRRC32)] are expressed on CD4+FoxP3- T cells expressing Helios (FoxP3-Helios+) in the steady state. Following TCR activation, GARP/LAP are up-regulated on CD4+Helios+ T cells regardless of FoxP3 expression (FoxP3+/-Helios+). We show that CD4+GARP+/-LAP+ Tregs make IL-10 immunosuppressive cytokine but not IFN-γ effector cytokine. Further characterization of FoxP3/Helios subpopulations showed that FoxP3+Helios+ Tregs proliferate in vitro significantly less than FoxP3+Helios- Tregs upon TCR stimulation. Unlike FoxP3+Helios- Tregs, FoxP3+Helios+ Tregs secrete IL-10 but not IFN-γ or IL-2, confirming they are bona fide Tregs with immunosuppressive characteristics. Taken together, Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP, and FoxP3+Helios+ Tregs have more suppressive characteristics, compared with FoxP3+Helios- Tregs. Our work implies that therapeutic modalities for treating autoimmune and inflammatory diseases, allergies and graft rejection should be designed to induce and/or expand FoxP3+Helios+ Tregs, while therapies against cancers or infectious diseases should avoid such expansion/induction.

  8. Three distinct domains contribute to nuclear transport of murine Foxp3.

    Directory of Open Access Journals (Sweden)

    Wayne W Hancock

    2009-11-01

    Full Text Available Foxp3, a 47-kDa transcription factor, is necessary for the function of CD4+CD25+ regulatory T cells (Tregs, with an essential role in the control of self-reactive T cells and in preventing autoimmunity. Activation of Tregs by TCR engagement results in upregulation of Foxp3 expression, followed by its rapid nuclear transport and binding to chromatin. Here, we identify three distinct Foxp3 domains that contribute to nuclear transport. The first domain (Domain 1 comprises the C-terminal 12 amino acids. The second domain (Domain 2 is located immediately N-terminal to the forkhead domain (FHD, recently reported to be a binding site for the runt-related transcription factor 1/acute myeloid leukemia 1 (Runx1/AML1. The third domain (Domain 3 is located within the N-terminal first 51 amino acids. Unlike the known nuclear localization signals (NLSs, none of these three regions are rich in basic residues and do not bear any similarity to known monopartite or bipartite NLSs that have one or more clusters of basic amino acids. The basic arginine-lysine-lysine-arginine (RKKR sequence, located 12-aa from the C-terminal end of Foxp3 was previously reported to be a nuclear localization signal (NLS for several proteins, including for a GFP-Foxp3 hybrid. Evidence is provided here that in the full-length native Foxp3 RKKR does not function as an NLS. The data reported in this study indicates that Foxp3 achieves nuclear transport by binding to other nuclear factors and co-transporting with them to the nucleus.

  9. FoxP2 isoforms delineate spatiotemporal transcriptional networks for vocal learning in the zebra finch

    Science.gov (United States)

    Day, Nancy F; Kimball, Todd Haswell; Aamodt, Caitlin M; Heston, Jonathan B; Hilliard, Austin T; Xiao, Xinshu; White, Stephanie A

    2018-01-01

    Human speech is one of the few examples of vocal learning among mammals yet ~half of avian species exhibit this ability. Its neurogenetic basis is largely unknown beyond a shared requirement for FoxP2 in both humans and zebra finches. We manipulated FoxP2 isoforms in Area X, a song-specific region of the avian striatopallidum analogous to human anterior striatum, during a critical period for song development. We delineate, for the first time, unique contributions of each isoform to vocal learning. Weighted gene coexpression network analysis of RNA-seq data revealed gene modules correlated to singing, learning, or vocal variability. Coexpression related to singing was found in juvenile and adult Area X whereas coexpression correlated to learning was unique to juveniles. The confluence of learning and singing coexpression in juvenile Area X may underscore molecular processes that drive vocal learning in young zebra finches and, by analogy, humans. PMID:29360038

  10. FoxP3 mRNA splice forms in synovial CD4+ T cells in rheumatoid arthritis and psoriatic arthritis

    DEFF Research Database (Denmark)

    Ryder, L Rebekka; Bartels, Else Marie; Woetmann, Anders

    2012-01-01

    Our aim was to elucidate the relative amount of the different splice forms of FoxP3 mRNA in CD4+ T cells in peripheral blood (PB) compared to synovial fluid (SF) in RA and PsA patients. FoxP3 mRNA was measured using a quantitative real-time PCR method. CD4+ T cells were isolated from 17 paired...... samples of PB and SF from RA and PsA patients, and PB from 10 controls. FoxP3fl and FoxP2 mRNA was significantly increased (6.7 and 2.1-fold, respectively) in PB CD4+ T cells from RA patients compared to controls. FoxP3fl and Δ2 mRNA in SF CD4+ T cells was increased compared to controls in sero......-negative RA and PsA, but not in sero-positive RA patients, who had a high FoxP3 expression in both PB and SF. The FoxP2Δ7 mRNA was barely detectable in patient samples, and not at all in healthy individuals. We provide evidence of an increased expression of FoxP3 splice forms in synovial CD4+ T cells from...

  11. Changes in natural Foxp3(+Treg but not mucosally-imprinted CD62L(negCD38(+Foxp3(+Treg in the circulation of celiac disease patients.

    Directory of Open Access Journals (Sweden)

    Marieke A van Leeuwen

    Full Text Available BACKGROUND: Celiac disease (CD is an intestinal inflammation driven by gluten-reactive CD4(+ T cells. Due to lack of selective markers it has not been determined whether defects in inducible regulatory T cell (Treg differentiation are associated with CD. This is of importance as changes in numbers of induced Treg could be indicative of defects in mucosal tolerance development in CD. Recently, we have shown that, after encounter of retinoic acid during differentiation, circulating gut-imprinted T cells express CD62L(negCD38(+. Using this new phenotype, we now determined whether alterations occur in the frequency of natural CD62L(+Foxp3(+ Treg or mucosally-imprinted CD62L(negCD38(+Foxp3(+ Treg in peripheral blood of CD patients. In particular, we compared pediatric CD, aiming to select for disease at onset, with adult CD. METHODS: Cell surface markers, intracellular Foxp3 and Helios were determined by flow cytometry. Foxp3 expression was also detected by immunohistochemistry in duodenal tissue of CD patients. RESULTS: In children, the percentages of peripheral blood CD4(+Foxp3(+ Treg were comparable between CD patients and healthy age-matched controls. Differentiation between natural and mucosally-imprinted Treg on the basis of CD62L and CD38 did not uncover differences in Foxp3. In adult patients on gluten-free diet and in refractory CD increased percentages of circulating natural CD62L(+Foxp3(+ Treg, but normal mucosally-imprinted CD62L(negCD38(+Foxp3(+ Treg frequencies were observed. CONCLUSIONS: Our data exclude that significant numeric deficiency of mucosally-imprinted or natural Foxp3(+ Treg explains exuberant effector responses in CD. Changes in natural Foxp3(+ Treg occur in a subset of adult patients on a gluten-free diet and in refractory CD patients.

  12. The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells.

    Science.gov (United States)

    van Keimpema, Martine; Grüneberg, Leonie J; Schilder-Tol, Esther J M; Oud, Monique E C M; Beuling, Esther A; Hensbergen, Paul J; de Jong, Johann; Pals, Steven T; Spaargaren, Marcel

    2017-03-01

    The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5'-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients. Copyright© Ferrata Storti Foundation.

  13. FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

    International Nuclear Information System (INIS)

    Ma, Gui-Fen; Chen, Shi-Yao; Sun, Zhi-Rong; Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng; Ma, Li-Li; Lian, Jing-Jing; Song, Dong-Li

    2013-01-01

    Highlights: ► The article revealed FoxP3 gene function in gastric cancer firstly. ► Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. ► Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. ► Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. ► FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis in GC cells by regulating apoptotic signaling, which could be a promising therapeutic approach for gastric cancer.

  14. Functional characterization of Foxp3-specific spontaneous immune responses

    DEFF Research Database (Denmark)

    Larsen, Susanne Købke; Munir, S; Andersen, Anders Woetmann

    2013-01-01

    Tumor-infiltrating CD4+CD25+ regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. The transcription factor forkhead box P3 (Foxp3) is generally expressed in Tregs. Here, we identify and characterize spontaneous cytotoxic immune responses to Foxp3-expressing cel....... Consequently, induction of Foxp3-specific cytotoxic T-cell responses appears as an attractive tool to boost spontaneous or therapeutically provoked immune responses, for example, for the therapy of cancer....

  15. Inhibition of FOXP3/NFAT interaction enhances T cell function after TCR stimulation

    NARCIS (Netherlands)

    Lozano, Teresa; Villanueva, Lorea; Durántez, Maika; Gorraiz, Marta; Ruiz, Marta; Belsúe, Virginia; Riezu-Boj, José I.; Hervás-Stubbs, Sandra; Oyarzábal, Julen; Bandukwala, Hozefa; Lourenço, Ana R.; Coffer, Paul J.; Sarobe, Pablo; Prieto, Jesús; Casares, Noelia; Lasarte, Juan J.

    2015-01-01

    Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer

  16. Expression of full-length and splice forms of FoxP3 in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ryder, L R; Woetmann, A; Madsen, H O

    2010-01-01

    OBJECTIVE: The aim of our study was to compare the presence of full-length and alternative splice forms of FoxP3 mRNA in CD4 cells from rheumatoid arthritis (RA) patients and healthy controls. METHODS: A quantitative real-time polymerase chain reaction (QRT-PCR) method was used to measure...... the amount of FoxP3 mRNA full-length and splice forms. CD4-positive T cells were isolated from peripheral blood from 50 RA patients by immunomagnetic separation, and the FoxP3 mRNA expression was compared with the results from 10 healthy controls. RESULTS: We observed an increased expression of full......-length FoxP3 mRNA in RA patients when compared to healthy controls, as well as an increase in CD25 mRNA expression, but no corresponding increase in CTLA-4 mRNA expression. The presence of an alternative splice form of FoxP3 lacking exon 2 was confirmed in both RA patients and healthy controls...

  17. HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression.

    Directory of Open Access Journals (Sweden)

    Nanae Yamamoto-Taguchi

    2013-09-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. The HTLV-1 basic leucine zipper factor (HBZ gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4⁺Foxp3⁺ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ. In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4⁺ T cells were enhanced in these mice. Foxp3⁻CD4⁺ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3⁻T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4⁺ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.

  18. CD4+CD62L+ Central Memory T Cells Can Be Converted to Foxp3+ T Cells

    Science.gov (United States)

    Zhang, Xiaolong; Chang Li, Xian; Xiao, Xiang; Sun, Rui; Tian, Zhigang; Wei, Haiming

    2013-01-01

    The peripheral Foxp3+ Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4+ T cells can be readily converted to Foxp3+ iTreg in vitro, and memory CD4+ T cells are resistant to conversion. In this study, we investigated the induction of Foxp3+ T cells from various CD4+ T-cell subsets in human peripheral blood. Though naive CD4+ T cells were readily converted to Foxp3+ T cells with TGF-β and IL-2 treatment in vitro, such Foxp3+ T cells did not express the memory marker CD45RO as do Foxp3+ T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4+ T cells, defined as CD62L+ central memory T cells, could be induced by TGF-β to differentiate into Foxp3+ T cells. It is well known that Foxp3+ T cells derived from human CD4+CD25- T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4+CD62L+ central memory T cell-derived Foxp3+ T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4+ T cell-derived Foxp3+ T cells. But further research showed that mouse CD4+ central memory T cells also could be induced to differentiate into Foxp3+ T cells, such Foxp3+ T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4+CD62L+ central memory T cells as a novel potential source of iTreg. PMID:24155942

  19. Neonatal immune responses to TLR2 stimulation: Influence of maternal atopy on Foxp3 and IL-10 expression

    Directory of Open Access Journals (Sweden)

    Gold Diane R

    2006-03-01

    Full Text Available Abstract Background Maternal atopic background and stimulation of the adaptive immune system with allergen interact in the development of allergic disease. Stimulation of the innate immune system through microbial exposure, such as activation of the innate Toll-like-receptor 2 (TLR2, may reduce the development of allergy in childhood. However, little is known about the immunological effects of microbial stimulation on early immune responses and in association with maternal atopy. Methods We analyzed immune responses of cord blood mononuclear cells (CBMC from 50 healthy neonates (31 non-atopic and 19 atopic mothers. Cells were stimulated with the TLR2 agonist peptidoglycan (Ppg or the allergen house dust mite Dermatophagoides farinae (Derf1, and results compared to unstimulated cells. We analyzed lymphocyte proliferation and cytokine secretion of CBMC. In addition, we assessed gene expression associated with T regulatory cells including the transcription factor Foxp3, the glucocorticoid-induced TNF receptor (GITR, and the cytotoxic lymphocyte antigen 4 (CTLA4. Lymphocyte proliferation was measured by 3H-Thymidine uptake, cytokine concentrations determined by ELISA, mRNA expression of T cell markers by real-time RT-PCR. Results Ppg stimulation induced primarily IL-10 cytokine production, in addition to IFN-γ, IL-13 and TNF-α secretion. GITR was increased following Ppg stimulation (p = 0.07. Ppg-induced IL-10 production and induction of Foxp3 were higher in CBMC without, than with maternal atopy (p = 0.04, p = 0.049. IL-10 production was highly correlated with increased expression of Foxp3 (r = 0.53, p = 0.001, GITR (r = 0.47, p = 0.004 and CTLA4 (r = 0.49, p = 0.003, independent of maternal atopy. Conclusion TLR2 stimulation with Ppg induces IL-10 and genes associated with T regulatory cells, influenced by maternal atopy. Increased IL-10 and Foxp3 induction in CBMC of non-atopic compared to atopic mothers, may indicate an increased capacity to

  20. FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Gui-Fen [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Shi-Yao, E-mail: shiyao_chen@163.com [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Sun, Zhi-Rong [Department of Anesthesiology, Cancer Center, Fudan University, Shanghai (China); Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Ma, Li-Li; Lian, Jing-Jing [Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Song, Dong-Li [Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer The article revealed FoxP3 gene function in gastric cancer firstly. Black-Right-Pointing-Pointer Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. Black-Right-Pointing-Pointer Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. Black-Right-Pointing-Pointer Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Black-Right-Pointing-Pointer FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis

  1. Foxp3-dependent transformation of human primary CD4+ T lymphocytes by the retroviral protein tax.

    Science.gov (United States)

    Chen, Li; Liu, Dan; Zhang, Yang; Zhang, Huan; Cheng, Hua

    2015-10-23

    The retroviral Tax proteins of human T cell leukemia virus type 1 and 2 (HTLV-1 and -2) are highly homologous viral transactivators. Both viral proteins can immortalize human primary CD4+ memory T cells, but when expressed alone they rarely transform T cells. In the present study, we found that the Tax proteins displayed a differential ability to immortalize human CD4+Foxp3+ T cells with characteristic expression of CTLA-4 and GITR. Because epidermal growth factor receptor (EGFR) was reportedly expressed and activated in a subset of CD4+Foxp3+ T cells, we introduced an activated EGFR into Tax-immortalized CD4+Foxp3+ T cells. We observed that these modified cells were grown independently of exogenous IL-2, correlating with a T cell transformation phenotype. In Tax-immortalized CD4+Foxp3- T cells, ectopic expression of Foxp3 was a prerequisite for Tax transformation of T cells. Accordingly, treatment of the transformed T cells with erlotinib, a selective inhibitor of EGFR, induced degradation of EGFR in lysosome, consequently causing T cell growth inhibition. Further, we identified autophagy as a crucial cellular survival pathway for the transformed T cells. Silencing key autophagy molecules including Beclin1, Atg5 and PI3 kinase class III (PI3KC3) resulted in drastic impairment of T cell growth. Our data, therefore, unveiled a previously unidentified role of Foxp3 in T cell transformation, providing a molecular basis for HTLV-1 transformation of CD4+Foxp3+ T cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Foxp3 Expression is Required for the Induction of Therapeutic Tissue Tolerance1

    Science.gov (United States)

    Regateiro, Frederico S.; Chen, Ye; Kendal, Adrian R.; Hilbrands, Robert; Adams, Elizabeth; Cobbold, Stephen P.; Ma, Jianbo; Andersen, Kristian G.; Betz, Alexander G.; Zhang, Mindy; Madhiwalla, Shruti; Roberts, Bruce; Waldmann, Herman; Nolan, Kathleen F.; Howie, Duncan

    2012-01-01

    CD4+Foxp3+ Treg are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGFβ dependent manner. Foxp3+ Treg are also required to achieve tolerance to transplanted tissues when induced by co receptor or co stimulation blockade. Using TCR transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGFβ signalling to T cells can wholly be explained by its role in induction of Foxp3, as such signalling proved dispensable for the suppressive process. We analysed the relative contribution of TGFβ and Foxp3 to the transcriptome of TGFβ-induced Treg and showed that TGFβ elicited a large set of down-regulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Thus, despite the large genetic influence of TGFβ exposure on iTreg, the crucial Foxp3-influenced signature independent of TGFβ is small. Retroviral mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4+ T cells, and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGFβ and Foxp3 in induced tolerance, where TGFβ stimulates Foxp3 expression, whose sustained expression is then associated with acquisition of tolerance. PMID:22988034

  3. Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression

    International Nuclear Information System (INIS)

    Choi, Byung-Min; Pae, Hyun-Ock; Jeong, Young-Ran; Kim, Young-Myeong; Chung, Hun-Taeg

    2005-01-01

    Foxp3, which encodes the transcription factor scurfin, is indispensable for the development and function of CD4 + CD25 + regulatory T cells (Treg). Recent data suggest conversion of peripheral CD4 + CD25 - naive T cells to CD4 + CD25 + Treg by acquisition of Foxp3 through costimulation with TCR and TGF-β or forced expression of the gene. One critical question is how Foxp3 causes T cells to become regulatory. In the present work, we demonstrate that Foxp3 can induce heme oxygenase-1 (HO-1) expression and subsequently such regulatory phenotypes as the suppression of nontransfected cells in a cell-cell contact-dependent manner as well as impaired proliferation and production of cytokines upon stimulation in Jurkat T cells. Moreover, we confirm the expression of both Foxp3 and HO-1 in peripheral CD4 + CD25 + Treg and suppressive function of the cells are relieved by the inhibition of HO-1 activity. In summary, we demonstrate that Foxp3 induces HO-1 expression and HO-1 engages in Foxp3-mediated immune suppression

  4. Foxp3 overexpression in tumor cells predicts poor survival in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Song, Jing-Jing; Zhao, Si-Jia; Fang, Juan; Ma, Da; Liu, Xiang-Qi; Chen, Xiao-Bing; Wang, Yun; Cheng, Bin; Wang, Zhi

    2016-01-01

    Forkhead Box P3 (Foxp3) is a regulatory T cells marker, and its expression correlates with prognosis in a number of malignancies. The aim of this study is to determine the relationship of Foxp3 expression with clinicopathological parameters and prognosis in oral squamous cell carcinoma (OSCC). Foxp3 expression was examined using immunohistochemistry (IHC) in paraffin-embedded tissue samples from 273 OSCC patients. Statistical analysis was performed to evaluate the associations between Foxp3 expression, the clinicopathologic characteristics and prognostic factors in OSCC. Foxp3 protein expression was significantly associated with lymph node metastasis (P <0.01). Both univariate and multivariate analyses revealed that Foxp3 was an independent factor for both 5 years overall survival (OS) and relapse-free survival (RFS) (both P <0.01). Patients with Foxp3 overexpression had shorter OS and RFS. Our results determined that elevated Foxp3 protein expression was a predictive factor of outcome in OSCC and could act as a promising therapeutic target

  5. Histone methylation mediates plasticity of human FOXP3(+) regulatory T cells by modulating signature gene expressions.

    Science.gov (United States)

    He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

    2014-03-01

    CD4(+) FOXP3(+) regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4(+) CD25(high) CD127(low/-) Treg cells convert to two subpopulations with distinctive FOXP3(+) and FOXP3(-) phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. © 2013 John Wiley & Sons Ltd.

  6. Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions

    Science.gov (United States)

    He, Haiqi; Ni, Bing; Tian, Yi; Tian, Zhiqiang; Chen, Yanke; Liu, Zhengwen; Yang, Xiaomei; Lv, Yi; Zhang, Yong

    2014-01-01

    CD4+ FOXP3+ regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4+ CD25high CD127low/− Treg cells convert to two subpopulations with distinctive FOXP3+ and FOXP3− phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events. PMID:24152290

  7. FOXP3 Transcription Factor: A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Leandra Fiori Lopes

    2014-01-01

    Full Text Available Triple negative breast cancer (TNBC is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2. FOXP3 (forkhead transcription factor 3 is a marker of regulatory T cells (Tregs, whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548 and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction. Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06 in relation to TNBC susceptibility. Most of the patients (83% showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P=0.026. In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples.

  8. Missed, Not Missing: Phylogenomic Evidence for the Existence of Avian FoxP3.

    Directory of Open Access Journals (Sweden)

    Michael P Denyer

    Full Text Available The Forkhead box transcription factor FoxP3 is pivotal to the development and function of regulatory T cells (Tregs, which make a major contribution to peripheral tolerance. FoxP3 is believed to perform a regulatory role in all the vertebrate species in which it has been detected. The prevailing view is that FoxP3 is absent in birds and that avian Tregs rely on alternative developmental and suppressive pathways. Prompted by the automated annotation of foxp3 in the ground tit (Parus humilis genome, we have questioned this assumption. Our analysis of all available avian genomes has revealed that the foxp3 locus is missing, incomplete or of poor quality in the relevant genomic assemblies for nearly all avian species. Nevertheless, in two species, the peregrine falcon (Falco peregrinus and the saker falcon (F. cherrug, there is compelling evidence for the existence of exons showing synteny with foxp3 in the ground tit. A broader phylogenomic analysis has shown that FoxP3 sequences from these three species are similar to crocodilian sequences, the closest living relatives of birds. In both birds and crocodilians, we have also identified a highly proline-enriched region at the N terminus of FoxP3, a region previously identified only in mammals.

  9. Immunohistochemical analysis of FoxP3+ cells in periapical granulomas and radicular cysts.

    Science.gov (United States)

    Peixoto, Raniel Fernandes; Pereira, Joabe dos Santos; Nonaka, Cassiano Francisco Weege; Silveira, Ericka Janine Dantas da; Miguel, Márcia Cristina da Costa

    2012-09-01

    To compare the number of FoxP3(+) cells between periapical granulomas (PGs) and radicular cysts (RCs), and to correlate this number with the intensity of the inflammatory infiltrate in these lesions and with epithelial thickness of RCs. Thirty PGs and 30 RCs were submitted to immunohistochemical analysis using an anti-FoxP3 polyclonal antibody. FoxP3(+) cells were counted under a light microscope (×400 magnification) in five fields and the mean value was calculated for each specimen. Statistical tests were used to evaluate differences in the number of FoxP3(+) cells according to type of lesion (PG vs. RC), intensity of the inflammatory infiltrate (grade I/II vs. grade III), and epithelial thickness of RCs (atrophic vs. hyperplastic). FoxP3(+) cells were detected in most PGs (93.3%) and RCs (93.3%). The median number of FoxP3(+) cells was 2.40 in PGs and 1.00 in RCs, with this difference being statistically significant (P=0.005). No significant differences in the number of FoxP3(+) cells were observed in terms of the intensity of the inflammatory infiltrate (P=0.465) or epithelial thickness of RCs (P=0.737). The present results suggest a greater participation of regulatory T cells in the modulation of the inflammatory response in PGs. In addition, the presence of a less effective regulatory environment in RCs, together with the high levels of inflammatory mediators as reported in the literature, may contribute to the greater growth potential of these lesions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

    DEFF Research Database (Denmark)

    Krejsgaard, T; Gjerdrum, L M; Ralfkiaer, E

    2008-01-01

    Sézary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3...... in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress...... the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappaB (NF...

  11. TGF-beta and 'adaptive' Foxp3(+) regulatory T cells.

    Science.gov (United States)

    Chen, Wanjun; Konkel, Joanne E

    2010-02-01

    In naïve T cells transforming growth factor-beta (TGF-beta) induces Foxp3, a transcription factor essential for programming and developing T regulatory cells (Treg cells). This finding reveals a physiological factor which can turn on the Foxp3 gene and establishes an experimental approach to induce antigen-specific Treg cells as a potential therapy for human diseases. While this role for TGF-beta is well confirmed, several critical questions remain largely unanswered and await further investigation. In this regard, it is imperative to understand the molecular pathways by which TGF-beta signaling initiates and regulates Foxp3 expression. It is also important to elucidate which factors and/or cytokines influence the TGF-beta-mediated conversion of naïve T cells and how to create an immunologically regulatory milieu to facilitate Treg cell generation in vivo. In this short article, we will highlight the key findings and recent progress in the field, discuss the molecular mechanisms underlying the TGF-beta-mediated induction of Foxp3, and attempt to outline the challenges ahead.

  12. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation

    Directory of Open Access Journals (Sweden)

    Boehm Franziska

    2012-07-01

    Full Text Available Abstract Background Mice lacking Foxp3+ regulatory T (Treg cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation. Methods Foxp3-GFP-DTR (human diphtheria toxin receptor C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin. The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag−/− C57BL/6 mice and the acute DSS-colitis model. Results Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag−/− C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines. Conclusion Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.

  13. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers.

    Science.gov (United States)

    Saito, Takuro; Nishikawa, Hiroyoshi; Wada, Hisashi; Nagano, Yuji; Sugiyama, Daisuke; Atarashi, Koji; Maeda, Yuka; Hamaguchi, Masahide; Ohkura, Naganari; Sato, Eiichi; Nagase, Hirotsugu; Nishimura, Junichi; Yamamoto, Hirofumi; Takiguchi, Shuji; Tanoue, Takeshi; Suda, Wataru; Morita, Hidetoshi; Hattori, Masahira; Honda, Kenya; Mori, Masaki; Doki, Yuichiro; Sakaguchi, Shimon

    2016-06-01

    CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3(+) T cell infiltration indicated better prognosis in some studies. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3(hi) Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3(lo) nonsuppressive T cells. The latter, which are distinguished from FOXP3(+) Treg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3(lo) T cells showed significantly better prognosis than those with predominantly FOXP3(hi) Treg cell infiltration. Development of such inflammatory FOXP3(lo) non-Treg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3(+) T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3(hi) Treg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3(lo) non-Treg cells could be used to suppress or prevent tumor formation.

  14. FOXP3 expression in papillary thyroid carcinoma with and without Hashimoto's thyroiditis

    Directory of Open Access Journals (Sweden)

    Murilo Pedreira Neves Junior

    2013-08-01

    Full Text Available INTRODUCTION: The forkhead box P3 (FOXP3 plays a role in cell development and control. In the presence of abnormal FOXP3 expression, tumor cells may evade the immunosurveillance of lymphoid cells, the first step for the maintenance of cancer cells in the thyroid tissue. OBJECTIVE: To identify the presence of FOXP3 in papillary thyroid carcinoma (PTC with and without Hashimoto's Thyroiditis (HT. METHODS: We conducted a series study of cases collected from 2000 to 2008, when 1,438 thyroidectomies were performed. We selected those diagnosed with PTC, comprising 466 cases. 30 patients were randomly selected for purposes of immunohistochemistry with antibodies against FOXP3. RESULT: FOXP3 revealed high positivity for PTC and positive immunostaining was present in 21 (72.4% from all analyzed cases. There was no difference regarding coexistent HT or not. DISCUSSION AND CONCLUSION: In the present study, it was evidenced that the focal or diffuse FOXP3 expression was commonly observed in neoplastic cells from PTC, hence indicating that the assessment of this molecule expression in suspected cases of thyroid cancer may contribute to its diagnosis.

  15. Association of aplastic anemia and FoxP3 gene polymorphisms in Koreans.

    Science.gov (United States)

    In, Ji Won; Lee, Nuri; Roh, Eun Youn; Shin, Sue; Park, Kyoung Un; Song, Eun Young

    2017-04-01

    Aplastic anemia (AA) is characterized by pancytopenia and bone marrow failure, and most acquired AA is an immune-mediated disorder. Regulatory T cells (T regs ) suppressing autoreactive T cells were decreased in AA patients. FoxP3 is a major regulator for the development and function of T regs . Polymorphism in FoxP3 was shown to be associated with various autoimmune diseases, however, has not yet been studied in AA. In this study, we examined the association between FoxP3 polymorphisms and AA in Korean patients. The study population consisted of 94 patients diagnosed by bone marrow examination in Seoul National University Hospital (SNUH) during 1997-2012 and 195 healthy controls. FoxP3 polymorphisms (rs5902434 del/ATT, rs3761548 C/A, rs3761549 C/T, rs2232365 A/G) were analyzed by PCR-sequencing method. We analyzed differences of genotype and allele frequencies between patients and controls. We also compared differences of genotype and allele frequencies between responder and non-responder in patients treated with immunosuppressive therapy (IST). For the statistical analysis, the chi-square test and Fisher's exact test were used and P < 0.05 was regarded as statistically significant. There was no significant difference in the genotype frequencies of FoxP3 polymorphisms between patients and controls. With regards to the allele frequencies, rs3761548 C allele was significantly higher in AA patients than in controls (87.4% vs. 79.7%, P = 0.047). In patients treated with IST, rs3761549 C allele was significantly higher in non-responder patients than in responders (89.6% vs. 66.7%, P = 0.036) and female rs3761549 C/C genotype carriers were associated with greater risk for non-response to IST (84.2% vs. 16.7%, P = 0.006). Polymorphisms in rs3761548 and rs3761549 of FoxP3 in our population were associated with disease susceptibility and response for IST, respectively. This study suggests an association between FoxP3 polymorphisms and AA in Korean patients

  16. Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour.

    Science.gov (United States)

    Bacon, C; Schneider, M; Le Magueresse, C; Froehlich, H; Sticht, C; Gluch, C; Monyer, H; Rappold, G A

    2015-05-01

    Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-Cre(Foxp1-/-)mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-Cre(Foxp1-/-) mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

  17. Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell CompartmentSummary

    Directory of Open Access Journals (Sweden)

    Duke Geem

    2016-05-01

    Full Text Available Background & Aims: Foxp3+ regulatory T cells (Tregs in the intestine promote immune tolerance to enteric antigens. Previous studies have shown that C-C chemokine receptor 7 (CCR7-dependent migration of intestinal dendritic cells to the mesenteric lymph nodes (mLN is involved in peripheral Foxp3+ Treg accumulation in the intestine and the establishment of oral tolerance. However, the relative contribution of this CCR7+ dendritic cell–mLN–Treg axis to the total intestinal Foxp3+ Treg pool during the steady-state remains unclear. In this study, the contribution of CCR7, as well as the mLN and gut-associated lymphoid tissue (GALT, to the intestinal Foxp3+ Treg compartment in the small intestine (SI and large intestine (LI was assessed. Methods: Intestinal Foxp3+ Tregs were quantitated in Ccr7-/- mice and in mice devoid of secondary lymphoid organs—including mLN and GALT—owing to a deficiency in lymphotoxin (LT signaling. Specific analyses of Foxp3+Helios+ thymically derived (tTregs and Foxp3+Helios- peripherally derived (pTregs in the SI and LI, as well as the role for the mLN in supporting Foxp3+ pTreg development using the B6.Cg-Tg(TcraTcrb425Cbn/J/ovalbumin (OVA feeding system, were performed. Results: Foxp3+ Tregs were enriched in the intestine relative to the mLN, independent of CCR7. In the absence of the mLN and GALT, normal frequency and numbers of Foxp3+ Tregs were observed in LTα-deficient (Lta-/- mice. However, Foxp3+Helios- pTregs were decreased in the SI of Lta-/- mice, corresponding with defective Foxp3+ pTreg expansion to OVA. In the LI, however, the proportion of Foxp3+Helios- pTregs and Foxp3+ pTreg induction to OVA was comparable between Lta-/- and Lta+/+ mice, which coincided with preferential expression of Treg-inducing/immunoregulatory cytokines. Conclusions: The overall size of the intestinal Foxp3+Treg pool is not impacted significantly by CCR7, mLN, or GALT during the steady-state. However, m

  18. In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4(+)CD25(+) T cells of patients with human T-lymphotropic virus type 1-associated myelopathy.

    Science.gov (United States)

    Ramirez, E; Cartier, L; Rodriguez, L; Alberti, C; Valenzuela, M A

    2010-11-01

    HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4(+)CD25(+) T-regulatory cells (Treg). For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-β, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years). The control group consisted of 23 non-infected subjects (12 women and 11 men) with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4(+)CD25(+) T cells). Foxp3, GITR, and CTLA-4 mRNA levels were lower in HAM/TSP patients (mean ± SD, 22.07 ± 0.78, 9.63 ± 0.36, and 4.54 ± 0.39, respectively) than in non-infected controls (47.15 ± 12.94, 22.14 ± 1.91, and 21.07 ± 2.31). Both groups had similar levels of TGF-β and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4(+)CD25(+) T cells in HAM/TSP patients.

  19. In vivo fluctuation of Tax, Foxp3, CTLA-4, and GITR mRNA expression in CD4+CD25+ T cells of patients with human T-lymphotropic virus type 1-associated myelopathy

    Directory of Open Access Journals (Sweden)

    E. Ramirez

    2010-11-01

    Full Text Available HTLV-1 Tax expression exerts an inhibitory effect on the Foxp3 transcription factor in CD4+CD25+ T-regulatory cells (Treg. For a better understanding of the role of Tax mRNA in the gene expression of cellular markers we measured Tax, Foxp3, CTLA-4, GITR, TGF-β, and IL-10 mRNA in Treg cells of 50 patients with human T-lymphotropic virus type 1 (HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP; 27 women and 23 men; mean age: 56.7 years. The control group consisted of 23 non-infected subjects (12 women and 11 men with a mean age of 51.3 years. Real-time PCR was used to measure mRNA of Tax proteins and several cellular markers of Treg function. Determinations revealed a high level of Tax mRNA in HAM/TSP (124.35 copies/100 CD4+CD25+ T cells. Foxp3, GITR, and CTLA-4 mRNA levels were lower in HAM/TSP patients (mean ± SD, 22.07 ± 0.78, 9.63 ± 0.36, and 4.54 ± 0.39, respectively than in non-infected controls (47.15 ± 12.94, 22.14 ± 1.91, and 21.07 ± 2.31. Both groups had similar levels of TGF-β and IL-10. An inverse relationship was found between Tax levels and Foxp3, CTLA-4, and GITR levels. Conversely, there was a direct correlation between levels of Foxp3, GITR, and CTLA-4. Disease severity and evolution time did not correlate with Tax or Foxp3 levels. The present results suggest that Tax and Foxp3 mRNA vary with the same degree of disease severity in HAM/TSP patients. Tax fluctuations may affect CTLA-4 and GITR expression via the Foxp3 pathway, causing virus-induced dysfunction of CD4+CD25+ T cells in HAM/TSP patients.

  20. FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression.

    Science.gov (United States)

    Katz, Gil; Voss, Kelsey; Yan, Toria F; Kim, Yong Chan; Kortum, Robert L; Scott, David W; Snow, Andrew L

    2018-05-01

    Restimulation-induced cell death (RICD) is an apoptotic program that regulates effector T cell expansion, triggered by repeated stimulation through the T cell receptor (TCR) in the presence of interleukin-2 (IL-2). Although CD4 + regulatory T cells (Tregs) consume IL-2 and experience frequent TCR stimulation, they are highly resistant to RICD. Resistance in Tregs is dependent on the forkhead box P3 (FOXP3) transcription factor, although the mechanism remains unclear. T cells from patients with X-linked lymphoproliferative disease (XLP-1), that lack the adaptor molecule SLAM-associated protein (SAP), are also resistant to RICD. Here we demonstrate that normal Tregs express very low levels of SAP compared to conventional T cells. FOXP3 reduces SAP expression by directly binding to and repressing the SH2D1A (SAP) promoter. Indeed, ectopic SAP expression restores RICD sensitivity in human FOXP3 + Tregs. Our findings illuminate the mechanism behind FOXP3-mediated RICD resistance in Tregs, providing new insight into their long-term persistence. Published by Elsevier Inc.

  1. Foxp3 regulates ratio of Treg and NKT cells in a mouse model of asthma.

    Science.gov (United States)

    Lu, Yanming; Guo, Yinshi; Xu, Linyun; Li, Yaqin; Cao, Lanfang

    2015-05-01

    Chronic inflammatory disorder of the airways causes asthma. Regulatory T cells (Treg cells) and Natural killer T cells (NKT cells) both play critical roles in the pathogenesis of asthma. Activation of Treg cells requires Foxp3, whereas whether Foxp3 may regulate the ratio of Treg and NKT cells to affect asthma is uncertain. In an ovalbumin (OVA)-induced mouse model of asthma, we either increased Treg cells by lentivirus-mediated forced expression of exogenous Foxp3, or increased NKT cells by stimulation with its activator α-GalCer. We found that the CD4+CD25+ Treg cells increased by forced Foxp3 expression, and decreased by α-GalCer, while the CD3+CD161+ NKT cells decreased by forced Foxp3 expression, and increased by α-GalCer. Moreover, forced Foxp3 expression, but not α-GalCer, significantly alleviated the hallmarks of asthma. Furthermore, forced Foxp3 increased levels of IL_10 and TGFβ1, and α-GalCer increased levels of IL_4 and INFγ in the OVA-treated lung. Taken together, our study suggests that Foxp3 may activate Treg cells and suppress NKT cells in asthma. Treg and NKT cells may antagonize the effects of each other in asthma.

  2. CD4+ Foxp3+ T-cells contribute to myocardial ischemia-reperfusion injury.

    Science.gov (United States)

    Mathes, Denise; Weirather, Johannes; Nordbeck, Peter; Arias-Loza, Anahi-Paula; Burkard, Matthias; Pachel, Christina; Kerkau, Thomas; Beyersdorf, Niklas; Frantz, Stefan; Hofmann, Ulrich

    2016-12-01

    The present study analyzed the effect of CD4 + Forkhead box protein 3 negative (Foxp3 - ) T-cells and Foxp3 + CD4 + T-cells on infarct size in a mouse myocardial ischemia-reperfusion model. We examined the infarct size as a fraction of the area-at-risk as primary study endpoint in mice after 30minutes of coronary ligation followed by 24hours of reperfusion. CD4 + T-cell deficient MHC-II KO mice showed smaller histologically determined infarct size (34.5±4.7% in MHCII KO versus 59.4±4.9% in wildtype (WT)) and better preserved ejection fraction determined by magnetic resonance tomography (56.9±2.8% in MHC II KO versus 39.0±4.2% in WT). MHC-II KO mice also displayed better microvascular perfusion than WT mice after 24hours of reperfusion. Also CD4 + T-cell sufficient OT-II mice, which express an in this context irrelevant T-cell receptor, revealed smaller infarct sizes compared to WT mice. However, MHC-II blocking anti-I-A/I-E antibody treatment was not able to reduce infarct size indicating that autoantigen recognition is not required for the activation of CD4 + T-cells during reperfusion. Flow-cytometric analysis also did not detect CD4 + T-cell activation in heart draining lymph nodes in response to 24hours of ischemia-reperfusion. Adoptive transfer of CD4 + T-cells in CD4 KO mice increased the infarct size only when including the Foxp3 + CD25 + subset. Depletion of CD4 + Foxp3 + T-cells in DEREG mice enabling specific conditional ablation of this subset by treatment with diphtheria toxin attenuated infarct size as compared to diphtheria toxin treated WT mice. CD4 + Foxp3 + T-cells enhance myocardial ischemia-reperfusion injury. CD4 + T-cells exert injurious effects without the need for prior activation by MHC-II restricted autoantigen recognition. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients.

    Science.gov (United States)

    Ridolfi, Laura; Petrini, Massimiliano; Granato, Anna Maria; Gentilcore, Giusy; Simeone, Ester; Ascierto, Paolo Antonio; Pancisi, Elena; Ancarani, Valentina; Fiammenghi, Laura; Guidoboni, Massimo; de Rosa, Francesco; Valmorri, Linda; Scarpi, Emanuela; Nicoletti, Stefania Vittoria Luisa; Baravelli, Stefano; Riccobon, Angela; Ridolfi, Ruggero

    2013-05-31

    In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.

  4. Phenotypically non-suppressive cells predominate among FoxP3-positive cells in oral lichen planus.

    Science.gov (United States)

    Schreurs, Olav; Karatsaidis, Andreas; Schenck, Karl

    2016-11-01

    Oral lichen planus (OLP) is a common T-cell-dominated oral chronic inflammatory disease occurring in periods of remission, quiescence, activity with pronounced inflammation, and acute ulceration. Cell infiltrates in OLP contain varying numbers of CD4 + T cells expressing the transcription factor FoxP3. FoxP3 + CD4 + T cells are, however, a heterogeneous cell population containing suppressive and non-suppressive cells, and their distribution in infiltrates from OLP is unknown. Biopsies were taken from normal oral mucosa (n = 8) and OLP lesions (n = 19), and a set of in situ methods for the determination of the functional phenotype of FoxP3 + CD4 + T cells was applied. Numbers of FoxP3 + CD4 + T cells were highest in the atrophic form of the disease, yet low in the ulcerative form. The main FoxP3 + CD4 + T-cell population observed was FoxP3 + CD45RA - CD25 + CD45RO + and CD15s - , a phenotype delineating a non-suppressive subset. Numbers of cells with an actively suppressing phenotype (FoxP3 + CD45RA - CD25 + CD45RO + and CD15s + ) were, however, about twice as high in reticular lesions as compared with the atrophic form. Many FoxP3 + CD4 + T cells expressed T-bet, the hallmark transcription factor for IFN-γ-producing T cells, indicating that they may enhance immune and inflammatory responses rather than suppress them. The absence of actively suppressing FoxP3 + CD4 + T cells may in part explain why OLP is a remarkably persisting condition, in spite of the presence of substantially high numbers of FoxP3 + CD4 + T cells. The findings emphasize that it is crucial to examine not only numbers but also functional phenotype of FoxP3 + CD4 + T cells in human tissues. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Ability of γδ T cells to modulate the Foxp3 T cell response is dependent on adenosine.

    Directory of Open Access Journals (Sweden)

    Dongchun Liang

    Full Text Available Whether γδ T cells inhibit or enhance the Foxp3 T cell response depends upon their activation status. The critical enhancing effector in the supernatant is adenosine. Activated γδ T cells express adenosine receptors at high levels, which enables them to deprive Foxp3+ T cells of adenosine, and to inhibit their expansion. Meanwhile, cell-free supernatants of γδ T cell cultures enhance Foxp3 T cell expansion. Thus, inhibition and enhancement by γδ T cells of Foxp3 T cell response are a reflection of the balance between adenosine production and absorption by γδ T cells. Non-activated γδ T cells produce adenosine but bind little, and thus enhance the Foxp3 T cell response. Activated γδ T cells express high density of adenosine receptors and have a greatly increased ability to bind adenosine. Extracellular adenosine metabolism and expression of adenosine receptor A2ARs by γδ T cells played a major role in the outcome of γδ and Foxp3 T cell interactions. A better understanding of the functional conversion of γδ T cells could lead to γδ T cell-targeted immunotherapies for related diseases.

  6. The role of Foxp3+ regulatory T cells in liver transplant tolerance.

    Science.gov (United States)

    Li, W; Carper, K; Zheng, X X; Kuhr, C S; Reyes, J D; Liang, Y; Perkins, D L; Thomson, A W; Perkins, J D

    2006-12-01

    The liver has long been considered a tolerogenic organ that favors the induction of peripheral tolerance. The mechanisms underlying liver tolerogenicity remain largely undefined. In this study, we characterized Foxp3-expressing CD4+ CD25+ regulatory T cells (Treg) in liver allograft recipients and examined the role of Treg in inherent liver tolerogenicity by employing the mouse spontaneous liver transplant tolerance model. Orthotopic liver transplantation was performed from C57BL/10 (H2b) to C3H/HeJ (H2k) mice. The percentage of CD4+ CD25+ Treg was expanded in the liver grafts and recipient spleens from day 5 up to day 100 posttransplantation, associated with high intracellular Foxp3 and CTLA4 expression. Immunohistochemistry further demonstrated significant numbers of Foxp3+ cells in the liver grafts and recipient spleens and increased transforming growth factor beta expression in the recipient spleens throughout the time courses. Adoptive transfer of spleen cells from the long-term liver allograft survivors significantly prolonged donor heart graft survival. Depletion of recipient CD4+ CD25+ Treg using anti-CD25 monoclonal antibody (250 microg/d) induced acute liver allograft rejection, associated with elevated anti-donor T-cell proliferative responses, CTL and natural killer activities, enhanced interleukin (IL)-2, interferon-gamma, IL-10, and decreased IL-4 production, and decreased T-cell apoptotic activity in anti-CD25-treated recipients. Moreover, CTLA4 blockade by anti-CTLA4 monoclonal antibody administration exacerbated liver graft rejection when combined with anti-CD25 monoclonal antibody. Thus, Foxp3+ CD4+ CD25+ Treg appear to underpin spontaneous acceptance of major histocompatability complex- mismatched liver allografts in mice. CTLA4, IL-4, and apoptosis of alloreactive T cells appear to contribute to the function of Treg and regulation of graft outcome.

  7. Effects of natalizumab treatment on Foxp3+ T regulatory cells.

    Science.gov (United States)

    Stenner, Max-Philipp; Waschbisch, Anne; Buck, Dorothea; Doerck, Sebastian; Einsele, Hermann; Toyka, Klaus V; Wiendl, Heinz

    2008-10-06

    Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients. A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs. Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment. We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

  8. Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T (Treg)-like cells

    International Nuclear Information System (INIS)

    Kim, Joon-Young; Kim, Han-Jong; Hurt, Elaine M.; Chen, Xin; Howard, O.M. Zack; Farrar, William L.

    2007-01-01

    FOXP3, a forkhead transcription factor is essential for the development and function of CD4 + CD25 + regulatory T cells (Tregs). In contrast to conversion of murine naive T cells to Tregs by transduction of Foxp3, it is controversial whether ectopic expression of FOXP3 in human CD4 + T cells is sufficient for acquisition of suppressive activity. Here, we show that retroviral transduction of FOXP3 induces a Treg phenotype in human leukemic CD4 + Jurkat-T cells, evidenced by increased expression of Treg-associated cell surface markers as well as inhibition of cytokine production. Furthermore, FOXP3-transduced Jurkat-T cells suppress the proliferation of human CD4 + CD25 - T cells. Additionally, DNA microarray analysis identifies Treg-related genes regulated by FOXP3. Our study demonstrates that enforced expression of FOXP3 confers Treg-like properties on Jurkat-T cells, which can be a convenient and efficient Treg-like cell model for further study to identify Treg cell surface markers and target genes regulated by FOXP3

  9. [Changes of FoxP3, CD4(+)CD25(+) regulatory T cells, TLR2 and TLR9 in children with infectious mononucleosis].

    Science.gov (United States)

    Wang, Qiang; Wang, Zuo-Feng; Cao, Mei; Wang, Zhi-Ying

    2013-04-01

    The aim of this study was to investigate the effects of TLR2, TLR9, CD4(+)CD25(+) regulatory T cells (Treg) and transcription factor FoxP3 in the pathogenesis of children with infectious mononucleosis (IM). Thirty-five acute IM patients admitted in our hospital from April 2010 to January 2011 were enrolled in this study. Thirty-five healthy subjects were taken as control. The thirty-five patients before treatment were considered as patients in acute stage, after treatment and without clinical symptom they were thought as patients in recovery stage. The expression levels of TLR2, TLR9 and FoxP3 mRNA were detected by real time PCR using SYBR Green I. The expression of T lymphocyte subset CD4(+)CD25(+) in peripheral blood mononuclear cells was detected by flow cytometry. The results showed that the relative levels of TLR2 mRNA (4.03 ± 0.56), TLR9 mRNA (8.88 ± 1.56) in peripheral blood mononuclear cells of IM patients in acute stage were significantly higher than those of the controls [TLR2 mRNA (2.22 ± 0.57), TLR9 mRNA (3.63 ± 1.30)] and IM patients in recovery stage [TLR2 mRNA (2.76 ± 0.83), TLR9 mRNA (5.34 ± 1.60)] (P 0.05). It is concluded that the expression of CD4(+)CD25(+)regulatory T cells is reduced, and its special transcription factor FoxP3 mRNA is down-regulated, but expression levels of TLR2 mRNA, TLR9 mRNA are up-regulated in IM patients of acute stage.

  10. FOXP3 expression is modulated by TGF-β1/NOTCH1 pathway in human melanoma

    Science.gov (United States)

    Skarmoutsou, Eva; Bevelacqua, Valentina; D'Amico, Fabio; Russo, Angela; Spandidos, Demetrios A.; Scalisi, Aurora

    2018-01-01

    Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-β (TGF-β) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-β-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The γ-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-β was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-β. TGF-β-mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-β stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-β-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability. PMID:29620159

  11. Effects of natalizumab treatment on Foxp3+ T regulatory cells.

    Directory of Open Access Journals (Sweden)

    Max-Philipp Stenner

    Full Text Available BACKGROUND: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4 exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs in multiple sclerosis (MS patients. METHODOLOGY: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs. PRINCIPAL FINDINGS: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4 differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(highCD127(lowFoxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment. CONCLUSIONS: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

  12. FoxP3+ regulatory T cells are distinct from leukemia cells in HTLV-1-associated adult T-cell leukemia.

    Science.gov (United States)

    Toulza, Frederic; Nosaka, Kisato; Takiguchi, Masafumi; Pagliuca, Tony; Mitsuya, Hiroaki; Tanaka, Yuetsu; Taylor, Graham P; Bangham, Charles R M

    2009-11-15

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). It has been postulated that ATLL cells might act as regulatory T cells (T(regs)) which, in common with ATLL cells, express both CD25 and FoxP3, and so contribute to the severe immune suppression typical of ATLL. We report here that the frequency of CD25(+) cells varied independently of the frequency of FoxP3(+) cells in both a cross-sectional study and in a longitudinal study of 2 patients with chronic ATLL. Furthermore, the capacity of ATLL cells to suppress proliferation of heterologous CD4(+)CD25(-) cells correlated with the frequency of CD4(+) FoxP3(+) cells but was independent of CD25 expression. Finally, the frequency of CD4(+)FoxP3(+) cells was inversely correlated with the lytic activity of HTLV-1-specific CTLs in patients with ATLL. We conclude that ATLL is not a tumor of FoxP3(+) regulatory T cells, and that a population of FoxP3(+) cells distinct from ATLL cells has regulatory functions and may impair the cell-mediated immune response to HTLV-1 in patients with ATLL.

  13. Silencing of Foxp3 delays the growth of murine melanomas and modifies the tumor immunosuppressive environment

    Directory of Open Access Journals (Sweden)

    Franco-Molina MA

    2016-01-01

    Full Text Available Moisés A Franco-Molina,* Diana F Miranda-Hernández,* Edgar Mendoza-Gamboa, Pablo Zapata-Benavides, Erika E Coronado-Cerda, Crystel A Sierra-Rivera, Santiago Saavedra-Alonso, Reyes S Taméz-Guerra, Cristina Rodríguez-Padilla Immunology and Virology Department, Biological Sciences Faculty, University Autonoma of Nuevo León (UANL, San Nicolás de los Garza, Nuevo León, Mexico*These authors contributed equally to this work Abstract: Forkhead box p3 (Foxp3 expression was believed to be specific for T-regulatory cells but has recently been described in non-hematopoietic cells from different tissue origins and in tumor cells from both epithelial and non-epithelial tissues. The aim of this study was to elucidate the role of Foxp3 in murine melanoma. The B16F10 cell line Foxp3 silenced with small interference Foxp3 plasmid transfection was established and named B16F10.1. These cells had lower levels of Foxp3 mRNA (quantitative real-time reverse transcription-polymerase chain reaction [0.235-fold], protein (flow cytometry [0.02%], CD25+ expression (0.06%, cellular proliferation (trypan blue staining, and interleukin (IL-2 production (enzyme-linked immunosorbent assay [72.35 pg/mL] than those in B16F10 wild-type (WT cells (P<0.05. Subcutaneous inoculation of the B16F10.1 cell line into C57BL/6 mice delayed the time of visible tumor appearance, increased the time of survival, and affected the weight of tumors, and also decreased the production of IL-10, IL-2, and transforming growth factor beta compared with mice inoculated with the B16F10 WT cell line. The B16F10.1 cells derived from tumors and free of T-cells (isolated by Dynabeads and plastic attachment expressed relatively lower levels of Foxp3 and CD25+ than B16F10 WT cells (P<0.05 in a time-dependent manner. The population of tumor-infiltrating lymphocytes of T CD4+ cells (CD4+, CD4+CD25+, and CD4+CD25+Foxp3+ increased in a time-dependent manner (P<0.05 in tumors derived from B16F10 WT cells

  14. Genetic variants of FOXP1 and FOXF1 are associated with the ...

    Indian Academy of Sciences (India)

    JIE ZHANG

    2018-03-01

    Mar 1, 2018 ... This study aimed to investigate whether the genetic variants of CRTC1, BARX1, FOXP1 and ... The student's t-test was used to compare FOXP1 expression in the tumour and the adjacent normal tissues. .... Quantitative PCR was carried out ..... Expression (GTEx) pilot analysis: multitissue gene regulation.

  15. Silencing of Foxp3 enhances the antitumor efficacy of GM-CSF genetically modified tumor cell vaccine against B16 melanoma

    Directory of Open Access Journals (Sweden)

    Miguel A

    2017-01-01

    Full Text Available Antonio Miguel,1 Luis Sendra,1 Verónica Noé,2 Carles J Ciudad,2 Francisco Dasí,3,4 David Hervas,5 María José Herrero,1,6 Salvador F Aliño17 1Department of Pharmacology, Faculty of Medicine, University of Valencia, 2Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Barcelona, 3Research University Hospital of Valencia, INCLIVA Health Research Institute, 4Department of Physiology, Faculty of Medicine, University of Valencia Foundation, 5Biostatistics Unit, 6Pharmacogenetics Unit, Instituto de Investigación Sanitaria La Fe (IIS La Fe, 7Clinical Pharmacology Unit, ACM Hospital Universitario y Politécnico La Fe, Valencia, Spain Abstract: The antitumor response after therapeutic vaccination has a limited effect and seems to be related to the presence of T regulatory cells (Treg, which express the immunoregulatory molecules CTLA4 and Foxp3. The blockage of CTLA4 using antibodies has shown an effective antitumor response conducing to the approval of the human anti-CTLA4 antibody ipilimumab by the US Food and Drug Administration. On the other hand, Foxp3 is crucial for Treg development. For this reason, it is an attractive target for cancer treatment. This study aims to evaluate whether combining therapeutic vaccination with CTLA4 or Foxp3 gene silencing enhances the antitumor response. First, the “in vitro” cell entrance and gene silencing efficacy of two tools, 2'-O-methyl phosphorotioate-modified oligonucleotides (2'-OMe-PS-ASOs and polypurine reverse Hoogsteen hairpins (PPRHs, were evaluated in EL4 cells and cultured primary lymphocytes. Following B16 tumor transplant, C57BL6 mice were vaccinated with irradiated B16 tumor cells engineered to produce granulocyte-macrophage colony-stimulating factor (GM-CSF and were intraperitoneally treated with CTLA4 and Foxp3 2'-OMe-PS-ASO before and after vaccination. Tumor growth, mice survival, and CTLA4 and Foxp3 expression in blood cells were measured. The following

  16. Analysis of FFAG accelerators and the evolution of circular accelerators

    International Nuclear Information System (INIS)

    Laslett, J.

    1961-01-01

    After rapidly comparing circular machines with the linear accelerator and the reasons for the choice of an annular high energy and very high intensity accelerator, recent problems concerning accelerator theory are discussed, with emphasis on their physical character. The FFAG principle. The limit of the energy of FFAG cyclotron. The setting-up and interpreting of mean energy of focusing terms for a spiral FFAG synchrotron. The limiting amplitude stable near the non-linear resonance 2Q z = Q r , as well as the linear coupling resonance of Walkinshaw 2Q z = Q r . The crossed-beam accelerator. The 40 MeV electron model of MURA. Two other parts deal with linear and non-linear methods of injection and extraction using a variable disturbance applied to the magnetic field, as well as to collective effects. The interaction of the beam with the accelerating cavities and the walls. The modification of the phase oscillation equation. The influence of the beams' high frequency fields on the Nielsen longitudinal instability. (author) [fr

  17. Expansion of CD4+CD25+FOXP3+ regulatory T cells in infants of mothers with type 1 diabetes.

    Science.gov (United States)

    Luopajärvi, Kristiina; Nieminen, Janne K; Ilonen, Jorma; Akerblom, Hans K; Knip, Mikael; Vaarala, Outi

    2012-08-01

    Reduced risk for type 1 diabetes (T1D) has been reported in the offspring of mothers with T1D when compared with children of affected fathers. To evaluate the hypothesis that exposure of the offspring to maternal insulin therapy induces regulatory mechanisms in utero, we compared the FOXP3 expressing regulatory T cells in cord blood (CB) of infants born to mothers with or without T1D. Cord blood mononuclear cells (CBMCs) from 20 infants with maternal T1D and from 20 infants with an unaffected mother were analyzed for the numbers of CD4+CD25+FOXP3+ cells ex vivo and after in vitro stimulation with human insulin by flow cytometry. The mRNA expression of FOXP3, NFATc2, STIM1, interleukin (IL)-10, and transforming growth factor (TGF)-β was measured by real-time reverse transcription polymerase chain reaction. The percentage of FOXP3+ cells in CD4+CD25(high) cells was higher in the CB of the infants with maternal T1D when compared with the infants of unaffected mothers (p = 0.023). After in vitro insulin stimulation an increase in the percentage of FOXP3+ cells in CD4+CD25(high) cells (p = 0.0002) as well as upregulation of FOXP3, NFATc2, STIM1, IL-10, and TGF-β transcripts in CBMCs (p mothers with T1D, in whom the disease-related PTPN22 allele was associated with reduced STIM1 and NFATc2 response in insulin-stimulated CBMCs (p = 0.007 and p = 0.014). We suggest that maternal insulin treatment induces expansion of regulatory T cells in the fetus, which might contribute to the lower risk of diabetes in children with maternal vs. paternal diabetes. © 2012 John Wiley & Sons A/S.

  18. IL-33 Effect on Quantitative Changes of CD4+CD25highFOXP3+ Regulatory T Cells in Children with Type 1 Diabetes

    Directory of Open Access Journals (Sweden)

    Monika Ryba-Stanisławowska

    2016-01-01

    Full Text Available IL-33 is an IL-1 cytokine family member, with ability to induce both Th1 and Th2 immune responses. It binds to ST2 receptor, whose deficiency is associated with enhanced inflammatory response. The most recent studies have shown the immunoregulatory effect of IL-33 on Tregs in animal models. As type 1 diabetes is an autoimmune, inflammatory disease, where Treg defects have been described, we aimed to analyze the in vitro influence of recombinant IL-33 on quantitative properties of regulatory CD4+CD25highFOXP3+ T cells. CD4+CD25highFOXP3+ as well as CD4+CD25highFOXP3+ST2+ Tregs were analyzed by flow cytometry. In a group of patients with type 1 diabetes in vitro IL-33 treatment induced regulatory CD4+CD25highFOXP3+ cell frequencies as well as upregulating the surface expression of ST2 molecule. In addition, the number of CD4+CD25highFOXP3+ cells carrying ST2 receptor increased significantly. Similar effect was observed in case of the FOXP3 expression. We did not observe any significant changes in IL-33 treated cells of healthy controls. The level of ST2 was higher in serum of patients with type 1 diabetes in comparison to their healthy counterparts. We propose that IL-33 becomes an additional immunostimulatory factor used to induce Treg expansion in future clinical trials of adoptive therapy in type 1 diabetes.

  19. FOXP3 positive regulatory T-cells in cutaneous and systemic CD30 positive T-cell lymphoproliferations

    DEFF Research Database (Denmark)

    Gjerdrum, Lise Mette; Woetmann, Anders; Ødum, Niels

    2008-01-01

    for FOXP3 expression in tumour cells and tumour infiltrating Tregs. Labelling of a majority of the neoplastic cells was seen in one case of C-ALCL. Another three cases (one LyP and two C-ALCL) displayed weak labelling of very occasional atypical T-cells. In the remaining 38 cases the atypical lymphoid...... infiltrate was FOXP3 negative. By contrast, all biopsies contained tumour infiltrating FOXP3-positive Tregs. Significant higher numbers were recorded in ALK negative S-ALCL and LyP than in C-ALCL and S-ALCL positive for ALK. In conclusion, it is shown that FOXP3 expression in cutaneous and systemic CD30...

  20. FOXP3: required but not sufficient. the role of GARP (LRRC32) as a safeguard of the regulatory phenotype.

    Science.gov (United States)

    Probst-Kepper, M; Balling, R; Buer, J

    2010-08-01

    FOXP3 is essential for the development and function of regulatory CD4(+)CD25(hi) T (T(reg)) cells. However, recent evidence suggests that FOXP3 alone is not sufficient to completely explain the regulatory phenotype of these key players in autoimmunity and inflammation: after being activated, conventional human CD4(+) T cells transiently up-regulate FOXP3 without acquiring a regulatory function. Researchers have recently found that glycoprotein A repetitions predominant (GARP, or LRRC32) is a T(reg)-specific receptor that binds latent TGF-beta and dominantly controls FOXP3 and the regulatory phenotype via a positive feedback loop. This finding provides a missing link in our molecular understanding of FOXP3 in T(reg) cells. This viewpoint focuses on GARP as safeguard of FOXP3 and the regulatory phenotype.

  1. FOXP3 and GARP (LRRC32): the master and its minion

    OpenAIRE

    Buer Jan; Probst-Kepper Michael

    2010-01-01

    Abstract The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype. Reviewers: Dr...

  2. FOXP3 and GARP (LRRC32): the master and its minion.

    Science.gov (United States)

    Probst-Kepper, Michael; Buer, Jan

    2010-02-05

    The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (T(reg)) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human T(reg) cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype.

  3. Eosinophils from eosinophilic oesophagitis patients have T cell suppressive capacity and express FOXP3.

    Science.gov (United States)

    Lingblom, C; Wallander, J; Ingelsten, M; Bergquist, H; Bove, M; Saalman, R; Welin, A; Wennerås, C

    2017-03-01

    Eosinophilic esophagitis (EoE) is an antigen-driven T cell-mediated chronic inflammatory disease where food and environmental antigens are thought to have a role. Human eosinophils express the immunoregulatory protein galectin-10 and have T cell suppressive capacity similar to regulatory T cells (T regs ). We hypothesized that one function of eosinophils in EoE might be to regulate the T cell-driven inflammation in the oesophagus. This was tested by evaluating the suppressive capacity of eosinophils isolated from the blood of adult EoE patients in a mixed lymphocyte reaction. In addition, eosinophilic expression of forkhead box protein 3 (FOXP3), the canonical transcription factor of T regs , was determined by conventional and imaging flow cytometry, quantitative polymerase chain reaction (qPCR), confocal microscopy and immunoblotting. It was found that blood eosinophils from EoE patients had T cell suppressive capacity, and that a fraction of the eosinophils expressed FOXP3. A comparison of EoE eosinophils with healthy control eosinophils indicated that the patients' eosinophils had inferior suppressive capacity. Furthermore, a higher percentage of the EoE eosinophils expressed FOXP3 protein compared with the healthy eosinophils, and they also had higher FOXP3 protein and mRNA levels. FOXP3 was found in the cytosol and nucleus of the eosinophils from both the patients and healthy individuals, contrasting with the strict nuclear localization of FOXP3 in T regs . To conclude, these findings suggest that the immunoregulatory function of eosinophils may be impaired in EoE. © 2016 British Society for Immunology.

  4. THE RELATIONSHIP OF FoxP3+ T REGULATORY CELLS TO DISEASE ACTIVITY AND ANTIBODY LEVELS IN EARLY RHEUMATOID ARTHRITIS

    Directory of Open Access Journals (Sweden)

    A. S. Avdeeva

    2017-01-01

    Full Text Available Objective: to analyze the relationship of the count of FoxP3+ T regulatory cells (Tregs to the clinical and laboratory parameters of disease activity and the levels of antibodies in a group of patients with early rheumatoid arthritis (RA.Subjects and methods. The investigation enrolled 45 patients with early RA (2010 ACR/EULAR criteria who had not previously received treatment with methotrexate, including 39 women; median age was 52.0 [32.5; 57.5] years; disease duration, 5 [4; 6] months, DAS28 5.01 [4.18; 5.8]; 71.1% of the patients were rheumatoid factor (RF positive and 88.9% were anti-cyclic citrullinated peptide positive. The relative and absolute counts of Treg (FoxP3+CD25+; CD152+surface; CD152+intracellular; FoxP3+CD127-; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; FoxP3+CD274+ were measured by immunofluorescence staining and multicolor flow cytometry. A control group consisted of 20 healthy donors who were matched for sex and age with the examined patients.Results and discussion. DАS28 was high, moderate, and low in 22 (48.9%, 20 (44.4%, and 3 (6.7% patients, respectively. As compared with the healthy donors, the patients with early RA were observed to have lower values in the percentage of FoxP3+CD25+ cells, in the percentage and absolute count of FoxP3+ICOS+ cells, in the percentage and absolute count of FoxP3+CD154+ and FoxP3+ CD274+ T cells; p<0.05 in all cases. Negative correlation was recorded between the percentage of FoxP3+CD25+ and C-reactive protein (CRP (r=-0.4; that of CD152+intracellular and DAS28 (r=-0.35, ESR (r=-0.46, CRP (r=-0.54; that of FoxP3+CD127 and CRP (r=-0.42; that of CD25+CD127 and DAS28 (r=-0.38, SDAI (r=-0.41, CDAI (r=-0.36, ESR (r=-0.39, CRP (r=-0.47; p<0.05 in all cases.The patients who were seronegative for RF were found to have higher values in the percentage of CD25+CD127, in the percentage and absolute count of Foxp3+CD154+ and Foxp3+CD274+ T lymphocytes.Conclusion. The given data may indicate that the

  5. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals

    Directory of Open Access Journals (Sweden)

    Satou Yorifumi

    2012-05-01

    Full Text Available Abstract Background HTLV-1 utilizes CD4 T cells as the main host cell and maintains the proviral load via clonal proliferation of infected CD4+ T cells. Infection of CD4+ T cells by HTLV-1 is therefore thought to play a pivotal role in HTLV-1-related pathogenicity, including leukemia/lymphoma of CD4+ T cells and chronic inflammatory diseases. Recently, it has been reported that a proportion of HTLV-1 infected CD4+ T cells express FoxP3, a master molecule of regulatory T cells. However, crucial questions remain unanswered on the relationship between HTLV-1 infection and FoxP3 expression. Results To investigate the effect of HTLV-1 infection on CD4+ T-cell subsets, we used flow cytometry to analyze the T-cell phenotype and HTLV-1 infection in peripheral mononuclear cells (PBMCs of four groups of subjects, including 23 HTLV-1-infected asymptomatic carriers (AC, 10 patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP, 10 patients with adult T-cell leukemia (ATL, and 10 healthy donors. The frequency of FoxP3+ cells in CD4+ T cells in AC with high proviral load and patients with HAM/TSP or ATL was higher than that in uninfected individuals. The proviral load was positively correlated with the percentage of CD4+ T cells that were FoxP3+. The CD4+FoxP3+ T cells, themselves, were frequently infected with HTLV-1. We conclude that FoxP3+ T- cells are disproportionately infected with HTLV-1 during chronic infection. We next focused on PBMCs of HAM/TSP patients. The expression levels of the Treg associated molecules CTLA-4 and GITR were decreased in CD4+FoxP3+ T cells. Further we characterized FoxP3+CD4+ T-cell subsets by staining CD45RA and FoxP3, which revealed an increase in CD45RA−FoxP3low non-suppressive T-cells. These findings can reconcile the inflammatory phenotype of HAM/TSP with the observed increase in frequency of FoxP3+ cells. Finally, we analyzed ATL cells and observed not only a high frequency of FoxP3 expression

  6. Structure, shape, and evolution of radiatively accelerated QSO emission-line clouds

    International Nuclear Information System (INIS)

    Blumenthal, G.R.; Mathews, W.G.

    1979-01-01

    The possibility that the broad emission-line regions of QSOs and active galactic nuclei are formed by a multitude of small clouds which are radiatively accelerated is discussed. Although this model is by no means certain at present, it has four virtues: (1) Observed emission-line widths can be produced with observationally allowed electron densities, UV luminosities, and ionization levels. (2) The acceleration force is coherent in each cloud are found. (3) Reasonable line profiles can result for all emission lines. (4) Photoionization of hydrogen accounts for both heating and acceleration of the emission-line gas. A self-consistent model is developed for the structure, shape, and evolution of radiatively accelerated clouds. The shape varies with cloud mass, and two distinct types of clouds. Fully ionized clouds of very low mass approach a nearly spherical shape. However, all clouds having masses greater than some critical mass adopt a ''pancake'' shape. The condition for constant cloud mass in the cloud frame is shown to be equivalent to the equation of motion of a cloud in the rest frame of the QSO. The emission-line profiles can be sensitive to radial variations in the properties of the intercloud medium, and those properties that correspond to observed profiles are discussed. Finally, the covering factor of a system of pancake clouds is estimated along with the total number of clouds required--approximately 10 14 clouds in each QSO

  7. Expression of Foxp3 in colorectal cancer but not in Treg cells correlates with disease progression in patients with colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Mia Kim

    Full Text Available BACKGROUND: Regulatory T cells (Treg expressing the transcription factor forkhead-box protein P3 (Foxp3 have been identified to counteract anti-tumor immune responses during tumor progression. Besides, Foxp3 presentation by cancer cells itself may also allow them to evade from effector T-cell responses, resulting in a survival benefit of the tumor. For colorectal cancer (CRC the clinical relevance of Foxp3 has not been evaluated in detail. Therefore the aim of this study was to study its impact in colorectal cancer (CRC. METHODS AND FINDINGS: Gene and protein analysis of tumor tissues from patients with CRC was performed to quantify the expression of Foxp3 in tumor infiltrating Treg and colon cancer cells. The results were correlated with clinicopathological parameters and patients overall survival. Serial morphological analysis demonstrated Foxp3 to be expressed in cancer cells. High Foxp3 expression of the cancer cells was associated with poor prognosis compared to patients with low Foxp3 expression. In contrast, low and high Foxp3 level in tumor infiltrating Treg cells demonstrated no significant differences in overall patient survival. CONCLUSIONS: Our findings strongly suggest that Foxp3 expression mediated by cancer cells rather than by Treg cells contribute to disease progression.

  8. Differential pattern and prognostic significance of CD4+, FOXP3+ and IL-17+ tumor infiltrating lymphocytes in ductal and lobular breast cancers

    International Nuclear Information System (INIS)

    Droeser, Raoul; Zlobec, Inti; Kilic, Ergin; Güth, Uwe; Heberer, Michael; Spagnoli, Giulio; Oertli, Daniel; Tapia, Coya

    2012-01-01

    Clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes. A tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival. CD4 + lymphocytes were more prevalent than FOXP3 + TILs whereas IL-17 + TILs were rare. Increased numbers of total CD4 + and FOXP3 + TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4 + and FOXP3 + lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3 + TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4 + infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3 + /CD4 + ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033). Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4 + and FOXP3 + TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3 + /CD4 + TILs in ductal carcinoma appears to represent an independent

  9. CD147 (Basigin/Emmprin) identifies FoxP3+CD45RO+CTLA4+-activated human regulatory T cells.

    Science.gov (United States)

    Solstad, Therese; Bains, Simer Jit; Landskron, Johannes; Aandahl, Einar Martin; Thiede, Bernd; Taskén, Kjetil; Torgersen, Knut Martin

    2011-11-10

    Human CD4(+)FoxP3(+) T cells are functionally and phenotypically heterogeneous providing plasticity to immune activation and regulation. To better understand the functional dynamics within this subset, we first used a combined strategy of subcellular fractionation and proteomics to describe differences at the protein level between highly purified human CD4(+)CD25(+) and CD4(+)CD25(-) T-cell populations. This identified a set of membrane proteins highly expressed on the cell surface of human regulatory T cells (Tregs), including CD71, CD95, CD147, and CD148. CD147 (Basigin or Emmprin) divided CD4(+)CD25(+) cells into distinct subsets. Furthermore, CD147, CD25, FoxP3, and in particular CTLA-4 expression correlated. Phenotypical and functional analyses suggested that CD147 marks the switch between resting (CD45RA(+)) and activated (CD45RO(+)) subsets within the FoxP3(+) T-cell population. Sorting of regulatory T cells into CD147(-) and CD147(+) populations demonstrated that CD147 identifies an activated and highly suppressive CD45RO(+) Treg subset. When analyzing CD4(+) T cells for their cytokine producing potential, CD147 levels grouped the FoxP3(+) subset into 3 categories with different ability to produce IL-2, TNF-α, IFN-γ, and IL-17. Together, this suggests that CD147 is a direct marker for activated Tregs within the CD4(+)FoxP3(+) subset and may provide means to manipulate cells important for immune homeostasis.

  10. FOXP3 and GARP (LRRC32: the master and its minion

    Directory of Open Access Journals (Sweden)

    Buer Jan

    2010-02-01

    Full Text Available Abstract The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32 recently identified as specific marker of activated human Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype. Reviewers: Dr Jim Di Danto, Dr Benedita Rocha and Dr Werner Solbach.

  11. Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

    Directory of Open Access Journals (Sweden)

    Kalpana Kalyanasundaram Bhanumathy

    2014-03-01

    Full Text Available Dendritic cells (DCs, the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdVIL-6 expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DCOVA/IL-6 by transfection of murine bone marrow-derived ovalbumin (OVA-pulsed DCs (DCOVA with AdVIL-6. We then assessed DCOVA/IL-6-stimulated cytotoxic T-lymphocyte (CTL responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DCOVA/IL-6 vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10OVA in vivo than the control DCOVA/Null vaccine. Moreover, DCOVA/IL-6-stimulated CTL responses were relatively maintained in mice with transfer of CD4+25+Foxp3+ Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4+25+Foxp3+ Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4+25+ Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.

  12. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells.

    Science.gov (United States)

    Wang, Rui; Kozhaya, Lina; Mercer, Frances; Khaitan, Alka; Fujii, Hodaka; Unutmaz, Derya

    2009-08-11

    The molecules that define human regulatory T cells (Tregs) phenotypically and functionally remain to be fully characterized. We recently showed that activated human Tregs express mRNA for a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32). Here, using a GARP-specific mAb, we demonstrate that expression of GARP on activated Tregs correlates with their suppressive capacity. However, GARP was not induced on T cells activated in the presence of TGFbeta, which expressed high levels of FOXP3 and lacked suppressive function. Ectopic expression of FOXP3 in conventional T cells was also insufficient for induction of GARP expression in most donors. Functionally, silencing GARP in Tregs only moderately attenuated their suppressive activity. CD25+ T cells sorted for high GARP expression displayed more potent suppressive activity compared with CD25+GARP- cells. Remarkably, CD25+GARP- T cells expanded in culture contained 3-5 fold higher IL-17-secreting cells compared with either CD25+GARP+ or CD25-GARP- cells, suggesting that high GARP expression can potentially discriminate Tregs from those that have switched to Th17 lineage. We also determined whether GARP expression correlates with FOXP3-expressing T cells in human immunodeficiency virus (HIV) -infected subjects. A subset of HIV+ individuals with high percentages of FOXP3+ T cells did not show proportionate increase in GARP+ T cells. This finding suggests that higher FOXP3 levels observed in these HIV+ individuals is possibly due to immune activation rather than to an increase in Tregs. Our findings highlight the significance of GARP both in dissecting duality of Treg/Th17 cell differentiation and as a marker to identify bona fide Tregs during diseases with chronic immune activation.

  13. Clinicopathological and prognostic significance of FOXP3+ tumor infiltrating lymphocytes in patients with breast cancer: a meta-analysis

    International Nuclear Information System (INIS)

    Jiang, Daqing; Gao, Zhaohua; Cai, Zhengang; Wang, Meixian; He, Jianjun

    2015-01-01

    The prognostic significance of FOXP3+ tumor-infiltrating lymphocytes (TILs) in patients with breast cancer remains controversial. The aims of our meta-analysis are to evaluate its association with clinicopathological characteristics and prognostic significance in patients with breast cancer. PubMed, Embase, Cochrane Database and the Ovid Database were systematically searched (up to April 2015). The meta-analysis was performed using hazard ratio (HR), odds ratio (OR) and 95 % confidence intervals (CI) as effect measures. Using the random-effects model, statistical analysis was performed using Stata software, version 12.0. Seventeen studies including 8277 patients with breast cancer were analyzed. The meta-analysis indicated that the incidence difference of FOXP3+ TILs was significant when comparing the lymph node positive group to negative group (OR = 1.305, 95 % CI [1.071, 1.590]), the histological grade III group to the I–II group (OR = 3.067, 95 % CI [2.288, 4.111]), the ER positive group to the negative group (OR = 0.435, 95 % CI [0.287, 0.660]), the PR positive group to the negative group (OR = 0.493, 95 % CI [0.296, 0.822]), the HER2 positive group to the negative group (OR = 1.896, 95 % CI [1.335, 2.692]), the TNBC group to the non TNBC group (OR = 2.456, 95 % CI [1.801, 3.348]). The detection of FOXP3+ TILs was significantly correlated with the recurrence-free survival (RFS) of patients (HR = 1.752, 95 % CI [1.188–2.584]) and the overall survival (OS) of patients (HR =1.447, 95 % CI [1.037–2.019]). Our meta-analysis demonstrates that the presence of high levels of FOXP3+ TILs is associated with prognosis for breast cancer patients and predicts lymph node metastasis, hormone receptor and HER-2 status

  14. Transcription of Toll-Like Receptors 2, 3, 4 and 9, FoxP3 and Th17 Cytokines in a Susceptible Experimental Model of Canine Leishmania infantum Infection

    Science.gov (United States)

    Hosein, Shazia; Rodríguez-Cortés, Alhelí; Blake, Damer P.; Allenspach, Karin; Alberola, Jordi; Solano-Gallego, Laia

    2015-01-01

    Canine leishmaniosis (CanL) due to Leishmania infantum is a chronic zoonotic systemic disease resulting from complex interactions between protozoa and the canine immune system. Toll-like receptors (TLRs) are essential components of the innate immune system and facilitate the early detection of many infections. However, the role of TLRs in CanL remains unknown and information describing TLR transcription during infection is extremely scarce. The aim of this research project was to investigate the impact of L. infantum infection on canine TLR transcription using a susceptible model. The objectives of this study were to evaluate transcription of TLRs 2, 3, 4 and 9 by means of quantitative reverse transcription polymerase chain reaction (qRT-PCR) in skin, spleen, lymph node and liver in the presence or absence of experimental L. infantum infection in Beagle dogs. These findings were compared with clinical and serological data, parasite densities in infected tissues and transcription of IL-17, IL-22 and FoxP3 in different tissues in non-infected dogs (n = 10), and at six months (n = 24) and 15 months (n = 7) post infection. Results revealed significant down regulation of transcription with disease progression in lymph node samples for TLR3, TLR4, TLR9, IL-17, IL-22 and FoxP3. In spleen samples, significant down regulation of transcription was seen in TLR4 and IL-22 when both infected groups were compared with controls. In liver samples, down regulation of transcription was evident with disease progression for IL-22. In the skin, upregulation was seen only for TLR9 and FoxP3 in the early stages of infection. Subtle changes or down regulation in TLR transcription, Th17 cytokines and FoxP3 are indicative of the silent establishment of infection that Leishmania is renowned for. These observations provide new insights about TLR transcription, Th17 cytokines and Foxp3 in the liver, spleen, lymph node and skin in CanL and highlight possible markers of disease susceptibility in

  15. Measurement of volatile evolution from polyurethane induced by accelerated ion beam irradiation

    International Nuclear Information System (INIS)

    Murphy, J.J.

    2003-01-01

    Irradiation of polymer samples using an accelerated beam of He 2+ ions passed through a 10μm thick window of havar foil has been performed. Such irradiation simulates the effects of large α radiation doses, on a vastly reduced time-scale. Analysis of volatiles evolved during irradiation is performed by a residual gas analyser (RGA), which is located close to the sample chamber. Presented in this paper are the results obtained during a radiation study on polyester/MDI based polyurethane materials. During high dose rate irradiation a number of high mass species were observed. A comparison between two similar polyurethanes formulated with slightly different polyesters indicated some differences. They were, however, too minor to link to specific degradation mechanisms. The dominant degradation products evident to the RGA at low dose rates were H 2 , CO and CO 2 . A series of polyurethane samples previously conditioned by γ irradiation at doses between 0 and 5MGy were irradiated in the ion beam. Identification of differences in trends in the rates of volatile evolution between these samples indicated the precise vacuum conditions at the time of irradiation had a major influence. There was also an indication that the surface of the sample had a small effect on rates of volatile evolution. Comparative plots of CO and CO 2 evolution for a series of 1MGy irradiations indicated variations in behaviour between samples with different γ doses. Evolution during the first 1MGy was inhibited for the unirradiated sample, the extent of inhibition diminished with increasing γ dose and was no longer evident in a sample with 1.5MGy γ dose. H 2 does not show an equivalent inhibition. Evidence for a low dose crosslinking reaction is put forward as a reason for the inhibition. Chemical reaction mechanisms are postulated and used to explain differences in the behaviour observed

  16. TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity.

    Directory of Open Access Journals (Sweden)

    Go Muto

    Full Text Available Regulatory T cells (Tregs maintain immune homeostasis by limiting inflammatory responses. TRAF6 plays a key role in the regulation of innate and adaptive immunity by mediating signals from various receptors including the T-cell receptor (TCR. T cell-specific deletion of TRAF6 has been shown to induce multiorgan inflammatory disease, but the role of TRAF6 in Tregs remains to be investigated. Here, we generated Treg-specific TRAF6-deficient mice using Foxp3-Cre and TRAF6-flox mice. Treg-specific TRAF6-deficient (cKO mice developed allergic skin diseases, arthritis, lymphadenopathy and hyper IgE phenotypes. Although TRAF6-deficient Tregs possess similar in vitro suppression activity compared to wild-type Tregs, TRAF6-deficient Tregs did not suppress colitis in lymphopenic mice very efficiently due to reduced number of Foxp3-positive cells. In addition, the fraction of TRAF6-deficient Tregs was reduced compared with wild-type Tregs in female cKO mice without inflammation. Moreover, adoptive transfer of Foxp3 (+ Tregs into Rag2(-/- mice revealed that TRAF6-deficient Tregs converted into Foxp3(- cells more rapidly than WT Tregs under lymphopenic conditions. Fate-mapping analysis also revealed that conversion of Tregs from Foxp3(+ to Foxp3(- (exFoxp3 cells was accelerated in TRAF6-deficient Tregs. These data indicate that TRAF6 in Tregs plays important roles in the maintenance of Foxp3 in Tregs and in the suppression of pathogenic Th2 type conversion of Tregs.

  17. FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival

    DEFF Research Database (Denmark)

    Gjerdrum, L M; Woetmann, A; Odum, Niels

    2007-01-01

    FOXP3 is a unique marker for CD4+CD25+ regulatory T cells (Tregs). In solid tumours, high numbers of Tregs are associated with a poor prognosis. Knowledge about the implications of Tregs for the behaviour of haematological malignancies is limited. In this study, skin biopsies from 86 patients...... with mycosis fungoides (MF) and cutaneous T-cell lymphoma (CTCL) unspecified were analysed for the expression of FOXP3 on tumour cells and tumour-infiltrating Tregs. Labelling of above 10% of the neoplastic cells was seen in one case classified as an aggressive epidermotropic CD8+ cytotoxic CTCL....... In the remaining 85 cases, the atypical neoplastic infiltrate was either FOXP3 negative (n=80) or contained only very occasional weakly positive cells (n=5). By contrast, all biopsies showed varying numbers of strongly FOXP3+ tumour-infiltrating Tregs. MF with early or infiltrated plaques had significantly higher...

  18. Dynamic changes of Foxp3(+) regulatory T cells in spleen and brain of canine distemper virus-infected dogs.

    Science.gov (United States)

    Qeska, V; Barthel, Y; Iseringhausen, M; Tipold, A; Stein, V M; Khan, M A; Baumgärtner, W; Beineke, A

    2013-12-15

    Canine distemper virus (CDV) infection causes immunosuppression and demyelinating leukoencephalitis in dogs. In viral diseases, an ambiguous function of regulatory T cells (Treg), with both beneficial effects by reducing immunopathology and detrimental effects by inhibiting antiviral immunity, has been described. However, the role of Treg in the pathogenesis of canine distemper remains unknown. In order to determine the effect of CDV upon immune homeostasis, the amount of Foxp3(+) Treg in spleen and brain of naturally infected dogs has been determined by immunohistochemistry. In addition, splenic cytokine expression has been quantified by reverse transcriptase polymerase chain reaction. Splenic depletion of Foxp3(+) Treg was associated with an increased mRNA-expression of tumor necrosis factor and decreased transcription of interleukin-2 in the acute disease phase, indicative of disturbed immunological counter regulation in peripheral lymphoid organs. In the brain, a lack of Foxp3(+) Treg in predemyelinating and early demyelinating lesions and significantly increased infiltrations of Foxp3(+) Treg in chronic demyelinating lesions were observed. In conclusion, disturbed peripheral and CNS immune regulation associated with a reduction of Treg represents a potential prerequisite for excessive neuroinflammation and early lesion development in canine distemper leukoencephalitis. © 2013 Elsevier B.V. All rights reserved.

  19. Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3+ Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

    Directory of Open Access Journals (Sweden)

    Yoon-Young Sung

    2017-01-01

    Full Text Available Illicium verum is used in traditional medicine to treat inflammation. The study investigates the effects of IVE and its component, trans-anethole (AET, on airway inflammation in ovalbumin- (OVA- induced asthmatic mice. Asthma was induced in BALB/c mice by systemic sensitization to OVA, followed by intratracheal, intraperitoneal, and aerosol allergen challenges. IVE and AET were orally administered for four weeks. We investigated the effects of treatment on airway hyperresponsiveness, IgE production, pulmonary eosinophilic infiltration, immune cell phenotypes, Th2 cytokine production in bronchoalveolar lavage, Th1/Th2 cytokine production in splenocytes, forkhead box protein 3 (Foxp3 expression, and lung histology. IVE and AET ameliorated OVA-driven airway hyperresponsiveness (p<0.01, pulmonary eosinophilic infiltration (p<0.05, mucus hypersecretion (p<0.01, and IL-4, IL-5, IL-13, and CCR3 production (p<0.05, as well as IgE levels (p<0.01. IVE and AET increased Foxp3 expression in lungs (p<0.05. IVE and AET reduced IL-4 and increased IFN-γ production in the supernatant of splenocyte cultures (p<0.05. Histological studies showed that IVE and AET inhibited eosinophilia and lymphocyte infiltration in lungs (p<0.01. These results indicate that IVE and AET exert antiasthmatic effects through upregulation of Foxp3+ regulatory T cells and inhibition of Th2 cytokines, suggesting that IVE may be a potential therapeutic agent for allergic lung inflammation.

  20. TGF-β-induced IκB-ζ controls Foxp3 gene expression

    Energy Technology Data Exchange (ETDEWEB)

    MaruYama, Takashi, E-mail: ta-maru@umin.ac.jp [Laboratory of Cell Recognition and Response, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578 (Japan); School of Medicine, Gifu University, Gifu 501-1194 (Japan)

    2015-08-21

    Inhibitor of kappa B (IκB)-ζ, a member of the nuclear IκB family of proteins, is induced by the transforming growth factor (TGF)-β signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. IκB-ζ deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of IκB-ζ deficiency on T-cell subsets were examined further. The data showed that IκB-ζ-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-β stimulation in the presence of cytokine-neutralizing antibodies. Mechanistically, IκB-ζ itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that IκB-ζ controlled Treg differentiation. - Highlights: • IκB-ζ-deficient T cells exhibited increased generation of Foxp3{sup +} Tregs. • IκB-ζ played a key role in Foxp3 gene expression. • Retroviral overexpression of IκB-ζ was achieved in T cells.

  1. TGF-β-induced IκB-ζ controls Foxp3 gene expression

    International Nuclear Information System (INIS)

    MaruYama, Takashi

    2015-01-01

    Inhibitor of kappa B (IκB)-ζ, a member of the nuclear IκB family of proteins, is induced by the transforming growth factor (TGF)-β signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. IκB-ζ deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of IκB-ζ deficiency on T-cell subsets were examined further. The data showed that IκB-ζ-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-β stimulation in the presence of cytokine-neutralizing antibodies. Mechanistically, IκB-ζ itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that IκB-ζ controlled Treg differentiation. - Highlights: • IκB-ζ-deficient T cells exhibited increased generation of Foxp3 + Tregs. • IκB-ζ played a key role in Foxp3 gene expression. • Retroviral overexpression of IκB-ζ was achieved in T cells

  2. Radio Evolution of Supernova Remnants Including Nonlinear Particle Acceleration: Insights from Hydrodynamic Simulations

    Science.gov (United States)

    Pavlović, Marko Z.; Urošević, Dejan; Arbutina, Bojan; Orlando, Salvatore; Maxted, Nigel; Filipović, Miroslav D.

    2018-01-01

    We present a model for the radio evolution of supernova remnants (SNRs) obtained by using three-dimensional hydrodynamic simulations coupled with nonlinear kinetic theory of cosmic-ray (CR) acceleration in SNRs. We model the radio evolution of SNRs on a global level by performing simulations for a wide range of the relevant physical parameters, such as the ambient density, supernova (SN) explosion energy, acceleration efficiency, and magnetic field amplification (MFA) efficiency. We attribute the observed spread of radio surface brightnesses for corresponding SNR diameters to the spread of these parameters. In addition to our simulations of Type Ia SNRs, we also considered SNR radio evolution in denser, nonuniform circumstellar environments modified by the progenitor star wind. These simulations start with the mass of the ejecta substantially higher than in the case of a Type Ia SN and presumably lower shock speed. The magnetic field is understandably seen as very important for the radio evolution of SNRs. In terms of MFA, we include both resonant and nonresonant modes in our large-scale simulations by implementing models obtained from first-principles, particle-in-cell simulations and nonlinear magnetohydrodynamical simulations. We test the quality and reliability of our models on a sample consisting of Galactic and extragalactic SNRs. Our simulations give Σ ‑ D slopes between ‑4 and ‑6 for the full Sedov regime. Recent empirical slopes obtained for the Galactic samples are around ‑5, while those for the extragalactic samples are around ‑4.

  3. Effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4⁺ CD25⁺ Foxp3⁺ Treg in asthma Balb/c mouse.

    Science.gov (United States)

    Yun, Xiang; Shang, Yunxiao; Li, Miao

    2015-01-01

    Bronchial asthma is a chronic airway inflammatory disease that involves T lymphocytes. In order to explore the effect of Lactobacillus salivarius on Th1/Th2 cytokines and the number of spleen CD4(+) CD25(+) Foxp3(+) Treg in asthma Balb/c mouse, we constructed acute asthma model with ovalbumin to observe the mouse behavior change in Balb/c mice. The expression of GATA-3 mRNA and T-bet mRNA was measured by real-time PCR. The proportion of CD4(+) CD25(+) Foxp3(+) Treg/CD4(+) was determined by flow cytometry. The results demonstrated that oral gavage with Lactobacillus salivarius before sensitization could alleviate the clinical symptoms, airway hyper-reactivity and airway inflammation in asthma mouse to some extent; Lactobacillus salivarius may improve the imbalance of Th1/Th2 in asthma mouse through increasing the expression of T-bet mRNA at the transcriptional level and inhibiting the expression of GATA-3 mRNA simultaneously. CD4(+) CD25(+) Foxp3(+) Treg cells may be involved in the pathogenesis of bronchial asthma, and may be the upstream regulatory mechanism of the improvement of Th1/Th2 imbalance by Lactobacillus salivarius.

  4. FoxP3+CD4+CD25+ T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease

    Science.gov (United States)

    Kelsen, J; Agnholt, J; Hoffmann, H J; Rømer, J L; Hvas, C L; Dahlerup, J F

    2005-01-01

    CD4+CD25+ regulatory T cells (Tregs) are involved in the maintenance of peripheral tolerance and ensure a balanced immune response competent of fighting pathogens and at the same time recognizing commensals as harmless. This feature is lost in Crohn's disease (CD). The forkhead/winged helix transcription factor FoxP3 is a master gene for Treg function and defects in the FoxP3 gene lead to a clinical picture similar to inflammatory bowel disease (IBD). Murine colitis can be cured by adoptive transfer of Tregs and ex vivo-generated gut-specific Tregs represent an attractive option for therapy in CD. Thus, defective Tregs could contribute to the development of CD. We cultured biopsies of colonic mucosa in the presence of high concentrations of interleukin (IL)-2 and IL-4 to overcome the anergic nature of naturally occurring CD4+CD25+ Tregs in the mucosa. We investigated the expression of FoxP3 and regulatory potential of gut-derived CD4+CD25+ T cells cultured from patients with CD and healthy individuals. The FoxP3 expression was analysed by reverse transcriptase polymerase chain reaction (RT-PCR), and the suppressive effect of FoxP3+CD4+CD25+ T cells on proliferation and cytokine production of autologous CD4+ T cells was assessed by flow cytometry. Cultured gut-derived T cells with CD4+CD25+ phenotype expressed FoxP3 and were able as the freshly isolated Tregs from peripheral blood to suppress proliferation and cytokine production of autologous CD4+ T cells. Thus, we demonstrate that FoxP3+CD4+CD25+ T cells with regulatory properties can be propagated in vitro from inflamed mucosa of CD patients, which may be of interest in adoptive immunotherapy. PMID:16045746

  5. ChIP-on-chip analysis identifies IL-22 as direct target gene of ectopically expressed FOXP3 transcription factor in human T cells

    Directory of Open Access Journals (Sweden)

    Jeron Andreas

    2012-12-01

    Full Text Available Abstract Background The transcription factor (TF forkhead box P3 (FOXP3 is constitutively expressed at high levels in naturally occurring CD4+CD25+ regulatory T cells (nTregs. It is not only the most accepted marker for that cell population but is also considered lineage determinative. Chromatin immunoprecipitation (ChIP of TFs in combination with genomic tiling microarray analysis (ChIP-on-chip has been shown to be an appropriate tool for identifying FOXP3 transcription factor binding sites (TFBSs on a genome-wide scale. In combination with microarray expression analysis, the ChIP-on-chip technique allows identification of direct FOXP3 target genes. Results ChIP-on-chip analysis of the human FOXP3 expressed in resting and PMA/ionomycin–stimulated Jurkat T cells revealed several thousand putative FOXP3 binding sites and demonstrated the importance of intronic regions for FOXP3 binding. The analysis of expression data showed that the stimulation-dependent down-regulation of IL-22 was correlated with direct FOXP3 binding in the IL-22 promoter region. This association was confirmed by real-time PCR analysis of ChIP-DNA. The corresponding ChIP-region also contained a matching FOXP3 consensus sequence. Conclusions Knowledge of the general distribution patterns of FOXP3 TFBSs in the human genome under resting and activated conditions will contribute to a better understanding of this TF and its influence on direct target genes, as well as its importance for the phenotype and function of Tregs. Moreover, FOXP3-dependent repression of Th17-related IL-22 may be relevant to an understanding of the phenomenon of Treg/Th17 cell plasticity.

  6. Induced Foxp3+ T cells colonising tolerated allografts exhibit the hypomethylation pattern typical of mature regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Robert eHilbrands

    2016-04-01

    Full Text Available Regulatory T cells expressing the transcription factor Foxp3 require acquisition of a specific hypomethylation pattern to ensure optimal functional commitment, limited lineage plasticity and long-term maintenance of tolerance. A better understanding of the molecular mechanisms involved in the generation of these epigenetic changes in vivo will contribute to the clinical exploitation of Foxp3+Treg. Here we show that both in vitro and in vivo generated antigen specific Foxp3+Treg can acquire Treg-specific epigenetic characteristics and prevent skin graft rejection in an animal model.

  7. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

    DEFF Research Database (Denmark)

    Brown, P J; Wong, K K; Felce, S L

    2016-01-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II......) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes......, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (PABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone...

  8. [Increased expressions of peripheral PD-1+ lymphocytes and CD4+CD25+FOXP3+ T cells in gastric adenocarcinoma patients].

    Science.gov (United States)

    Li, Hao; Li, Songyan; Hu, Shidong; Zou, Guijun; Hu, Zilong; Wei, Huahua; Wang, Yufeng; Du, Xiaohui

    2017-01-01

    Objective To detect the frequencies of peripheral programmed death-1 + (PD-1 + ) lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in patients with gastric adenocarcinoma. Methods The study enrolled 29 patients with gastric adenocarcinoma and 29 age- and sex-matched healthy controls. Frequencies of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells were detected using flow cytometry. Results The number of PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood was higher in patients with gastric adenocarcinoma than that in the control group. Moreover, linear correlation analysis indicated a positive correlation between PD-1 expression and frequency of CD4 + CD25 + FOXP3 + regulatory T cells in peripheral blood of the patients. Conclusion Gastric adenocarcinoma patients present with increased PD-1 + lymphocytes and CD4 + CD25 + FOXP3 + regulatory T cells in the peripheral blood.

  9. All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.

    Directory of Open Access Journals (Sweden)

    Ling Lu

    Full Text Available It has been documented all-trans retinoic acid (atRA promotes the development of TGF-β-induced CD4(+Foxp3(+ regulatory T cells (iTreg that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.Addition of atRA to naïve CD4(+CD25(- cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3(+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4(+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4(+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4(+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4(+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.We have identified the cellular and molecular mechanism(s by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.

  10. Micro-RNA 10a Is Increased in Feline T Regulatory Cells and Increases Foxp3 Protein Expression Following In Vitro Transfection

    Directory of Open Access Journals (Sweden)

    Yan Wang

    2017-02-01

    Full Text Available CD4+CD25+Foxp3+ T regulatory (Treg cells are activated during the course of lentiviral infection and exhibit heightened suppressor function when compared to Treg cells from uninfected controls. Foxp3 is essential to Treg cell function and multiple studies have documented that lentivirus-activated Treg cells exhibit heightened Foxp3 expression when compared to Treg cells from uninfected controls. Our hypothesis was that lentivirus-induced micro-RNAs (miRNAs contribute to heightened Treg cell suppressor function by stabilizing Foxp3 expression. We demonstrated that CD4+CD25+ T cells from both feline immunodeficiency virus infected (FIV+ cats and uninfected control cats exhibit increased miRNA 10a and 21 levels compared to autologous CD4+CD25− T cells but there was no difference in the levels of these miRNAs when Treg cells from FIV+ cats were compared to Treg cells from uninfected controls. Further, there was no increase in Foxp3 mRNA following transfection of miRNA 10a or 21 into a feline cell line. However, transfection with miRNA 10a resulted in increased Foxp3 protein expression.

  11. Autoimmunity as a Driving Force of Cognitive Evolution

    Directory of Open Access Journals (Sweden)

    Serge Nataf

    2017-10-01

    emphasis is given here to the potential evolutionary role exerted by two families of genes, namely the MHC class II genes, involved in antigen presentation to T-cells, and the Foxp genes, which play crucial roles in language (Foxp2 and the regulation of autoimmunity (Foxp3.

  12. Spectrum Evolution of Accelerating or Slowing down Soliton at its Propagation in a Medium with Gold Nanorods

    Science.gov (United States)

    Trofimov, Vyacheslav A.; Lysak, Tatiana M.

    2018-04-01

    We investigate both numerically and analytically the spectrum evolution of a novel type soliton - nonlinear chirped accelerating or decelerating soliton - at a femtosecond pulse propagation in a medium containing noble nanoparticles. In our consideration, we take into account one- or two-photon absorption of laser radiation by nanorods, and time-dependent nanorod aspect ratio changing due to their melting or reshaping because of laser energy absorption. The chirped solitons are formed due to the trapping of laser radiation by the nanorods reshaping fronts, if a positive or negative phase-amplitude grating is induced by laser radiation. Accelerating or slowing down chirped soliton formation is accompanied by the soliton spectrum blue or red shift. To prove our numerical results, we derived the approximate analytical law for the spectrum maximum intensity evolution along the propagation coordinate, based on earlier developed approximate analytical solutions for accelerating and decelerating solitons.

  13. Zinc supplementation induces CD4+CD25+Foxp3+ antigen-specific regulatory T cells and suppresses IFN-γ production by upregulation of Foxp3 and KLF-10 and downregulation of IRF-1.

    Science.gov (United States)

    Maywald, Martina; Rink, Lothar

    2017-08-01

    The essential trace element zinc plays a fundamental role in immune function and regulation since its deficiency is associated with autoimmunity, allergies, and transplant rejection. Thus, we investigated the influence of zinc supplementation on the Th1-driven alloreaction in mixed lymphocyte cultures (MLC), on generation of antigen-specific T cells, and analyzed underlying molecular mechanisms. Cell proliferation and pro-inflammatory cytokine production were monitored by [ 3 H]-thymidine proliferation assay and ELISA, respectively. Analysis of surface and intracellular T cell marker was performed by flow cytometry. Western blotting and mRNA analysis were used for Foxp3, KLF-10, and IRF-1 expression. Zinc supplementation on antigen-specific T cells in physiological doses (50 µM) provokes a significant amelioration of cell proliferation and pro-inflammatory cytokine production after reactivation compared to untreated controls. Zinc administration on MLC results in an increased induction and stabilization of CD4 + CD25 + Foxp3 + and CD4 + CD25 + CTLA-4 + T cells (p zinc-induced upregulation of Foxp3 and KLF-10 and downregulation of IRF-1. However, in resting lymphocytes zinc increases IRF-1. In summary, zinc is capable of ameliorating the allogeneic immune reaction by enhancement of antigen-specific iTreg cells due to modulation of essential molecular targets: Foxp3, KLF-10, and IRF-1. Thus, zinc can be seen as an auspicious tool for inducing tolerance in adverse immune reactions.

  14. FOXP1 and TP63 involvement in the progression of myelodysplastic syndrome with 5q- and additional cytogenetic abnormalities

    International Nuclear Information System (INIS)

    L’Abbate, Alberto; Tagliafico, Enrico; Minoia, Carla; De Tullio, Giacoma; Guarini, Attilio; Testoni, Nicoletta; Agostinelli, Claudio; Storlazzi, Clelia Tiziana; Lo Cunsolo, Crocifissa; Macrì, Ettore; Iuzzolino, Paolo; Mecucci, Cristina; Doglioni, Claudio; Coco, Michelina; Muscarella, Lucia Anna; Salati, Simona

    2014-01-01

    The progression of low-risk del(5q) myelodysplastic syndrome to acute myeloid leukemia is increased when associated with mutations of TP53, or with additional chromosomal abnormalities. However, to date the prognostic impact and molecular consequences of these rearrangements were poorly investigated. Single additional alterations to del(5q) by balanced chromosome rearrangements were rarely found in myelodysplasia. In particular, balanced alterations involving TP63 and FOXP1 genes were never reported in the literature. Here we report on a 79-year woman with an aggressive form of myelodysplastic syndrome with del(5q), no TP53 mutation, and a novel complex rearrangement of chromosome 3 in bone marrow cells. Our results revealed that the FOXP1 and TP63 genes were both relocated along chromosome 3. Strikingly, immunohistochemistry analysis showed altered protein levels, disclosing that this rearrangement triggered the expression of FOXP1 and TP63 genes. FOXP1 was also found activated in other patients with myelodysplasia and acute myeloid leukemia, showing that it is an important, recurrent event. We document an apparent role of FOXP1 and TP63, up to now poorly documented, in the progression of MDS in our patient who is lacking mutations in the TP53 tumor suppressor gene normally associated with poor outcome in myelodysplastic syndrome with 5q-. Finally, our results may suggest a possible broader role of FOXP1 in the pathogenesis and progression of myelodysplasia and acute myeloid leukemia

  15. Interplay of T Helper 17 Cells with CD4+CD25high FOXP3+ Tregs in Regulation of Allergic Asthma in Pediatric Patients

    Directory of Open Access Journals (Sweden)

    Amit Agarwal

    2014-01-01

    Full Text Available Background. There is evidence that Tregs are important to prevent allergic diseases like asthma but limited literature exists on role of TH17 cells in allergic diseases. Methods. Fifty children with asthma and respiratory allergy (study group and twenty healthy children (control group were recruited in this study. Total IgE levels and pulmonary function tests were assessed. The expression of Tregs and cytokines was determined by flow cytometry. Results. The average level of total IgE in study group (316.8 ± 189.8 IU/mL was significantly higher than controls (50 ± 17.5 IU/mL, P<0.0001. The frequency of TH17 cells and culture supernatant level of IL-17 in study group (12.09 ± 8.67 pg/mL was significantly higher than control group (2.01 ± 1.27 pg/mL, P<0.001. Alternatively, the frequency of FOXP3 level was significantly lower in study group [(49.00 ± 13.47%] than in control group [(95.91 ± 2.63%] and CD4+CD25+FOXP3+ to CD4+CD25+ ratio was also significantly decreased in study group [(6.33 ± 2.18%] compared to control group [(38.61 ± 11.04%]. The total serum IgE level is negatively correlated with FOXP3 level (r=-0.5273, P<0.0001. The FOXP3 expression is negatively correlated with the IL-17 levels (r=-0.5631, P<0.0001 and IL-4 levels (r=-0.2836, P=0.0460. Conclusions. Imbalance in TH17/Tregs, elevated IL-17, and IL-4 response and downregulation of FOXP3 were associated with allergic asthma.

  16. Upregulation of CD200 is associated with Foxp3+ regulatory T cell expansion and disease progression in acute myeloid leukemia.

    Science.gov (United States)

    Memarian, Ali; Nourizadeh, Maryam; Masoumi, Farimah; Tabrizi, Mina; Emami, Amir Hossein; Alimoghaddam, Kamran; Hadjati, Jamshid; Mirahmadian, Mahroo; Jeddi-Tehrani, Mahmood

    2013-02-01

    Immunosuppression in acute myeloid leukemia (AML) is an important mechanism of tumor escape. CD200, as an immunosuppressive molecule, is overexpressed in some hematological malignancies and it has also been shown to be an independent prognostic factor in AML. In the current study, simultaneous CD200 expression and Foxp3(+) regulatory T cell levels were investigated in Iranian patients with AML by flow cytometry. We also assessed the effect of CD200-CD200R blockade on Th1 and T-reg cytokine production and T cell proliferation in autologous AML- and monocyte-DC mixed lymphocyte reactions (MLRs). ELISA assay was performed to detect IL-2, IL-12, IFN-γ, IL-10, and TGF-β production in MLR supernatants. Expression of Foxp3, IL-10, and TGF-β mRNAs in MLRs were detected by real-time PCR. Our results demonstrated significant overexpression of CD200 (P = 0.001) in association with higher frequencies of Foxp3(+) T cells in AML patients (r = 0.8, P T cell levels with lower Foxp3 intensity was also shown in CD200-CD200R-blocked MLRs. Expression of IL-10 mRNA declined significantly only in AML-DC MLRs where CD200-CD200R interaction was blocked and the same result was observed for TGF-β and Foxp3 mRNA in both AML- and monocyte-DC MLRs. These data present a significant role for CD200 in suppressing anti-tumor immune response through stimulation of regulatory mechanisms in AML patients and suggest that CD200 may have a prognostic value in this malignancy and its blockade may be used as a target for AML immunotherapy.

  17. Foxp3(+) T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis.

    Science.gov (United States)

    Kawamoto, Shimpei; Maruya, Mikako; Kato, Lucia M; Suda, Wataru; Atarashi, Koji; Doi, Yasuko; Tsutsui, Yumi; Qin, Hongyan; Honda, Kenya; Okada, Takaharu; Hattori, Masahira; Fagarasan, Sidonia

    2014-07-17

    Foxp3(+) T cells play a critical role for the maintenance of immune tolerance. Here we show that in mice, Foxp3(+) T cells contributed to diversification of gut microbiota, particularly of species belonging to Firmicutes. The control of indigenous bacteria by Foxp3(+) T cells involved regulatory functions both outside and inside germinal centers (GCs), consisting of suppression of inflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches, respectively. Diversified and selected IgAs contributed to maintenance of diversified and balanced microbiota, which in turn facilitated the expansion of Foxp3(+) T cells, induction of GCs, and IgA responses in the gut through a symbiotic regulatory loop. Thus, the adaptive immune system, through cellular and molecular components that are required for immune tolerance and through the diversification as well as selection of antibody repertoire, mediates host-microbial symbiosis by controlling the richness and balance of bacterial communities required for homeostasis. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model.

    Science.gov (United States)

    Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

    2016-07-26

    PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.

  19. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth

    Science.gov (United States)

    Hutzler, Marina; Abel, Simone; Alter, Christina; Stockmann, Christian; Kliche, Stefanie; Albert, Juliane; Sparwasser, Tim; Sakaguchi, Shimon; Westendorf, Astrid M.; Schadendorf, Dirk; Buer, Jan; Helfrich, Iris

    2012-01-01

    Infiltration of Foxp3+ regulatory T (T reg) cells is considered to be a critical step during tumor development and progression. T reg cells supposedly suppress locally an effective anti-tumor immune response within tumor tissues, although the precise mechanism by which T reg cells infiltrate the tumor is still unclear. We provide evidence that Neuropilin 1 (Nrp-1), highly expressed by Foxp3+ T reg cells, regulates the immunological anti-tumor control by guiding T reg cells into the tumor in response to tumor-derived vascular endothelial growth factor (VEGF). We demonstrate for the first time that T cell–specific ablation of Nrp-1 expression results in a significant breakdown in tumor immune escape in various transplantation models and in a spontaneous, endogenously driven melanoma model associated with strongly reduced tumor growth and prolonged tumor-free survival. Strikingly, numbers of tumor-infiltrating Foxp3+ T reg cells were significantly reduced accompanied by enhanced activation of CD8+ T cells within tumors of T cell–specific Nrp-1–deficient mice. This phenotype can be reversed by adoptive transfer of Nrp-1+ T reg cells from wild-type mice. Thus, our data strongly suggest that Nrp-1 acts as a key mediator of Foxp3+ T reg cell infiltration into the tumor site resulting in a dampened anti-tumor immune response and enhanced tumor progression. PMID:23045606

  20. Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis.

    Science.gov (United States)

    Chae, Wook-Jin; Park, Jong-Hyun; Henegariu, Octavian; Yilmaz, Saliha; Hao, Liming; Bothwell, Alfred L M

    2017-10-01

    Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3 + regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4 + T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3 + Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3 + Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3 + Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  1. Diagnosis of Weibel instability evolution in the rear surface density scale lengths of laser solid interactions via proton acceleration

    International Nuclear Information System (INIS)

    Scott, G G; Brenner, C M; Clarke, R J; Green, J S; Heathcote, R I; Rusby, D R; McKenna, P; Neely, D; Bagnoud, V; Zielbauer, B; Gonzalez-Izquierdo, B; Powell, H W

    2017-01-01

    It is shown for the first time that the spatial and temporal distribution of laser accelerated protons can be used as a diagnostic of Weibel instability presence and evolution in the rear surface scale lengths of a solid density target. Numerical modelling shows that when a fast electron beam is injected into a decreasing density gradient on the target rear side, a magnetic instability is seeded with an evolution which is strongly dependent on the density scale length. This is manifested in the acceleration of a filamented proton beam, where the degree of filamentation is also found to be dependent on the target rear scale length. Furthermore, the energy dependent spatial distribution of the accelerated proton beam is shown to provide information on the instability evolution on the picosecond timescale over which the protons are accelerated. Experimentally, this is investigated by using a controlled prepulse to introduce a target rear scale length, which is varied by altering the time delay with respect to the main pulse, and similar trends are measured. This work is particularly pertinent to applications using laser pulse durations of tens of picoseconds, or where a micron level density scale length is present on the rear of a solid target, such as proton-driven fast ignition, as the resultant instability may affect the uniformity of fuel energy coupling. (paper)

  2. Dynamical decoupling assisted acceleration of two-spin evolution in XY spin-chain environment

    Energy Technology Data Exchange (ETDEWEB)

    Wei, Yong-Bo; Zou, Jian [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Wang, Zhao-Ming [Department of Physics, Ocean University of China, Qingdao 266100 (China); Shao, Bin, E-mail: sbin610@bit.edu.cn [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Hai [School of Information and Electronic Engineering, Shandong Institute of Business and Technology, Yantai 264000 (China)

    2016-01-28

    We study the speed-up role of dynamical decoupling in an open system, which is modeled as two central spins coupled to their own XY spin-chain environment. We show that the fast bang–bang pulses can suppress the system evolution, which manifests the quantum Zeno effect. In contrast, with the increasing of the pulse interval time, the bang–bang pulses can enhance the decay of the quantum speed limit time and induce the speed-up process, which displays the quantum anti-Zeno effect. In addition, we show that the random pulses can also induce the speed-up of quantum evolution. - Highlights: • We propose a scheme to accelerate the dynamical evolution of central spins in an open system. • The quantum speed limit of central spins can be modulated by changing pulse frequency. • The random pulses can play the same role as the regular pulses do for small perturbation.

  3. Genoarchitecture of the extended amygdala in zebra finch, and expression of FoxP2 in cell corridors of different genetic profile.

    Science.gov (United States)

    Vicario, Alba; Mendoza, Ezequiel; Abellán, Antonio; Scharff, Constance; Medina, Loreta

    2017-01-01

    We used a battery of genes encoding transcription factors (Pax6, Islet1, Nkx2.1, Lhx6, Lhx5, Lhx9, FoxP2) and neuropeptides to study the extended amygdala in developing zebra finches. We identified different components of the central extended amygdala comparable to those found in mice and chickens, including the intercalated amygdalar cells, the central amygdala, and the lateral bed nucleus of the stria terminalis. Many cells likely originate in the dorsal striatal domain, ventral striatal domain, or the pallidal domain, as is the case in mice and chickens. Moreover, a cell subpopulation of the central extended amygdala appears to originate in the prethalamic eminence. As a general principle, these different cells with specific genetic profiles and embryonic origin form separate or partially intermingled cell corridors along the extended amygdala, which may be involved in different functional pathways. In addition, we identified the medial amygdala of the zebra finch. Like in the chickens and mice, it is located in the subpallium and is rich in cells of pallido-preoptic origin, containing minor subpopulations of immigrant cells from the ventral pallium, alar hypothalamus and prethalamic eminence. We also proposed that the medial bed nucleus of the stria terminalis is composed of several parallel cell corridors with different genetic profile and embryonic origin: preoptic, pallidal, hypothalamic, and prethalamic. Several of these cell corridors with distinct origin express FoxP2, a transcription factor implicated in synaptic plasticity. Our results pave the way for studies using zebra finches to understand the neural basis of social behavior, in which the extended amygdala is involved.

  4. Foxp3+ Regulatory T Cells Delay Expulsion of Intestinal Nematodes by Suppression of IL-9-Driven Mast Cell Activation in BALB/c but Not in C57BL/6 Mice

    Science.gov (United States)

    Brenz, Yannick; Eschbach, Marie-Luise; Hartmann, Wiebke; Haben, Irma; Sparwasser, Tim; Huehn, Jochen; Kühl, Anja; Feyerabend, Thorsten B.; Rodewald, Hans-Reimer; Breloer, Minka

    2014-01-01

    Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6

  5. Vorticity generation and evolution in shock-accelerated density-stratified interfaces

    International Nuclear Information System (INIS)

    Yang, X.; Chern, I.; Zabusky, N.J.; Samtaney, R.; Hawley, J.F.

    1992-01-01

    The results of direct numerical simulations of inviscid planar shock-accelerated density-stratified interfaces in two dimensions are presented and compared with shock tube experiments of Haas [(private communication, 1988)] and Sturtevant [in Shock Tubes and Waves, edited by H. Gronig (VCH, Berlin, 1987), p. 89] . Heavy-to-light (''slow/fast or s/f) and light-to-heavy (''fast/slow,'' or f/s) gas interfaces are examined and early-time impulsive vorticity deposition and the evolution of coherent vortex structures are emphasized and quantified. The present second-order Godunov scheme yields excellent agreement with shock-polar analyses at early time. A more physical vortex interpretation explains the commonly used (i.e., linear paradigm) designations of ''unstable'' and ''stable'' for the f/s and s/f interfaces, respectively. The later time events are Rayleigh--Taylor like and can be described in terms of the evolution of a vortex layer (large-scale translation and rotation): asymmetric tip vortex ''roll-up'' and ''binding;'' layer ''instability;'' convective mixing; and baroclinic vorticity generation from secondary shock--interface interactions

  6. Total glucosides of paeony induces regulatory CD4(+)CD25(+) T cells by increasing Foxp3 demethylation in lupus CD4(+) T cells.

    Science.gov (United States)

    Zhao, Ming; Liang, Gong-ping; Tang, Mei-ni; Luo, Shuang-yan; Zhang, Jing; Cheng, Wen-jing; Chan, Tak-mao; Lu, Qian-jin

    2012-05-01

    Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling. Copyright © 2012 Elsevier Inc. All rights reserved.

  7. Comparative Approach to Define Increased Regulatory T Cells in Different Cancer Subtypes by Combined Assessment of CD127 and FOXP3

    Directory of Open Access Journals (Sweden)

    Marc Beyer

    2011-01-01

    Full Text Available In recent years an increase of functional CD4+CD25+ regulatory T cells (Treg cells has been established for patients with solid tumors, acute leukemias, and lymphomas. We have reported an expanded pool of CD4+CD25high Treg cells in patients with chronic lymphatic leukemia (CLL, multiple myeloma (MM as well as its premalignant precursor monoclonal gammopathy of undetermined significance (MGUS. In healthy individuals, low-level expression of CD127 on T cells in addition to the expression of FOXP3 has been associated with Treg cells. Here, we demonstrate that the expanded FOXP3+ T-cell population in patients with colorectal cancer, CLL, MGUS, MM, follicular lymphoma, and Hodgkin's disease are exclusively CD127low Treg cells and were strongly suppressive. A significant portion of CD127lowFOXP3+ Treg cells expressed only low levels of CD25 suggesting that the previously reported expansion of CD25+ Treg cells underestimates the true expansion. The assessment of CCR7 and CD45RA expression on the expanded CD4+CD127lowFOXP3+ Treg cells revealed an increase of both naïve as well as central and effector memory Treg cells in peripheral blood. Our data strongly support superiority of combined CD127 and FOXP3 analysis in comparison to CD25 and FOXP3 assessment for further quantification of Treg cells in malignant diseases.

  8. On a temporal evolution of the ultra-relativistic electron spectrum by action of synchrotron losses and turbulent acceleration

    International Nuclear Information System (INIS)

    Samsonov, A.M.; Fedorenko, V.N.

    1981-01-01

    The kinetic equation describing temporal evolution of the ultra-relativistic electrons' energy spectrum effected by synchrotron losses and turbulent acceleration is solved for the isotropic part of the electrons' distribution function. The original distribution is assumed to be given in the form of a power spectrum. Turbulence properties are stated by means of the turbulent acceleration coefficient depending on epsilon energy D(epsilon)=D 0 epsilon 3 which is related to the synchrotron losses coefficient b(epsilon)=b 0 epsilon 3 so that the isotropization of the distribution function is provided without essential acceleration of particles. The initial spectrum is conserved up to some values of time t and energy epsilon connected by inequality epsilonb 0 t 0 /D 0 -2 if epsilonD 0 t>>1 and b 0 >>D 0 . Finally, are possible applications of the solution to description of processes in supernova shells and radio galaxies are discussed [ru

  9. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Science.gov (United States)

    Wang, Rui; Wan, Qi; Kozhaya, Lina; Fujii, Hodaka; Unutmaz, Derya

    2008-07-16

    Regulatory T (T(reg)) cells control immune activation and maintain tolerance. How T(regs) mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32), which within T cells is specifically expressed in T(regs) activated through the T cell receptor (TCR). Ectopic expression of GARP in human naïve T (T(N)) cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N) cells induced expression of T(reg) master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg) cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  10. Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.

    Directory of Open Access Journals (Sweden)

    Rui Wang

    2008-07-01

    Full Text Available Regulatory T (T(reg cells control immune activation and maintain tolerance. How T(regs mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32, which within T cells is specifically expressed in T(regs activated through the T cell receptor (TCR. Ectopic expression of GARP in human naïve T (T(N cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N cells induced expression of T(reg master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.

  11. Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3+ T-regulatory Cell Function and Promotes Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Liqing Wang

    2016-11-01

    Full Text Available Foxp3+ T-regulatory (Treg cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or “secondary” modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3+ Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.

  12. Prognostic and predictive role of FOXP3 positive tumor infiltrating lymphocytes (TILs in curatively resected non small cell lung cancer other than stage IA

    Directory of Open Access Journals (Sweden)

    Fatih Kose

    2017-12-01

    Full Text Available Lung cancer is the leading cause of cancer-related mortality and responsible for 1.6 million deaths per year through world-wide. Surgical resection with negative margin combined with the adjuvant therapy [except for stage IA and IB (<4 cm] is the Standard treatment for early-stage Non-small cell lung cancer (NSCLC. Early-stage NSCLC, however, has relapse rate over 40% mostly at distant sites. Therefore, high relapse rate necessitates urgent novel biomarker for these patients. In this study, we aim to evaluate the predictive and prognostic role of FOXP3+ Treg cells along with well defined Clinicohistopathological factors in early-stage non-small cell lung cancer (NSCLC. FOXP3 expression in tumor infiltrating lymphocytes (TIL was examined by immunohistochemical staining from resected early-stage 48 NSCLC patients. Data of patients and FOXP3 expression status along with common clinicohistopathological prognostic factors were evaluated retrospectively. Median age of patients was 62 years-old (range 43–78. Mean follow-up, median overall survival (OS, and disease-free survival (DFS were 49, 49 and 30 months, respectively. FOXP3 expression was positive in 23 (47.9% patients. Adjuvant chemotherapy (4 cycles of cisplatin-vinorelbine was given to 16 patients (33.3% at physician discretion. Patients with a FOXP3 expression of 25% or higher significantly lower OS and DFS when compared with patients with a FOXP3 staining lower than 25% with p-value of 0.016 and 0.032, respectively. In the patients with high FOXP3 expression, platin-based adjuvant chemotherapy had showed a detrimental effect on DFS and OS. These results suggest that FOXP3 expression may be used as useful prognostic biomarker in resected NSCLC. Our findings also suggest that resected NSCLC patients with FOXP3 expression of 25% or higher staining intensity may not get any benefit even disfavor from adjuvant platin chemotherapy.

  13. CD4+CD25+ T cells expressing FoxP3 in Icelandic horses affected with insect bite hypersensitivity.

    Science.gov (United States)

    Hamza, Eman; Steinbach, Falko; Marti, Eliane

    2012-07-15

    Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis caused by bites of midges from the genus Culicoides. We have shown previously that peripheral blood mononuclear cells (PBMC) from IBH-affected horses produce higher levels of IL-4 and lower levels of IL-10 and TGF-β1 than those from healthy horses, suggesting that IBH is associated with a reduced regulatory immune response. FoxP3 is a crucial marker of regulatory T cells (Tregs). Here we have determined the proportion of CD4(+)CD25(+)FoxP3(+) T cells by flow cytometry in PBMC directly after isolation or after stimulation with Culicoides extract or a control antigen (Tetanus Toxoid). There were no differences between healthy and IBH horses either in the proportion of FoxP3(+)CD4(+)CD25(+) cells in freshly isolated PBMC or in the following stimulation with Tetanus Toxoid. However, upon stimulation of PBMC with the allergen, expression of FoxP3 by CD4(+)CD25(+high) and CD4(+)CD25(+dim) cells was significantly higher in healthy than in IBH horses. Addition of recombinant IL-4 to PBMC from healthy horses stimulated with the allergen significantly decreased the proportion of FoxP3 expressing cells within CD4(+)CD25(+high). These results suggest that IBH is associated with a decreased number of allergen-induced Tregs. This could be a consequence of the increased IL-4 production by PBMC of IBH-affected horses. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. SPARC, FOXP3, CD8 and CD45 correlation with disease recurrence and long-term disease-free survival in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Angela Chew

    Full Text Available BACKGROUND: SPARC is a matricellular protein involved in tissue remodelling, cell migration and angiogenesis, while forkhead box P3 (FOXP3 protein functions as a transcription factor involved in immune cell regulation. Both SPARC and FOXP3 can play an anti-tumorigenic role in cancer progression. The aim was to determine if SPARC, FOXP3, CD8 and CD45RO expression levels are associated with colorectal cancer (CRC stage, disease outcome and long-term cancer-specific survival (CSS in stage II and III CRC. METHODS AND FINDINGS: SPARC expression was initially assessed in 120 paired normal and stage I-IV CRCs. Subsequently, approximately 1000 paired patient samples of stage II or III CRCs in tissue microarrays were stained for SPARC, FOXP3, CD8 or CD45RO. Proportional hazards modelling assessed correlations between these markers and clinicopathological data, including disease outcome and cancer specific survival (CSS. Both SPARC and FOXP3 expression were significantly greater in CRC than normal colon (p<0.0001. High SPARC expression correlated with good disease outcome (≥60 mths without disease recurrence, p = 0.0039 and better long-term CSS in stage II CRC (<0.0001. In stage III CRC, high SPARC expression correlated with better long-term CSS (p<0.0001 and less adjuvant chemotherapy use (p = 0.01. High FOXP3 correlated with a good disease outcome, better long-term CSS and less adjuvant chemotherapy use in stage II (p<0.0037, <0.0001 and p = 0.04 respectively, but not in stage III CRC. High CD8 and CD45RO expression correlated with better disease outcome in stage II CRC, and better CSS, but the differences were not as marked as for SPARC and FOXP3. CONCLUSIONS: These data suggest that high SPARC and FOXP3 are associated with better disease outcome in stage II CRC and may be prognostic indicators of CSS. Further assessment of whether these markers predict patients at high risk of recurrence with stage II CRC and functional studies of these

  15. IP-10, p53, and Foxp3 Expression in Hepatocytes of Chronic Hepatitis B Patients with Cirrhosis and Hepatocellular Carcinoma.

    Science.gov (United States)

    Shahera, Umme; Munshi, Saifullah; Jahan, Munira; Nessa, Afzalun; Alam, Shahinul; Tabassum, Shahina

    2016-01-01

    Elucidating differences in gene expression may be useful in understanding the molecular pathogenesis and for developing specific markers for the outcome of hepatitis B virus (HBV) infection. In the present study, expressions of host gene interferon gamma-inducible protein (IP-10), p53, and Foxp3 were studied in hepatocytes of patients with chronic HBV infection to determine a possible link between selected host gene expression and the outcome of HBV infection. The study was conducted in 60 patients with chronic HBV infection and they were divided into four groups: HBV-positive cirrhosis (n = 15), HBV-negative cirrhosis (n = 15), HBV-positive hepatocellular carcinoma (HCC) (n = 15) and HBV-negative HCC (n = 15). Total messenger ribonucleic acid (mRNA) extraction was done followed by complementary deoxyribonucleic acid (cDNA) synthesis, and finally gene expression was performed using real-time polymerase chain reaction (PCR) technique. IP-10 and p53 gene expressions were lower in HBV-positive cirrhosis, and Foxp3 gene expression was upregulated in HBV-positive cirrhosis in comparison to HBV-negative cirrhosis. The expressions of all the three genes were upregulated among HBV-positive HCC in comparison to HBV-negative HCC. The expression of IP-10, p53, and Foxp3 genes was upregulated in HBV-positive HCC in comparison to HBV-positive cirrhosis. This study indicates that there are variations in the expression of the selected genes among cirrhosis and HCC patients with or without HBV. All the three selected genes were more or less upregulated in HBV-positive HCC patients, but only Foxp3 expression was upregulated in HBV-positive cirrhosis. These three particular genes may have a role in the molecular pathogenesis and clinical outcome of HBV-positive cirrhosis and HCC patients. These aspects need further evaluation by studies with larger numbers of cirrhosis and HCC patients. Shahera U, Munshi S, Jahan M, Nessa A, Alam S, Tabassum S. IP-10, p53, and Foxp3 Expression in

  16. Maternal variant in the upstream of FOXP3 gene on the X chromosome is associated with recurrent infertility in Japanese Black cattle.

    Science.gov (United States)

    Arishima, Taichi; Sasaki, Shinji; Isobe, Tomohiro; Ikebata, Yoshihisa; Shimbara, Shinichi; Ikeda, Shogo; Kawashima, Keisuke; Suzuki, Yutaka; Watanabe, Manabu; Sugano, Sumio; Mizoshita, Kazunori; Sugimoto, Yoshikazu

    2017-12-06

    Repeat breeding, which is defined as cattle failure to conceive after three or more inseminations in the absence of clinical abnormalities, is a substantial problem in cattle breeding. To identify maternal genetic variants of repeat breeding in Japanese Black cattle, we selected 29 repeat-breeding heifers that failed to conceive following embryo transfer (ET) and conducted a genome-wide association study (GWAS) using the traits. We found that a single-nucleotide polymorphism (SNP; g.92,377,635A > G) in the upstream region of the FOXP3 gene on the X chromosome was highly associated with repeat breeding and failure to conceive following ET (P = 1.51 × 10 -14 ). FOXP3 is a master gene for differentiation of regulatory T (T reg ) cells that function in pregnancy maintenance. Reporter assay results revealed that the activity of the FOXP3 promoter was lower in reporter constructs with the risk-allele than in those with the non-risk-allele by approximately 0.68 fold. These findings suggest that the variant in the upstream region of FOXP3 with the risk-allele decreased FOXP3 transcription, which in turn, could reduce the number of maternal T reg cells and lead to infertility. The frequency of the risk-allele in repeat-breeding heifers is more than that in cows, suggesting that the risk-allele could be associated with infertility in repeat-breeding heifers. This GWAS identified a maternal variant in the upstream region of FOXP3 that was associated with infertility in repeat-breeding Japanese Black cattle that failed to conceive using ET. The variant affected the level of FOXP3 mRNA expression. Thus, the results suggest that the risk-allele could serve as a useful marker to reduce and eliminate animals with inferior fertility in Japanese Black cattle.

  17. Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function.

    Directory of Open Access Journals (Sweden)

    Karina Trojan

    Full Text Available There is circumstantial evidence that IFNy+ Treg might have clinical relevance in transplantation. IFNy+ Treg express IFNy receptors and are induced by IFNy. In the present study we investigated in kidney transplant recipients with good long-term stable graft function the absolute cell counts of IFNy+ Treg subsets and whether their expression of Foxp3 is stable or transient.Helios expression determined by eight-color-fluorescence flow cytometry and methylation status of the Foxp3 Treg specific demethylation region (TSDR served as indicators for stability of Foxp3 expression. Methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations originating from peripheral blood using high resolution melt analysis. A total of 136 transplant recipients and 52 healthy controls were studied.Proportions of IFNy+ Treg were similar in patients and healthy controls (0.05% and 0.04% of all CD4+ lymphocytes; p = n.s.. Patients also had similar absolute counts of IFNy producing Helios+ and Helios- Treg (p = n.s.. Most of the IFNy+ and IFNy- Treg in transplant recipients had a methylated Foxp3 TSDR, however, there was a sizeable proportion of IFNy+ and IFNy- Treg with demethylated Foxp3 TSDR. Male and female patients showed more frequently methylated IFNy+ and IFNy- Treg than male and female controls (all p<0.05.Kidney transplant recipients with good long-term stable graft function have similar levels of IFNy+ Treg as healthy controls. IFNy+ and IFNy- Treg subsets in patients consist of cells with stable and cells with transient Foxp3 expression; however, patients showed more frequently methylated IFNy+ and IFNy- Treg than controls. The data show increased levels of Treg subsets with stable as well as transient Foxp3 expression in patients with stable allograft acceptance compared to healthy controls.

  18. The evolution of high energy accelerators

    International Nuclear Information System (INIS)

    Courant, E.D.

    1994-01-01

    Accelerators have been devised and built for two reasons: In the first place, by physicists who needed high energy particles in order to have a means to explore the interactions between particles that probe the fundamental elementary forces of nature. And conversely, sometimes accelerator builders produce new machines for higher energy than ever before just because it can be done, and then challenge potential users to make new discoveries with the new means at hand. These two approaches or motivations have gone hand in hand. This lecture traces how high energy particle accelerators have grown from tools used for esoteric small-scale experiments to the gigantic projects of today. So far all the really high-energy machines built and planned in the world--except the SLC--have been ring accelerators and storage rings using the strong-focusing method. But this method has not removed the energy limit, it has only pushed it higher. It would seem unlikely that one can go beyond the Large Hadron Collider (LHC)--but in fact a workshop was held in Sicily in November 1991, concerned with the question of extrapolating to 100 TeV. Other acceleration and beam-forming methods are now being discussed--collective fields, laser acceleration, wake-field accelerators etc., all aimed primarily at making linear colliders possible and more attractive than with present radiofrequency methods. So far it is not entirely clear which of these schemes will dominate particle physics in the future--maybe something that has not been thought of as yet

  19. Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.

    Science.gov (United States)

    Blankenhaus, Birte; Reitz, Martina; Brenz, Yannick; Eschbach, Marie-Luise; Hartmann, Wiebke; Haben, Irma; Sparwasser, Tim; Huehn, Jochen; Kühl, Anja; Feyerabend, Thorsten B; Rodewald, Hans-Reimer; Breloer, Minka

    2014-02-01

    Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3⁺ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3⁺ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6

  20. Historical evolution of nuclear energy systems development and related activities in JAERI. Fission, fusion, accelerator utilization

    Energy Technology Data Exchange (ETDEWEB)

    Tone, Tatsuzo [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment

    2001-03-01

    Overview of the historical evolution of nuclear energy systems development and related activities in JAERI is given in the report. This report reviews the research and development for light water reactor, fast breeder reactor, high temperature gas reactor, fusion reactor and utilization of accelerator-based neutron source. (author)

  1. Accelerated Evolution and Functional Divergence of the Dim Light Visual Pigment Accompanies Cichlid Colonization of Central America.

    Science.gov (United States)

    Hauser, Frances E; Ilves, Katriina L; Schott, Ryan K; Castiglione, Gianni M; López-Fernández, Hernán; Chang, Belinda S W

    2017-10-01

    Cichlids encompass one of the most diverse groups of fishes in South and Central America, and show extensive variation in life history, morphology, and colouration. While studies of visual system evolution in cichlids have focussed largely on the African rift lake species flocks, Neotropical cichlids offer a unique opportunity to investigate visual system evolution at broader temporal and geographic scales. South American cichlid colonization of Central America has likely promoted accelerated rates of morphological evolution in Central American lineages as they encountered reduced competition, renewed ecological opportunity, and novel aquatic habitats. To investigate whether such transitions have influenced molecular evolution of vision in Central American cichlids, we sequenced the dim-light rhodopsin gene in 101 Neotropical cichlid species, spanning the diversity of the clade. We find strong evidence for increased rates of evolution in Central American cichlid rhodopsin relative to South American lineages, and identify several sites under positive selection in rhodopsin that likely contribute to adaptation to different photic environments. We expressed a Neotropical cichlid rhodopsin protein invitro for the first time, and found that while its spectral tuning properties were characteristic of typical vertebrate rhodopsin pigments, the rate of decay of its active signalling form was much slower, consistent with dim light adaptation in other vertebrate rhodopsins. Using site-directed mutagenesis combined with spectroscopic assays, we found that a key amino acid substitution present in some Central American cichlids accelerates the rate of decay of active rhodopsin, which may mediate adaptation to clear water habitats. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

    KAUST Repository

    Schmidt, Angelika

    2018-04-27

    BackgroundRegulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest, and first-in-man trials of Treg transfer have achieved promising outcomes. Yet, the mechanisms governing induced Treg (iTreg) differentiation and the regulation of FOXP3 are incompletely understood.ResultsTo gain a comprehensive and unbiased molecular understanding of FOXP3 induction, we performed time-series RNA sequencing (RNA-Seq) and proteomics profiling on the same samples during human iTreg differentiation. To enable the broad analysis of universal FOXP3-inducing pathways, we used five differentiation protocols in parallel. Integrative analysis of the transcriptome and proteome confirmed involvement of specific molecular processes, as well as overlap of a novel iTreg subnetwork with known Treg regulators and autoimmunity-associated genes. Importantly, we propose 37 novel molecules putatively involved in iTreg differentiation. Their relevance was validated by a targeted shRNA screen confirming a functional role in FOXP3 induction, discriminant analyses classifying iTregs accordingly, and comparable expression in an independent novel iTreg RNA-Seq dataset.ConclusionThe data generated by this novel approach facilitates understanding of the molecular mechanisms underlying iTreg generation as well as of the concomitant changes in the transcriptome and proteome. Our results provide a reference map exploitable for future discovery of markers and drug candidates governing control of Tregs, which has important implications for the treatment of cancer, autoimmune, and inflammatory diseases.

  3. The Expression of T Cell FOXP3 and T-Bet Is Upregulated in Severe but Not Euthyroid Hashimoto’s Thyroiditis

    Directory of Open Access Journals (Sweden)

    Stana Tokić

    2016-01-01

    Full Text Available Hashimoto’s thyroiditis (HT is an organ-specific autoimmune disorder characterized by progressive thyroid failure. Th1 and Treg subset of CD4+ cells have been implicated in the pathogenesis; however, less is known about their respective roles across the spectrum of HT clinical presentations. To shed more light on CD4+ subsets role in HT, we investigated the mRNA expression levels of several Th1/Treg-associated transcription factors (T-bet/ETS1, HIF1α/BLIMP1/FOXP3 in peripheral blood T cells of 10 hypothyroid, untreated HT patients, 10 hypothyroid patients undergoing hormone replacement therapy, 12 euthyroid HT subjects, and 11 healthy controls by the qRT-PCR. Compared to euthyroid HT patients and controls, both hypothyroid (2.34-fold difference versus controls, P<0.01 and thyroxine-supplemented patients (2.5-fold, P<0.001 showed an increased FOXP3 mRNA expression in T cells. Similarly, mRNA expression levels of T-bet were upregulated in severely affected but not in euthyroid HT subjects (2.37-fold and 3.2-fold, hypothyroid and thyroxine-supplemented HT patients versus controls, resp., P<0.01. By contrast, no differences in mRNA expression levels of ETS1, BLIMP1, and HIF1α were observed across the study groups. In summary, severe but not euthyroid HT was associated with robust upregulation of T-bet and FOXP3 mRNA in peripheral T cells, independent of the thyroid hormone status but proportional to disease activity.

  4. A Lactobacillus rhamnosus strain induces a heme oxygenase dependent increase in Foxp3+ regulatory T cells.

    Directory of Open Access Journals (Sweden)

    Khalil Karimi

    Full Text Available We investigated the consequences of feeding with a Lactobacillus species on the immune environment in GALT, and the role of dendritic cells and heme oxygenase-1 in mediating these responses. Feeding with a specific strain of Lactobacillus rhamnosus induced a significant increase in CD4+CD25+Foxp3+ functional regulatory T cells in GALT. This increase was greatest in the mesenteric lymph nodes and associated with a marked decrease in TNF and IFNγ production. Dendritic cell regulatory function and HO-1 expression was also increased. The increase in Foxp3+ T cells could be prevented by treatment with a heme oxygenase inhibitor. However, neither inhibition of heme oxygenase nor blockade of IL-10 and TGFβ prevented the inhibition of inflammatory cytokine production. In conclusion Lactobacillus feeding induced a tolerogenic environment in GALT. HO-1 was critical to the enhancement of Foxp3+ regulatory T cells while additional, as yet unknown, pathways were involved in the down-regulation of inflammatory cytokine production by T cells.

  5. Effect of everolimus initiation and early calcineurin inhibitor withdrawal on myocardial FOXP3+ regulatory T cells in heart transplantation

    DEFF Research Database (Denmark)

    Mirza, Kiran; Gustafsson, Finn; Gullestad, Lars

    2016-01-01

    BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We hypothes......BACKGROUND: Through immunosuppression CD4+FoxP3+ regulatory T-cells (Tregs) play an indispensable role in allograft rejection. Post-HTx treatment with everolimus is associated with slower progression of cardiac allograft vasculopathy (CAV) - chronic rejection - than CNI based therapy. We...... hypothesized treatment with everolimus reduced the risk of CAV by modulating myocardial FoxP3 levels. METHODS: 15 patients from the Schedule trial comparing everolimus, MMF, steroid and early CNI (Everolimus, n=8) withdrawal to conventional CNI based immunosuppression (Controls, n=7) after de novo HTx were...

  6. Fenofibrate Enhances the In Vitro Differentiation of Foxp3+ Regulatory T Cells in Mice

    Directory of Open Access Journals (Sweden)

    Zhou Zhou

    2012-01-01

    Full Text Available Foxp3+ regulatory T cells (Tregs play a critical role in maintaining immune self-tolerance. Reduced number and activity of Tregs are usually found in autoimmune and inflammatory diseases, and enhancing the differentiation of Tregs may be a promising therapeutic strategy. Some reports suggested an anti-inflammatory and anti-autoimmune potential for fenofibrate, a hypolipidemic drug used worldwide, whose lipid effects are mediated by the activation of peroxisome proliferator-activated receptor (PPAR. In the present paper, we found that fenofibrate dose-dependently increased transforming growth factor- and interleukin-2-induced Treg differentiation in vitro, by 1.96-fold from 0 to 20 M (12.59±1.34% to 24.69±3.03%, <0.05. Other PPAR activators, WY14643 (100 M, gemfibrozil (50 M, and bezafibrate (30 M, could not enhance Treg differentiation. In addition, PPAR could not upregulate the promoter activity of the Treg-specific transcription factor Foxp3. Fenofibrate might exert its function by enhancing Smad3 phosphorylation, a critical signal in Treg differentiation, via Akt suppression. Our work reveals a new PPAR independent anti-inflammatory mechanism of fenofibrate in up-regulating mouse Treg differentiation.

  7. Regulation of CD8+ T cell responses to retinal antigen by local FoxP3+ regulatory T cells

    Directory of Open Access Journals (Sweden)

    Scott W McPherson

    2012-06-01

    Full Text Available While pathogenic CD4 T cells are well known mediators of autoimmune uveoretinitis, CD8 T cells can also be uveitogenic. Since preliminary studies indicated that C57BL/6 mice were minimally susceptible to autoimmune uveoretinitis induction by CD8 T cells, the basis of the retinal disease resistance was sought. Mice that express β-galactosidase (βgal on a retina-specific promoter (arrβgal mice were backcrossed to mice expressing green fluorescent protein and diphtheria toxin receptor under control of the Foxp3 promoter (Foxp3-DTR/GFP mice, and to T cell receptor transgenic mice that produce βgal specific CD8 T cells (BG1 mice. These mice were used to explore the role of regulatory T cells in the resistance to retinal autoimmune disease. Experiments with T cells from double transgenic BG1 x Foxp3-DTR/GFP mice transferred into Foxp3-DTR/GFP x arrβgal mice confirmed that the retina was well protected from attempts to induce disease by adoptive transfer of activated BG1 T cells. The successful induction of retinal disease following unilateral intraocular administration of diphtheria toxin to deplete regulatory T cells showed that the protective activity was dependent on local, toxin-sensitive regulatory T cells; the opposite, untreated eye remained disease-free. Although there were very few Foxp3+ regulatory T cells in the parenchyma of quiescent retina, and they did not accumulate in retina, their depletion by local toxin administration led to disease susceptibility. We propose that these regulatory T cells modulate the pathogenic activity of βgal-specific CD8 T cells in the retinas of arrβgal mice on a local basis, allowing immunoregulation to be responsive to local conditions.

  8. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion.

    Directory of Open Access Journals (Sweden)

    Natalay Kouprina

    2004-05-01

    Full Text Available Primary microcephaly (MCPH is a neurodevelopmental disorder characterized by global reduction in cerebral cortical volume. The microcephalic brain has a volume comparable to that of early hominids, raising the possibility that some MCPH genes may have been evolutionary targets in the expansion of the cerebral cortex in mammals and especially primates. Mutations in ASPM, which encodes the human homologue of a fly protein essential for spindle function, are the most common known cause of MCPH. Here we have isolated large genomic clones containing the complete ASPM gene, including promoter regions and introns, from chimpanzee, gorilla, orangutan, and rhesus macaque by transformation-associated recombination cloning in yeast. We have sequenced these clones and show that whereas much of the sequence of ASPM is substantially conserved among primates, specific segments are subject to high Ka/Ks ratios (nonsynonymous/synonymous DNA changes consistent with strong positive selection for evolutionary change. The ASPM gene sequence shows accelerated evolution in the African hominoid clade, and this precedes hominid brain expansion by several million years. Gorilla and human lineages show particularly accelerated evolution in the IQ domain of ASPM. Moreover, ASPM regions under positive selection in primates are also the most highly diverged regions between primates and nonprimate mammals. We report the first direct application of TAR cloning technology to the study of human evolution. Our data suggest that evolutionary selection of specific segments of the ASPM sequence strongly relates to differences in cerebral cortical size.

  9. FOXP3-stained image analysis for follicular lymphoma: optimal adaptive thresholding with maximal nucleus coverage

    Science.gov (United States)

    Senaras, C.; Pennell, M.; Chen, W.; Sahiner, B.; Shana'ah, A.; Louissaint, A.; Hasserjian, R. P.; Lozanski, G.; Gurcan, M. N.

    2017-03-01

    Immunohistochemical detection of FOXP3 antigen is a usable marker for detection of regulatory T lymphocytes (TR) in formalin fixed and paraffin embedded sections of different types of tumor tissue. TR plays a major role in homeostasis of normal immune systems where they prevent auto reactivity of the immune system towards the host. This beneficial effect of TR is frequently "hijacked" by malignant cells where tumor-infiltrating regulatory T cells are recruited by the malignant nuclei to inhibit the beneficial immune response of the host against the tumor cells. In the majority of human solid tumors, an increased number of tumor-infiltrating FOXP3 positive TR is associated with worse outcome. However, in follicular lymphoma (FL) the impact of the number and distribution of TR on the outcome still remains controversial. In this study, we present a novel method to detect and enumerate nuclei from FOXP3 stained images of FL biopsies. The proposed method defines a new adaptive thresholding procedure, namely the optimal adaptive thresholding (OAT) method, which aims to minimize under-segmented and over-segmented nuclei for coarse segmentation. Next, we integrate a parameter free elliptical arc and line segment detector (ELSD) as additional information to refine segmentation results and to split most of the merged nuclei. Finally, we utilize a state-of-the-art super-pixel method, Simple Linear Iterative Clustering (SLIC) to split the rest of the merged nuclei. Our dataset consists of 13 region-ofinterest images containing 769 negative and 88 positive nuclei. Three expert pathologists evaluated the method and reported sensitivity values in detecting negative and positive nuclei ranging from 83-100% and 90-95%, and precision values of 98-100% and 99-100%, respectively. The proposed solution can be used to investigate the impact of FOXP3 positive nuclei on the outcome and prognosis in FL.

  10. Role of accelerated segment switch in exons to alter targeting (ASSET in the molecular evolution of snake venom proteins

    Directory of Open Access Journals (Sweden)

    Kini R Manjunatha

    2009-06-01

    Full Text Available Abstract Background Snake venom toxins evolve more rapidly than other proteins through accelerated changes in the protein coding regions. Previously we have shown that accelerated segment switch in exons to alter targeting (ASSET might play an important role in its functional evolution of viperid three-finger toxins. In this phenomenon, short sequences in exons are radically changed to unrelated sequences and hence affect the folding and functional properties of the toxins. Results Here we analyzed other snake venom protein families to elucidate the role of ASSET in their functional evolution. ASSET appears to be involved in the functional evolution of three-finger toxins to a greater extent than in several other venom protein families. ASSET leads to replacement of some of the critical amino acid residues that affect the biological function in three-finger toxins as well as change the conformation of the loop that is involved in binding to specific target sites. Conclusion ASSET could lead to novel functions in snake venom proteins. Among snake venom serine proteases, ASSET contributes to changes in three surface segments. One of these segments near the substrate binding region is known to affect substrate specificity, and its exchange may have significant implications for differences in isoform catalytic activity on specific target protein substrates. ASSET therefore plays an important role in functional diversification of snake venom proteins, in addition to accelerated point mutations in the protein coding regions. Accelerated point mutations lead to fine-tuning of target specificity, whereas ASSET leads to large-scale replacement of multiple functionally important residues, resulting in change or gain of functions.

  11. Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia.

    Science.gov (United States)

    Shimazu, Yayoi; Shimazu, Yutaka; Hishizawa, Masakatsu; Hamaguchi, Masahide; Nagai, Yuya; Sugino, Noriko; Fujii, Sumie; Kawahara, Masahiro; Kadowaki, Norimitsu; Nishikawa, Hiroyoshi; Sakaguchi, Shimon; Takaori-Kondo, Akifumi

    2016-02-01

    Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1. Because of its immunosuppressive property and resistance to treatment, patients with ATL have poor prognoses. ATL cells possess the regulatory T cell (Treg) phenotype, such as CD4 and CD25, and usually express forkhead box P3 (FOXP3). However, the mechanisms of FOXP3 expression and its association with Treg-like characteristics in ATL remain unclear. Selective demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene leads to stable FOXP3 expression and defines natural Tregs. Here, we focus on the functional and clinical relationship between the epigenetic pattern of the TSDR and ATL. Analysis of DNA methylation in specimens from 26 patients with ATL showed that 15 patients (58%) hypomethylated the TSDR. The FOXP3(+) cells were mainly observed in the TSDR-hypomethylated cases. The TSDR-hypomethylated ATL cells exerted more suppressive function than the TSDR-methylated ATL cells. Thus, the epigenetic analysis of the FOXP3 gene identified a distinct subtype with Treg properties in heterogeneous ATL. Furthermore, we observed that the hypomethylation of TSDR was associated with poor outcomes in ATL. These results suggest that the DNA methylation status of the TSDR is an important hallmark to define this heterogeneous disease and to predict ATL patient prognosis. ©2015 American Association for Cancer Research.

  12. Evaluation of CD4+ CD25+ FoxP3+ regulatory T cells during treatment of patients with brucellosis.

    Science.gov (United States)

    Hasanjani Roushan, M R; Bayani, M; Soleimani Amiri, S; Mohammadnia-Afrouzi, M; Nouri, H R; Ebrahimpour, S

    2016-01-01

    Cell-mediated immunity (CMI) plays a critical role in the control of brucellosis. Regulatory T cells (Tregs) have a functional character in modulating the balance between host immune response and tolerance, which can eventually lead to chronic infection or relapse. The aim of this study was to assess the alteration of Tregs in cases of brucellosis before and after treatment. Thirty cases of acute brucellosis with the mean age of 41.03±15.15 years (case group) and 30 healthy persons with the mean age of 40.63±13.95 years (control group) were selected and assessed. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of all individuals. We analyzed the alteration of Treg cell count using flow cytometry for CD4, CD25, and FoxP3 markers. The level of CD4+ CD25+ FoxP3+ Treg cells was increased in active patients compared with controls (2.5±0.99% vs 1.6±0.84%, p= 0.0004), but it had declined in the treated cases (1.83±0.73%, p=0.02). The level of Tregs was elevated in three relapsed cases. The frequency of Tregs and Treg/Teff (effector T cell) ratio was correlated with inverse serum agglutination test (SAT) and, 2-mercaptoethanol (2-ME) titers as markers of treatment in brucellosis. Based on our findings, we suggest that regulatory cells, such as CD4+ CD25+ FoxP3+ Treg cells, may contribute to the development of infection processes involving immune responses in brucellosis, and evaluation of regulatory T-cell levels may be a potential diagnostic strategy for the treatment outcome in chronic and relapsed cases of brucellosis.

  13. Analysis of FFAG accelerators and the evolution of circular accelerators; L'analyse des accelerateurs FFAG et l'evolution des accelerateurs circulaires

    Energy Technology Data Exchange (ETDEWEB)

    Laslett, J [Commissariat a l' Energie Atomique, Saclay (France). Centre d' Etudes Nucleaires; [Iowa State Univ., U.S. Office of Naval Research, Dept. of Physics and Institute for Atomic Research, Ames (United States)

    1961-07-01

    After rapidly comparing circular machines with the linear accelerator and the reasons for the choice of an annular high energy and very high intensity accelerator, recent problems concerning accelerator theory are discussed, with emphasis on their physical character. The FFAG principle. The limit of the energy of FFAG cyclotron. The setting-up and interpreting of mean energy of focusing terms for a spiral FFAG synchrotron. The limiting amplitude stable near the non-linear resonance 2Q{sub z} = Q{sub r}, as well as the linear coupling resonance of Walkinshaw 2Q{sub z} = Q{sub r}. The crossed-beam accelerator. The 40 MeV electron model of MURA. Two other parts deal with linear and non-linear methods of injection and extraction using a variable disturbance applied to the magnetic field, as well as to collective effects. The interaction of the beam with the accelerating cavities and the walls. The modification of the phase oscillation equation. The influence of the beams' high frequency fields on the Nielsen longitudinal instability. (author) [French] Apres une comparaison rapide des machines circulaires avec l'accelerateur lineaire et une motivation du choix en faveur d'un accelerateur circulaire de haute energie et tres haute intensite, des problemes recents de la theorie des accelerateurs sont discutes, en insistant sur leur contenu physique. Le principe FFAG. La limitation en energie des cyclotrons FFAG. L'etablissement et l'interpretation des termes de la force moyenne de focalisation d'un synchrotron FFAG spirale. L'amplitude de limite stable a proximite de la resonance non-lineaire Q{sub r} = N/3, ainsi que la resonance lineaire de couplage de Walkinshaw 2Q{sub z} = Q{sub r}. L'accelerateur a faisceaux croises. Le modele a electrons de 40 MeV du MURA. Deux autres chapitres sont consacres a des methodes lineaires et non-lineaires d'injection et d'extraction a l'aide d'une perturbation variable appliquee au champ magnetique, ainsi qu'aux effets collectifs. L

  14. Absence of Foxp3+ regulatory T cells during allergen provocation does not exacerbate murine allergic airway inflammation.

    Directory of Open Access Journals (Sweden)

    Abdul Mannan Baru

    Full Text Available Regulatory T cells (Tregs play a non-redundant role in maintenance of immune homeostasis. This is achieved by suppressing both, priming of naïve cells and effector cell functions. Although Tregs have been implicated in modulating allergic immune responses, their influence on distinct phases of development of allergies remains unclear. In this study, by using bacterial artificial chromosome (BAC-transgenic Foxp3-DTR (DEREG mice we demonstrate that the absence of Foxp3(+ Tregs during the allergen challenge surprisingly does not exacerbate allergic airway inflammation in BALB/c mice. As genetic disposition due to strain specificity may contribute significantly to development of allergies, we performed similar experiment in C57BL/6 mice, which are less susceptible to allergy in the model of sensitization used in this study. We report that the genetic background does not influence the consequence of this depletion regimen. These results signify the temporal regulation exerted by Foxp3(+ Tregs in limiting allergic airway inflammation and may influence their application as potential therapeutics.

  15. Short Rotations in Forest Plantations Accelerate Virulence Evolution in Root-Rot Pathogenic Fungi

    Directory of Open Access Journals (Sweden)

    Jean-Paul Soularue

    2017-06-01

    Full Text Available As disease outbreaks in forest plantations are causing concern worldwide, a clear understanding of the influence of silvicultural practices on the development of epidemics is still lacking. Importantly, silvicultural practices are likely to simultaneously affect epidemiological and evolutionary dynamics of pathogen populations. We propose a genetically explicit and individual-based model of virulence evolution in a root-rot pathogenic fungus spreading across forest landscapes, taking the Armillaria ostoyae–Pinus pinaster pathosystem as reference. We used the model to study the effects of rotation length on the evolution of virulence and the propagation of the fungus within a forest landscape composed of even-aged stands regularly altered by clear-cutting and thinning operations. The life cycle of the fungus modeled combines asexual and sexual reproduction modes, and also includes parasitic and saprotrophic phases. Moreover, the tree susceptibility to the pathogen is primarily determined by the age of the stand. Our simulations indicated that the shortest rotation length accelerated both the evolution of virulence and the development of the epidemics, whatever the genetic variability in the initial fungal population and the asexuality rate of the fungal species

  16. Genes expressed in specific areas of the human fetal cerebral cortex display distinct patterns of evolution.

    Directory of Open Access Journals (Sweden)

    Nelle Lambert

    2011-03-01

    Full Text Available The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits.

  17. "small ACCELERATORS" 24 May - 2 June 2005

    CERN Multimedia

    2005-01-01

    CERN Accelerator School and Kernfysisch Versneller Instituut (KVI) Groningen, the Netherlands announce a course on "Small Accelerators", Hotel Golden Tulip Drenthe, Zeegse, the Netherlands, 24 May - 2 June 2005. This specialised course is dedicated to the physics and the main applications of small accelerators. The course will review the different accelerator types as well as their specificities in terms of accelerator physics.

  18. Stability of cylindrical thin shell wormhole during evolution of universe from inflation to late time acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Setare, M.R. [Department of Science, Campus of Bijar, University of Kurdistan,Bijar (Iran, Islamic Republic of); Sepehri, A. [Faculty of Physics, Shahid Bahonar University,P.O. Box 76175, Kerman (Iran, Islamic Republic of)

    2015-03-16

    In this paper, we consider the stability of cylindrical wormholes during evolution of universe from inflation to late time acceleration epochs. We show that there are two types of cylindrical wormholes. The first type is produced at the corresponding point where k black F-strings are transited to BIon configuration. This wormhole transfers energy from extra dimensions into our universe, causes inflation, loses it’s energy and vanishes. The second type of cylindrical wormhole is created by a tachyonic potential and causes a new phase of acceleration. We show that wormhole parameters grow faster than the scale factor in this era, overtake it at ripping time and lead to the destruction of universe at big rip singularity.

  19. Niobium LEP 2 accelerating cavities

    CERN Multimedia

    An accelerating cavity from LEP. This could be cut open to show the layer of niobium on the inside. Operating at 4.2 degrees above absolute zero, the niobium is superconducting and carries an accelerating field of 6 million volts per metre with negligible losses. Each cavity has a surface of 6 m2. The niobium layer is only 1.2 microns thick, ten times thinner than a hair. Such a large area had never been coated to such a high accuracy. A speck of dust could ruin the performance of the whole cavity so the work had to be done in an extremely clean environment. These challenging requirements pushed European industry to new achievements. 256 of these cavities were used in an upgrade of the LEP accelerator to double the energy of the particle beams.

  20. Foxp3⁺ regulatory T cells delay expulsion of intestinal nematodes by suppression of IL-9-driven mast cell activation in BALB/c but not in C57BL/6 mice.

    Directory of Open Access Journals (Sweden)

    Birte Blankenhaus

    2014-02-01

    Full Text Available Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3⁺ regulatory T cells (Treg in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3⁺ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in

  1. Increased numbers of Foxp3-positive regulatory T cells in gastritis, peptic ulcer and gastric adenocarcinoma

    Science.gov (United States)

    Cheng, Hsin-Hung; Tseng, Guan-Ying; Yang, Hsiao-Bai; Wang, Hung-Jung; Lin, Hwai-Jeng; Wang, Wen-Ching

    2012-01-01

    AIM: To determine the number of regulatory T cells (Tregs) in gastric mucosa of patients with gastritis, peptic ulcers and gastric cancer. METHODS: This study was a retrospective analysis of gastric antrum biopsy specimens from healthy controls (n = 22) and patients with gastritis (n = 30), peptic ulcer (n = 83), or gastric cancer (n = 32). Expression of CD4, CD25 and Foxp3 was determined by immunohistochemistry in three consecutive sections per sample. RESULTS: Compared with healthy controls, there was an increased number of CD25+ and Foxp3+ cells in patients with gastritis (P = 0.004 and P = 0.008), peptic ulcer (P gastritis (P gastritis and peptic ulcer groups. PMID:22228968

  2. FOXP3+ T Regulatory Cell Modifications in Inflammatory Bowel Disease Patients Treated with Anti-TNFα Agents

    Directory of Open Access Journals (Sweden)

    Luisa Guidi

    2013-01-01

    Full Text Available Treg modulation has been hypothesized as one of the mechanisms by which antitumor necrosis factor α (TNFα agents exert their action in rheumatoid arthritis (RA and inflammatory bowel disease (IBD. However, data in IBD are still conflicting. We evaluated CD4+CD25+FOXP3+ (Tregs by flow cytometry in peripheral blood from 32 adult IBD patient before (T0 and after the induction of anti-TNFα therapy (T1. Eight healthy controls (HCs were included. We also evaluated the number of FOXP3+ cells in the lamina propria (LP in biopsies taken in a subset of patients and controls. Treg frequencies were significantly increased in peripheral blood from our patients after anti-TNFα therapy compared to T0. T1 but not T0 levels were higher than HC. The increase was detectable only in clinical responders to the treatment. A negative correlation was found among delta Treg levels and the age of patients or disease duration and with the activity score of Crohn’s disease (CD. No significant differences were found in LP FOXP3+ cells. Our data suggest the possibility that in IBD patients the treatment with anti-TNFα may affect Treg percentages and that Treg modifications may correlate with clinical response, but differently in early versus late disease.

  3. Nano-copper-bearing stainless steel promotes fracture healing by accelerating the callus evolution process

    Directory of Open Access Journals (Sweden)

    Wang L

    2017-11-01

    superior for 317L-Cu SS. Histological staining displayed large amounts of fibrous tissues at 3 weeks, and cartilage and new bone at 6 weeks. Further, histomorphometric analysis indicated that the callus possessed higher osteogenic efficiency at 6 weeks, and a high Cu2+ content and increased Runx2 expression were observed in the callus for 317L-Cu SS. Besides, the mechanical strength of the fracture site was much better than that of the control group. Overall, we conclude that 317L-Cu SS possesses the ability to increase Cu2+ content and promote osteogenesis in the callus, which could accelerate the callus evolution process and bone formation to provide faster and better fracture healing. Keywords: nano-sized copper, lysyl oxidase, osteogenesis, fracture healing, callus evolution 

  4. Expression of FOXP3, CD14, and ARG1 in Neuroblastoma Tumor Tissue from High-Risk Patients Predicts Event-Free and Overall Survival

    Directory of Open Access Journals (Sweden)

    Sara Stigliani

    2015-01-01

    Full Text Available The prognosis of children with metastatic neuroblastoma (NB > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression of CD45, CD14, ARG1, CD163, CD4, FOXP3, Perforin-1 (PRF1, Granzyme B (GRMB, and IL-10 mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.. Children with high expression of CD14, ARG1 and FOXP3 mRNA in their primary tumors had significantly better EFS. Elevated expression of CD14, and FOXP3 mRNA was significantly associated to better OS. CD14 mRNA expression levels significantly correlated to all markers, with the exception of CD4. Strong positive correlations were found between PRF1 and CD163, as well as between PFR1 and FOXP3. It is worth noting that the combination of high levels of CD14, FOXP3, and ARG1 mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels of CD14 were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer.

  5. Accelerating networks

    International Nuclear Information System (INIS)

    Smith, David M D; Onnela, Jukka-Pekka; Johnson, Neil F

    2007-01-01

    Evolving out-of-equilibrium networks have been under intense scrutiny recently. In many real-world settings the number of links added per new node is not constant but depends on the time at which the node is introduced in the system. This simple idea gives rise to the concept of accelerating networks, for which we review an existing definition and-after finding it somewhat constrictive-offer a new definition. The new definition provided here views network acceleration as a time dependent property of a given system as opposed to being a property of the specific algorithm applied to grow the network. The definition also covers both unweighted and weighted networks. As time-stamped network data becomes increasingly available, the proposed measures may be easily applied to such empirical datasets. As a simple case study we apply the concepts to study the evolution of three different instances of Wikipedia, namely, those in English, German, and Japanese, and find that the networks undergo different acceleration regimes in their evolution

  6. Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.

    Science.gov (United States)

    Cook, Laura; Munier, C Mee Ling; Seddiki, Nabila; van Bockel, David; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K; Levings, Megan K; Reid, Hugh H; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John J; Tye-Din, Jason A; Kelleher, Anthony D

    2017-12-01

    Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) + Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 + T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 + T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 + T cells were FOXP3 + CD39 + Treg cells, which reside within the pool of memory CD4 + CD25 + CD127 low CD45RO + Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3 + CD39 + Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3 + CD39 + Treg cell frequency within circulating gluten-specific CD4 + T cells after oral gluten challenge of patients with celiac disease. FOXP3 + CD39 + Treg cells comprised a major proportion of all circulating gluten-specific CD4 + T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key

  7. Lactobacillus reuteri DSM 17938 changes the frequency of Foxp3+ regulatory T cells in the intestine and mesenteric lymph node in experimental necrotizing enterocolitis.

    Directory of Open Access Journals (Sweden)

    Yuying Liu

    Full Text Available Necrotizing enterocolitis (NEC is an inflammatory disease of the intestine in premature infants. Lactobacillus reuteri DSM 17938 improves survival and reduces the incidence and severity of NEC in a rodent model. Foxp3(+ regulatory T cells (Tregs maintain intestinal homeostasis by controlling inflammation and inducing tolerance. To determine whether there are insufficient numbers of Tregs to control inflammation in NEC and to determine if LR17938 increases the frequency of Tregs, we studied selected groups of newborn Sprague-Dawley rats according to feeding plan: dam±LR17938, formula±LR17938, and NEC±LR17938. NEC was induced by gavage feeding with special formula and exposure to hypoxic conditions. Lymphocytes isolated from ileum, mesenteric lymph nodes (MLN, spleen and thymus were labeled for T cell surface markers (CD3, CD4, CD8 and intracellular Foxp3; and labeled cells were analyzed by flow cytometry. The percentage of CD3(+ T cells and Foxp3(+ Tregs in the ileum significantly decreased in pups with NEC, compared to normal controls. Feeding LR17938 to neonatal rats with NEC increased the % of Foxp3(+ T cells in the ileum while decreasing the percentage of cells in the MLN. Administration of LR17938 to dam-fed rats significantly increased Foxp3(+Tregs in the ileum as early as day of life (DOL1 but did not produce an increase in Tregs in formula-fed rats on DOL1. These results suggest that factors in breast milk may enhance the early immunomodulatory effects of LR17938. An anti-inflammatory effect of LR17938 in NEC was associated with the modulation of immune responses and induction and what appears to be migration of Foxp3(+ Tregs to the diseased gut. Probiotic-facilitated development of Tregs might play an important role in the prevention of NEC.

  8. The effect of extracorporeal photopheresis alone or in combination therapy on circulating CD4+Foxp3+CD25- T-cells in patients with leukemic cutaneous T-cell lymphoma

    Science.gov (United States)

    Shiue, Lisa H.; Couturier, Jacob; Lewis, Dorothy E.; Wei, Caimiao; Ni, Xiao; Duvic, Madeleine

    2015-01-01

    Purpose Extracorporeal photopheresis (ECP) alone or in combination therapy is effective for treatment of leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanism(s) of action remain unclear. This study was designed to investigate the effect of ECP on regulatory T-cell and CD8+ T-cells in L-CTCL patients. Experimental Design Peripheral blood from 18 L-CTCL patients at baseline, Day 2, 1-month, 3-month, and 6-month post-ECP therapy were analyzed by flow cytometry for CD4+CD25+/high, CD4+Foxp3+CD25+/-, CD3+CD8+, CD3+CD8+CD69+, and CD3+CD8+IFN-γ+ T-cells. Clinical responses were assessed and correlated with changes in these T-cell subsets. Results Twelve of 18 patients achieved clinical responses. The average baseline number of CD4+CD25+/high T-cells of PBMCs in L-CTCL patients was normal (2.2%), but increased at 6-month post-therapy (4.3%, p<0.01). The average baseline number of CD4+Foxp3+ T-cells out of CD4+ T-cells in 9 evaluable patients was high (66.8±13.7%), mostly CD25 negative. The levels of CD4+Foxp3+ T cells in responders were higher (n=6, 93.1±5.7%) than non-responders (n=3, 14.2±16.0%, p<0.01), and they declined in parallel with malignant T-cells. The numbers of CD3+CD8+CD69+ and CD3+CD8+ IFN-γ+ T-cells increased at 3-month post-therapy in 5 of 6 patients studied. Conclusions ECP alone or in combination therapy might be effective in L-CTCL patients whose malignant T-cells have a CD4+Foxp3+CD25- phenotype. PMID:25772268

  9. Interacting with accelerators

    International Nuclear Information System (INIS)

    Dasgupta, S.

    1994-01-01

    Accelerators are research machines which produce energetic particle beam for use as projectiles to effect nuclear reactions. These machines along with their services and facilities may occupy very large areas. The man-machine interface of accelerators has evolved with technological changes in the computer industry and may be partitioned into three phases. The present paper traces the evolution of man-machine interface from the earliest accelerators to the present computerized systems incorporated in modern accelerators. It also discusses the advantages of incorporating expert system technology for assisting operators. (author). 8 ref

  10. CO2 laser technology for advanced particle accelerators

    International Nuclear Information System (INIS)

    Pogorelsky, I.V.

    1996-06-01

    Short-pulse, high-power CO 2 lasers open new prospects for development of ultra-high gradient laser-driven electron accelerators. The advantages of λ=10 μm CO 2 laser radiation over the more widely exploited solid state lasers with λ∼1 μm are based on a λ 2 -proportional ponderomotive potential, λ-proportional phase slippage, and λ-proportional scaling of the laser accelerator structures. We show how a picosecond terawatt CO 2 laser that is under construction at the Brookhaven Accelerator Test Facility may benefit the ATF's experimental program of testing far-field, near-field, and plasma accelerator schemes

  11. Accelerated evolution of innate immunity proteins in social insects: adaptive evolution or relaxed constraint?

    Science.gov (United States)

    Harpur, Brock A; Zayed, Amro

    2013-07-01

    The genomes of eusocial insects have a reduced complement of immune genes-an unusual finding considering that sociality provides ideal conditions for disease transmission. The following three hypotheses have been invoked to explain this finding: 1) social insects are attacked by fewer pathogens, 2) social insects have effective behavioral or 3) novel molecular mechanisms for combating pathogens. At the molecular level, these hypotheses predict that canonical innate immune pathways experience a relaxation of selective constraint. A recent study of several innate immune genes in ants and bees showed a pattern of accelerated amino acid evolution, which is consistent with either positive selection or a relaxation of constraint. We studied the population genetics of innate immune genes in the honey bee Apis mellifera by partially sequencing 13 genes from the bee's Toll pathway (∼10.5 kb) and 20 randomly chosen genes (∼16.5 kb) sequenced in 43 diploid workers. Relative to the random gene set, Toll pathway genes had significantly higher levels of amino acid replacement mutations segregating within A. mellifera and fixed between A. mellifera and A. cerana. However, levels of diversity and divergence at synonymous sites did not differ between the two gene sets. Although we detect strong signs of balancing selection on the pathogen recognition gene pgrp-sa, many of the genes in the Toll pathway show signatures of relaxed selective constraint. These results are consistent with the reduced complement of innate immune genes found in social insects and support the hypothesis that some aspect of eusociality renders canonical innate immunity superfluous.

  12. Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion1

    Science.gov (United States)

    Turner, Michael S.; Kane, Lawrence P.; Morel, Penelope A.

    2009-01-01

    The definitions of tolerogenic vs. immunogenic dendritic cells (DC) remain controversial. Immature DC have been shown to induce T regulatory cells (Treg) specific for foreign and allo-antigens. However, we have previously reported that mature DC (G4DC) prevented the onset of autoimmune diabetes whereas immature DC (GMDC) were therapeutically ineffective. In this study, islet-specific CD4+ T cells from BDC2.5 TCR Tg mice were stimulated, in the absence of exogenous cytokine, with GMDC or G4DC pulsed with high- or low-affinity antigenic peptides and examined for Treg induction. Both GMDC and G4DC presenting low peptide doses induced weak TCR signaling via the Akt/mTOR pathway, resulting in significant expansion of Foxp3+ Treg. Furthermore, unpulsed G4DC, but not GMDC, also induced Treg. High peptide doses induced strong Akt/mTOR signaling and favored the expansion of Foxp3neg Th cells. The inverse correlation of Foxp3 and Akt/mTOR signaling was also observed in DO11.10 and OT-II TCR-Tg T cells and was recapitulated with anti-CD3/CD28 stimulation in the absence of DC. IL-6 production in these cultures correlated positively with antigen dose and inversely with Treg expansion. Studies with T cells or DC from IL-6−/− mice revealed that IL-6 production by T cells was more important in the inhibition of Treg induction at low antigen doses. These studies indicate that strength of Akt/mTOR signaling, a critical T cell intrinsic determinant for Treg vs Th induction, can be controlled by adjusting the dose of antigenic peptide. Furthermore, this operates in a dominant fashion over DC phenotype and cytokine production. PMID:19801514

  13. Late Pleistocene acceleration of deformation across the northern Tianshan piedmont (China) evidenced from the morpho-tectonic evolution of the Dushanzi anticline

    Science.gov (United States)

    Charreau, Julien; Saint-Carlier, Dimitri; Lavé, Jérôme; Dominguez, Stéphane; Blard, Pierre-Henri; Avouac, Jean-Philippe; Brown, Nathan D.; Malatesta, Luca Claude; Wang, Shengli; Rhodes, Edward J.

    2018-04-01

    We document the temporal evolution of deformation in the northern Tianshan piedmont where the deformation is partitioned across several thrusts and folds. We focus on the Dushanzi anticline, where abandoned terraces and growth strata allow us to constrain the history of folding since the Miocene. Based on subsurface seismic imaging, structural measurements and morphological analysis, we show that this anticline is associated with two decollement levels. We use kink band migration in growth strata dated by paleomagnetism to constrain the shortening from the Mio-Pliocene to the Holocene. Our results show that the Dushanzi anticline has been active since at least 8 Ma and that the fold grew at a steady shortening rate of 0.6 ± 0.1 mm/yr from 8 to 1.5 Ma with possible variations from 2.5 to 1.5 Ma. Then it accelerated rapidly to a rate of 4.3 ± 1.0 mm/yr over at least the last 100 ka. These results, together with similar temporal shortening evolutions across other structures, suggest that the deformation rate across the eastern Tianshan piedmont increased relatively recently. This may reflect either a redistribution of the deformation from the internal structures toward the borders or a general acceleration of the deformation across the entire range.

  14. [Changes of CD(4)(+) Foxp3+ regulatory T cells and CD(4)(+)IL-17+T cells in acrolein exposure rats].

    Science.gov (United States)

    Wei, Ming; Tu, Ling; Liang, Yinghong; Li, Jia; Gong, Yanjie; Zhang, Yihua; Yang, Lu

    2015-09-01

    To evaluate the changes of CD(4)(+) IL-17+T (Th17) and CD(4)(+)Foxp3+regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF) , and therefore to explore the role of Th17 and Treg in acrolein exposure airway inflammation in rats. Forty male Wistar rats were randomly divided into 4 groups: a 2 wk acrolein exposure group, a 4 wk acrolein exposure group, a 2 wk control group and a 4 wk control group (n=10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts.IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17+T and CD(4)(+) Foxp3+Treg in peripheral blood and BALF were determined by flow cytometry.The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 2 wk acrolein exposure group and the 4 wk acrolein exposure group in serum [(52.64 ± 1.89) ng/L, (76.73 ± 5.57) ng/L], and BALF [(79.07 ± 5.67) ng/L, (96.61 ± 6.44) ng/L] compared with the 2 wk control group [(40.05 ± 3.12) ng/L, (56.75 ± 4.37) ng/L] and the 4 wk control group [(38.75 ± 3.23) ng/L, (53.27 ± 4.48) ng/L], all Pcells and macrophages (r=0.5126, 0.5437, all Pcells and an vary of inflammatory cytokines were evident in airway inflammation of acrolein exposed rats, suggesting that Treg was involved in the immunological regulation and Th17 was associated with the persistent inflammation in acrolein induced airway inflammation in rats.

  15. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

    International Nuclear Information System (INIS)

    Ghebeh, Hazem; Barhoush, Eman; Tulbah, Asma; Elkum, Naser; Al-Tweigeri, Taher; Dermime, Said

    2008-01-01

    Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T regs ). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T regs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease. Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease. A co-existence of B7-H1 + T lymphocytes and FOXP3 + T regs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3 + T regs , B7-H1 + and PD-1 + TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022). Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T regs and B7-H1/PD-1 molecules

  16. Kaempferol enhances the suppressive function of Treg cells by inhibiting FOXP3 phosphorylation.

    Science.gov (United States)

    Lin, Fang; Luo, Xuerui; Tsun, Andy; Li, Zhiyuan; Li, Dan; Li, Bin

    2015-10-01

    Kaempferol is a natural flavonoid found in many vegetables and fruits. Epidemiologic studies have described that Kaempferol intake could reduce risk of cancer, especially lung, gastric, pancreatic and ovarian cancers. Recent studies have shown that Kaempferol could also be beneficial to the body to defend against inflammation, and infection by bacteria and viruses; however, the molecular mechanism of its immunoregulatory function remains largely unknown. Through screening a small molecule library of traditional Chinese medicine (TCM), we identified that Kaempferol could enhance the suppressive function of regulatory T cells (Tregs). Kaempferol was found to increase FOXP3 expression level in Treg cells and prevent pathological symptoms of collagen-induced arthritis in a rat animal model. Kaempferol could also reduce PIM1-mediated FOXP3 phosphorylation at S422. Our study reveals a molecular mechanism that underlies the anti-inflammatory action of Kaempferol for the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. TNFR2 expression on CD25hiFOXP3+ T cells induced upon TCR stimulation of CD4 T cells identifies maximal cytokine-producing effectors.

    Directory of Open Access Journals (Sweden)

    Chindu eGovindaraj

    2013-08-01

    Full Text Available In this study, we show that CD25hiTNFR2+ cells can be rapidly generated in vitro from circulating CD4 lymphocytes by polyclonal stimuli anti-CD3 in the presence of anti-CD28. The in vitro induced CD25hiTNFR2+ T cells express a conventional Treg phenotype FOXP3+CTLA4+CD127lo/-, but produce effector and immunoregulatory cytokines including IL-2, IL-10 and IFN-g. These induced CD25hiTNFR2+ T cells do not suppress target cell proliferation, but enhance it instead. Thus the CD25hiTNFR2+ phenotype induced rapidly following CD3/28 cross linking of CD4 T cells identifies cells with maximal proliferative and effector cytokine producing capability. The in vivo counterpart of this cell population may play an important role in immune response initiation.

  18. CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression

    Directory of Open Access Journals (Sweden)

    Luyan Mu

    2017-11-01

    Full Text Available BackgroundAngiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL and tumor blood-vasculatures in the context of glioma progression.MethodsPaired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA recurred as DA, DA recurred as glioblastomas (GBM, and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.ResultsUpon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors. Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS (HR = 4.199, 95% CI 1.522–11.584, p = 0.006.ConclusionThe minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3

  19. Picosecond CO2 laser for relativistic particle acceleration

    International Nuclear Information System (INIS)

    Pogorelsky, I.; Ben-Zvi, I.; Kimura, W.D.; Kurnit, N.A.; Kannari, F.

    1994-01-01

    A table-top 20-GW 50-ps CO 2 laser system is under operation at the Brookhaven Accelerator Test Facility. We compare laser performance with model predictions. Extrapolations suggest the possibility of compact terawatt CO 2 laser systems suitable as laser accelerator drivers and for other strong-field applications. Latest progress on an Inverse Cherenkov Laser Accelerator experiment is reported

  20. Observations of the Coronal Mass Ejection with a Complex Acceleration Profile

    Science.gov (United States)

    Reva, A. A.; Kirichenko, A. S.; Ulyanov, A. S.; Kuzin, S. V.

    2017-12-01

    We study the coronal mass ejection (CME) with a complex acceleration profile. The event occurred on 2009 April 23. It had an impulsive acceleration phase, an impulsive deceleration phase, and a second impulsive acceleration phase. During its evolution, the CME showed signatures of different acceleration mechanisms: kink instability, prominence drainage, flare reconnection, and a CME–CME collision. The special feature of the observations is the usage of the TESIS EUV telescope. The instrument could image the solar corona in the Fe 171 Å line up to a distance of 2 {R}ȯ from the center of the Sun. This allows us to trace the CME up to the LASCO/C2 field of view without losing the CME from sight. The onset of the CME was caused by kink instability. The mass drainage occurred after the kink instability. The mass drainage played only an auxiliary role: it decreased the CME mass, which helped to accelerate the CME. The first impulsive acceleration phase was caused by the flare reconnection. We observed the two-ribbon flare and an increase of the soft X-ray flux during the first impulsive acceleration phase. The impulsive deceleration and the second impulsive acceleration phases were caused by the CME–CME collision. The studied event shows that CMEs are complex phenomena that cannot be explained with only one acceleration mechanism. We should seek a combination of different mechanisms that accelerate CMEs at different stages of their evolution.

  1. 2nd European Advanced Accelerator Concepts Workshop

    CERN Document Server

    Assmann, Ralph; Grebenyuk, Julia; EAAC 2015

    2016-01-01

    The European Advanced Accelerator Concepts Workshop has the mission to discuss and foster methods of beam acceleration with gradients beyond state of the art in operational facilities. The most cost effective and compact methods for generating high energy particle beams shall be reviewed and assessed. This includes diagnostics methods, timing technology, special need for injectors, beam matching, beam dynamics with advanced accelerators and development of adequate simulations. This workshop is organized in the context of the EU-funded European Network for Novel Accelerators (EuroNNAc2), that includes 52 Research Institutes and universities.

  2. Resonant ion acceleration by collisionless magnetosonic shock waves

    International Nuclear Information System (INIS)

    Ohsawa, Y.

    1985-01-01

    Resonant ion acceleration ( the ν/sub rho/xΒ acceleration ) in laminar magnetosonic shock waves is studied by theory and simulation. Theoretical analysis based on a two-fluid model shows that, in laminar shocks, the electric field strength in the direction of the wave normal is about (m/sub i/m/sub e/) 1 2 times large for quasi-perpendicular shocks than that for the quasi-parallel shocks, which is a reflection of the fact that the width of quasi-perpendicular shocks is much smaller than that of the quasi-parallel shocks. Trapped ions can be accelerated up to the speed about ν/sub A/(m/sub i/m/sub e/) 1 2(M/sub A/-1) 3 2 in quasi-perpendicular shocks. Time evolution of self-consistent magnetosonic shock waves is studied by using a 2-12 dimensional fully relativistic, fully electromagnetic particle simulation with full ion and electron dynamics. Even a low-Mach-number shock wave can significantly accelerate trapped ions by the ν/sub rho/xΒ acceleration. The resonant ion acceleration occurs more strongly in quasi-perpendicular shocks, because the magnitude of this acceleration is proportional to the electric field strength

  3. Increased FOXP3 expression in tumour-associated tissues of horses affected with equine sarcoid disease.

    Science.gov (United States)

    Mählmann, K; Hamza, E; Marti, E; Dolf, G; Klukowska, J; Gerber, V; Koch, C

    2014-12-01

    Recent studies suggest that regulatory T cells (Tregs) are associated with disease severity and progression in papilloma virus induced neoplasia. Bovine papilloma virus (BPV) is recognised as the most important aetiological factor in equine sarcoid (ES) disease. The aim of this study was to compare expression levels of Treg markers and associated cytokines in tissue samples of ES-affected equids with skin samples of healthy control horses. Eleven ES-affected, and 12 healthy horses were included in the study. Expression levels of forkhead box protein 3 (FOXP3), interleukin 10 (IL10), interleukin 4 (IL4) and interferon gamma (IFNG) mRNA in lesional and tumour-distant samples from ES-affected horses, as well as in dermal samples of healthy control horses were measured using quantitative reverse transcription polymerase chain reaction (PCR). Expression levels were compared between lesional and tumour-distant as well as between tumour-distant and control samples. Furthermore, BPV-1 E5 DNA in samples of ES-affected horses was quantified using quantitative PCR, and possible associations of viral load, disease severity and gene expression levels were evaluated. Expression levels of FOXP3, IL10 and IFNG mRNA and BPV-1 E5 copy numbers were significantly increased in lesional compared to tumour-distant samples. There was no difference in FOXP3 and cytokine expression in tumour-distant samples from ES- compared with control horses. In tumour-distant samples viral load was positively correlated with IL10 expression and severity score. The increased expression of Treg markers in tumour-associated tissues of ES-affected equids indicates a local, Treg-induced immune suppression. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome

    DEFF Research Database (Denmark)

    Pedersen, Martin Bjerregård; Hamilton-Dutoit, Stephen Jacques; Bendix, Knud

    2014-01-01

    Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome.......Identification of a subset of perpheral T-cell lymphoma, not otherwise specified, characterized by FOXP3-positive regulatory T-cell phenotype, HTLV-1 negativity and poor outcome....

  5. CO2 laser technology for advanced particle accelerators. Revision

    International Nuclear Information System (INIS)

    Pogorelsky, I.V.

    1996-06-01

    Short-pulse, high-power CO 2 lasers open new prospects for development of ultra-high gradient laser-driven electron accelerators. The advantages of λ=10 μm CO 2 laser radiation over the more widely exploited solid state lasers with λ∼1 μm are based on a λ 2 -proportional ponderomotive potential, λ-proportional phase slippage distance, and λ-proportional scaling of the laser accelerator structures. We show how a picosecond terawatt CO 2 laser that is under construction at the Brookhaven Accelerator Test Facility may benefit the ATF's experimental program of testing far-field, near-field, and plasma accelerator schemes

  6. A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells.

    Science.gov (United States)

    Guo, Zhiyong; Khattar, Mithun; Schroder, Paul M; Miyahara, Yoshihiro; Wang, Guohua; He, Xiaoshung; Chen, Wenhao; Stepkowski, Stanislaw M

    2013-04-01

    The molecular mechanism of the extrathymic generation of adaptive, or inducible, CD4(+)Foxp3(+) regulatory T cells (iTregs) remains incompletely defined. We show that exposure of splenic CD4(+)CD25(+)Foxp3(-) cells to IL-2, but not other common γ-chain cytokines, resulted in Stat5 phosphorylation and induced Foxp3 expression in ∼10% of the cells. Thus, IL-2/Stat5 signaling may be critical for Foxp3 induction in peripheral CD4(+)CD25(+)Foxp3(-) iTreg precursors. In this study, to further define the role of IL-2 in the formation of iTreg precursors as well as their subsequent Foxp3 expression, we designed a two-step iTreg differentiation model. During the initial "conditioning" step, CD4(+)CD25(-)Foxp3(-) naive T cells were activated by TCR stimulation. Inhibition of IL-2 signaling via Jak3-Stat5 was required during this step to generate CD4(+)CD25(+)Foxp3(-) cells containing iTreg precursors. During the subsequent Foxp3-induction step driven by cytokines, IL-2 was the most potent cytokine to induce Foxp3 expression in these iTreg precursors. This two-step method generated a large number of iTregs with relatively stable expression of Foxp3, which were able to prevent CD4(+)CD45RB(high) cell-mediated colitis in Rag1(-/-) mice. In consideration of this information, whereas initial inhibition of IL-2 signaling upon T cell priming generates iTreg precursors, subsequent activation of IL-2 signaling in these precursors induces the expression of Foxp3. These findings advance the understanding of iTreg differentiation and may facilitate the therapeutic use of iTregs in immune disorders.

  7. MID-INFRARED EVIDENCE FOR ACCELERATED EVOLUTION IN COMPACT GROUP GALAXIES

    International Nuclear Information System (INIS)

    Walker, Lisa May; Johnson, Kelsey E.; Gallagher, Sarah C.; Hibbard, John E.; Hornschemeier, Ann E.; Tzanavaris, Panayiotis; Charlton, Jane C.; Jarrett, Thomas H.

    2010-01-01

    Compact galaxy groups are at the extremes of the group environment, with high number densities and low velocity dispersions that likely affect member galaxy evolution. To explore the impact of this environment in detail, we examine the distribution in the mid-infrared (MIR) 3.6-8.0 μm color space of 42 galaxies from 12 Hickson compact groups (HCGs) in comparison with several control samples, including the LVL+SINGS galaxies, interacting galaxies, and galaxies from the Coma Cluster. We find that the HCG galaxies are strongly bimodal, with statistically significant evidence for a gap in their distribution. In contrast, none of the other samples show such a marked gap, and only galaxies in the Coma infall region have a distribution that is statistically consistent with the HCGs in this parameter space. To further investigate the cause of the HCG gap, we compare the galaxy morphologies of the HCG and LVL+SINGS galaxies, and also probe the specific star formation rate (SSFR) of the HCG galaxies. While galaxy morphology in HCG galaxies is strongly linked to position with MIR color space, the more fundamental property appears to be the SSFR, or star formation rate normalized by stellar mass. We conclude that the unusual MIR color distribution of HCG galaxies is a direct product of their environment, which is most similar to that of the Coma infall region. In both cases, galaxy densities are high, but gas has not been fully processed or stripped. We speculate that the compact group environment fosters accelerated evolution of galaxies from star-forming and neutral gas-rich to quiescent and neutral gas-poor, leaving few members in the MIR gap at any time.

  8. Identification of accelerated evolution in the metalloproteinase ...

    African Journals Online (AJOL)

    U

    2016-02-24

    Feb 24, 2016 ... drugs for different diseases. Key words: SVMPs, evolution, multiple sequence alignment, phylogenic tree, secondary structure, homology. ... in matrix metalloproteinase genes MMP1, MMP9 and. MMP12 are shown to be ... Evolution and diversification of snake venom is a very interesting phenomenon.

  9. The evolution of high energy accelerators

    International Nuclear Information System (INIS)

    Courant, E.D.

    1989-10-01

    In this lecture I would like to trace how high energy particle accelerators have grown from tools used for esoteric small-scale experiments to gigantic projects being hotly debated in Congress as well as in the scientific community

  10. Intermediate Inflation or Late Time Acceleration?

    International Nuclear Information System (INIS)

    Sanyal, A.K.

    2008-01-01

    The expansion rate of intermediate inflation lies between the exponential and power law expansion but corresponding accelerated expansion does not start at the onset of cosmological evolution. Present study of intermediate inflation reveals that it admits scaling solution and has got a natural exit form it at a later epoch of cosmic evolution, leading to late time acceleration. The corresponding scalar field responsible for such feature is also found to behave as a tracker field for gravity with canonical kinetic term.

  11. Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

    Directory of Open Access Journals (Sweden)

    Jeffrey P. Perley

    2014-11-01

    Full Text Available Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKC and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and Isignaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1 SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2 CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3 elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs, is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

  12. Pump depletion limited evolution of the relativistic plasma wave-front in a forced laser-wakefield accelerator

    International Nuclear Information System (INIS)

    Fang, F; Clayton, C E; Marsh, K A; Pak, A E; Ralph, J E; Joshi, C; Lopes, N C

    2009-01-01

    In a forced laser-wakefield accelerator experiment (Malka et al 2002 Science 298 1596) where the length of the pump laser pulse is a few plasma periods long, the leading edge of the laser pulse undergoes frequency downshifting and head erosion as the laser energy is transferred to the wake. Therefore, after some propagation distance, the group velocity of the leading edge of the pump pulse-and thus of the driven electron plasma wave-will slow down. This can have implications for the dephasing length of the accelerated electrons and therefore needs to be understood experimentally. We have carried out an experimental investigation where we have measured the velocity v f of the 'wave-front' of the plasma wave driven by a nominally 50 fs (full width half maximum), intense (a 0 ≅ 1), 0.815 μm laser pulse. To determine the speed of the wave front, time- and space-resolved refractometry, interferometry and Thomson scattering were used. Although a laser pulse propagating through a relatively low-density plasma (n e = 1.3 x 10 19 cm -3 ) showed no measurable changes in v f over 1.3 mm (and no accelerated electrons), a high-density plasma (n e = 5 x 10 19 cm -3 ) generated accelerated electrons and showed a continuous change in v f as the laser pulse propagated through the plasma. Possible causes and consequences of the observed v f evolution are discussed.

  13. [Changes of CD(4)(+)Foxp3(+) regulatory T cells and CD(4)(+)IL-17(+)T cells in cigarette smoke-exposed rats].

    Science.gov (United States)

    Meng, Jing-jing; Zhong, Xiao-ning; Bai, Jing; He, Zhi-yi; Zhang, Jian-quan; Huang, Qiu-pin

    2012-01-01

    To evaluate the changes of CD(4)(+)IL-17(+) T (Th17) and CD(4)(+)Foxp3(+) regulatory T (Treg) cells in peripheral blood and bronchoalveolar lavage fluid (BALF), and therefore to explore the role of Th17 and Treg in cigarette smoke-induced airway inflammation/COPD in rats. Forty male Wistar rats were randomly divided into 4 groups: a 12 wk smoke-exposure group, a 24 wk smoke-exposure group, a 12 wk control group and a 24 wk control group (n = 10 each). Cells in BALF were collected and analyzed by absolute and differential cell counts. IL-17 and IL-6 levels in serum and BALF were tested by enzyme linked immunosorbent assay (ELISA). The proportion of CD(4)(+)IL-17(+) T and CD(4)(+)Foxp3(+) Treg in peripheral blood and BALF were determined by flow cytometry. The mRNA expressions of IL-17 and Foxp3 were measured by real-time PCR. Comparisons of the data between different groups were performed using one-way ANOVA, and SNK and Games-Howell test were used for comparison between 2 groups. Levels of IL-17 were remarkable increased in the 12 wk smoke-exposure group and the 24 wk smoke-exposure group in serum [(52.6 ± 1.8) ng/L, (75.4 ± 6.0) ng/L] and BALF [(78.1 ± 5.8) ng/L, (95.0 ± 6.8) ng/L] compared with the 12 wk control group [(40.0 ± 3.2)ng/L, (54.5 ± 4.6) ng/L] and the 24 wk control group [(36.7 ± 3.2) ng/L, (53.9 ± 3.7) ng/L], all P cells and macrophages (r = 0.512, 0.543, all P cells and an increase of inflammatory cytokines were evident in airway inflammation of cigarette smoke-exposed rats, suggesting that Treg was involved in the immunological regulation and Th17 was associated with the persistent inflammation in cigarette smoke-induced airway inflammation in rats.

  14. Accelerator-TEM interface facility and application

    International Nuclear Information System (INIS)

    Liu Chuansheng; Li Ming; He Jun; Yang Zheng; Zhou Lin; Wang Zesong; Guo Liping; Jiang Changzhong; Yang Shibo; Fu Dejun; Fan Xiangjun; Liu Jiarui; Lee J C

    2010-01-01

    An accelerator-TEM interface facility has been established at Wuhan University in 2008. The system consists of an H800 TEM linked to a 200 kV ion implanter and a 2 x 1.7 MV tandem accelerator. Nitrogen ions at 115 keV were successfully transported from the implanter into the TEM chamber through the interface system, and the ion currents measured at the entrance of the TEM column were between 20 and 180 nA. Structural evolution caused by ion irradiation in Si, GaAs, nanocrystal Ag was observed in situ. The in situ observation showed that the critical implantation dose for amorphization of Si is 10 14 cm -2 . The nuclear material C276 samples implanted with 115 keV Ar + was also studied, and dislocation loops sized at 3-12 nm were clearly observed after implantation to doses of over 1 x 10 15 cm -2 . The density of the loops increased with the dose. Evolution to polycrystalline and amorphous structures were observed at 5 x l0 15 cm -2 and 3 x 10 16 cm -2 , respectively. An in situ RBS/C chamber was installed on the transport line of the accelerator-TEM interface system. This enables in situ measurement of composition and location of the implanted species in lattice of the samples. In addition, a 50 kV low-energy gaseous ion generator was installed close to the TEM chamber, which facilitates in situ TEM observation of helium bubbles formed in helium-implanted materials. (authors)

  15. Allogeneic effector/memory Th-1 cells impair FoxP3+ regulatory T lymphocytes and synergize with chaperone-rich cell lysate vaccine to treat leukemia.

    Science.gov (United States)

    Janikashvili, Nona; LaCasse, Collin J; Larmonier, Claire; Trad, Malika; Herrell, Amanda; Bustamante, Sara; Bonnotte, Bernard; Har-Noy, Michael; Larmonier, Nicolas; Katsanis, Emmanuel

    2011-02-03

    Therapeutic strategies combining the induction of effective antitumor immunity with the inhibition of the mechanisms of tumor-induced immunosuppression represent a key objective in cancer immunotherapy. Herein we demonstrate that effector/memory CD4(+) T helper-1 (Th-1) lymphocytes, in addition to polarizing type-1 antitumor immune responses, impair tumor-induced CD4(+)CD25(+)FoxP3(+) regulatory T lymphocyte (Treg) immunosuppressive function in vitro and in vivo. Th-1 cells also inhibit the generation of FoxP3(+) Tregs from naive CD4(+)CD25(-)FoxP3(-) T cells by an interferon-γ-dependent mechanism. In addition, in an aggressive mouse leukemia model (12B1), Th-1 lymphocytes act synergistically with a chaperone-rich cell lysate (CRCL) vaccine, leading to improved survival and long-lasting protection against leukemia. The combination of CRCL as a source of tumor-specific antigens and Th-1 lymphocytes as an adjuvant has the potential to stimulate efficient specific antitumor immunity while restraining Treg-induced suppression.

  16. Accelerators for research and applications

    International Nuclear Information System (INIS)

    Alonso, J.R.

    1990-06-01

    The newest particle accelerators are almost always built for extending the frontiers of research, at the cutting edge of science and technology. Once these machines are operating and these technologies mature, new applications are always found, many of which touch our lives in profound ways. The evolution of accelerator technologies will be discussed, with descriptions of accelerator types and characteristics. The wide range of applications of accelerators will be discussed, in fields such as nuclear science, medicine, astrophysics and space-sciences, power generation, airport security, materials processing and microcircuit fabrication. 13 figs

  17. Community Petascale Project for Accelerator Science and Simulation: Advancing Computational Science for Future Accelerators and Accelerator Technologies

    Energy Technology Data Exchange (ETDEWEB)

    Spentzouris, P.; /Fermilab; Cary, J.; /Tech-X, Boulder; McInnes, L.C.; /Argonne; Mori, W.; /UCLA; Ng, C.; /SLAC; Ng, E.; Ryne, R.; /LBL, Berkeley

    2011-11-14

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The ComPASS organization

  18. Regulatory function of a novel population of mouse autoantigen-specific Foxp3 regulatory T cells depends on IFN-gamma, NO, and contact with target cells.

    Directory of Open Access Journals (Sweden)

    Cyndi Chen

    Full Text Available BACKGROUND: Both naturally arising Foxp3(+ and antigen-induced Foxp3(- regulatory T cells (Treg play a critical role in regulating immune responses, as well as in preventing autoimmune diseases and graft rejection. It is known that antigen-specific Treg are more potent than polyclonal Treg in suppressing pathogenic immune responses that cause autoimmunity and inflammation. However, difficulty in identifying and isolating a sufficient number of antigen-specific Treg has limited their use in research to elucidate the mechanisms underlying their regulatory function and their potential role in therapy. METHODOLOGY/PRINCIPAL FINDINGS: Using a novel class II MHC tetramer, we have isolated a population of CD4(+ Foxp3(- T cells specific for the autoantigen glutamic acid decarboxylase p286-300 peptide (NR286 T cells from diabetes-resistant non-obese resistant (NOR mice. These Foxp3(- NR286 T cells functioned as Treg that were able to suppress target T cell proliferation in vitro and inhibit type 1 diabetes in animals. Unexpected results from mechanistic studies in vitro showed that their regulatory function was dependent on not only IFN-gamma and nitric oxide, but also on cell contact with target cells. In addition, separating NR286 Treg from target T cells in transwell assays abolished both production of NO and suppression of target T cells, regardless of whether IFN-gamma was produced in cell cultures. Therefore, production of NO, not IFN-gamma, was cell contact dependent, suggesting that NO may function downstream of IFN-gamma in mediating regulatory function of NR286 Treg. CONCLUSIONS/SIGNIFICANCE: These studies identified a unique population of autoantigen-specific Foxp3(- Treg that can exert their regulatory function dependent on not only IFN-gamma and NO but also cell contact with target cells.

  19. Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection.

    Directory of Open Access Journals (Sweden)

    Shuo Li

    2009-12-01

    Full Text Available We reported previously that a proportion of natural CD25(+ cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25(+ cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of approximately 46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25(+ cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker, accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection.

  20. Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3+ Regulatory T Cells Frequency and Function during the Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Yingxia Zheng

    2017-05-01

    Full Text Available Ulcerative colitis (UC pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1 treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFβ and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1 expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFα, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC.

  1. Time evolution of damage in thermally induced creep rupture

    KAUST Repository

    Yoshioka, N.

    2012-01-01

    We investigate the time evolution of a bundle of fibers subject to a constant external load. Breaking events are initiated by thermally induced stress fluctuations followed by load redistribution which subsequently leads to an avalanche of breakings. We compare analytic results obtained in the mean-field limit to the computer simulations of localized load redistribution to reveal the effect of the range of interaction on the time evolution. Focusing on the waiting times between consecutive bursts we show that the time evolution has two distinct forms: at high load values the breaking process continuously accelerates towards macroscopic failure, however, for low loads and high enough temperatures the acceleration is preceded by a slow-down. Analyzing the structural entropy and the location of consecutive bursts we show that in the presence of stress concentration the early acceleration is the consequence of damage localization. The distribution of waiting times has a power law form with an exponent switching between 1 and 2 as the load and temperature are varied.

  2. Time-resolved transcriptome and proteome landscape of human regulatory T cell (Treg) differentiation reveals novel regulators of FOXP3

    KAUST Repository

    Schmidt, Angelika; Marabita, Francesco; Kiani, Narsis A.; Gross, Catharina C.; Johansson, Henrik J.; É liá s, Szabolcs; Rautio, Sini; Eriksson, Matilda; Fernandes, Sunjay Jude; Silberberg, Gilad; Ullah, Ubaid; Bhatia, Urvashi; Lä hdesmä ki, Harri; Lehtiö , Janne; Gomez-Cabrero, David; Wiendl, Heinz; Lahesmaa, Riitta; Tegner, Jesper

    2018-01-01

    BackgroundRegulatory T cells (Tregs) expressing the transcription factor FOXP3 are crucial mediators of self-tolerance, preventing autoimmune diseases but possibly hampering tumor rejection. Clinical manipulation of Tregs is of great interest

  3. Pump depletion limited evolution of the relativistic plasma wave-front in a forced laser-wakefield accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Fang, F; Clayton, C E; Marsh, K A; Pak, A E; Ralph, J E; Joshi, C [Department of Electrical Engineering, University of California, Los Angeles, CA 90095 (United States); Lopes, N C [Grupo de Lasers e Plasmas, Instituto Superior Tecnico, Lisbon (Portugal)], E-mail: cclayton@ucla.edu

    2009-02-15

    In a forced laser-wakefield accelerator experiment (Malka et al 2002 Science 298 1596) where the length of the pump laser pulse is a few plasma periods long, the leading edge of the laser pulse undergoes frequency downshifting and head erosion as the laser energy is transferred to the wake. Therefore, after some propagation distance, the group velocity of the leading edge of the pump pulse-and thus of the driven electron plasma wave-will slow down. This can have implications for the dephasing length of the accelerated electrons and therefore needs to be understood experimentally. We have carried out an experimental investigation where we have measured the velocity v{sub f} of the 'wave-front' of the plasma wave driven by a nominally 50 fs (full width half maximum), intense (a{sub 0} {approx_equal} 1), 0.815 {mu}m laser pulse. To determine the speed of the wave front, time- and space-resolved refractometry, interferometry and Thomson scattering were used. Although a laser pulse propagating through a relatively low-density plasma (n{sub e} = 1.3 x 10{sup 19} cm{sup -3}) showed no measurable changes in v{sub f} over 1.3 mm (and no accelerated electrons), a high-density plasma (n{sub e} = 5 x 10{sup 19} cm{sup -3}) generated accelerated electrons and showed a continuous change in v{sub f} as the laser pulse propagated through the plasma. Possible causes and consequences of the observed v{sub f} evolution are discussed.

  4. Increase of circulating CD4+CD25highFoxp3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2

    DEFF Research Database (Denmark)

    Berntsen, Annika; Brimnes, Marie Klinge; thor Straten, Per

    2010-01-01

    Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2...... in patients with metastatic renal cell carcinoma on the frequency of CD4+CD25highFoxp3+ Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P...

  5. Topics in quantum chromodynamics: two loop Feynman gauge calculation of the meson nonsinglet evolution potential and fourier acceleration of the calculation of the fermion propagator in lattice QCD

    International Nuclear Information System (INIS)

    Katz, G.R.

    1986-01-01

    Part I of this thesis is a perturbative QCD calculation to two loops of the meson nonsinglet evolution potential in the Feynman gauge. The evolution potential describes the momentum dependence of the distribution amplitude. This amplitude is needed for the calculation to beyond leading order of exclusive amplitudes and form factors. Techniques are presented that greatly simplify the calculation. The results agree with an independent light-cone gauge calculation and disagree with predictions made using conformal symmetry. In Part II the author presents a Fourier acceleration method that is effective in accelerating the computation of the fermion propagator in lattice QCD. The conventional computation suffers from critical slowing down: the long distance structure converges much slower than the short distance structure. by evaluating the fermion propagator in momentum space using fast Fourier transforms, it is possible to make different length scales converge at a more equal rate. From numerical experiments made on a 8 4 lattice, the author obtained savings of a factor of 3 to 4 by using Fourier acceleration. He also discusses the important of gauge fixing when using Fourier acceleration

  6. Characteristics of particle beam acceleration on KUMS tandem electrostatic accelerator 5SDH-2

    OpenAIRE

    谷池, 晃; 古山, 雄一; 北村, 晃

    2006-01-01

    The KUMS tandem electrostatic accelerator, 5SDH-2, was installed in 1996. Ten years have passed since it installed and we obtain some data for accelerator operations. We report the particle beam characteristics such as relation between beam species and switcher magnet current, and dependence of ion charge fraction on stripper gas thickness. We also try to generate nitrogen ion beams, and low energy ion beams.

  7. CEBAF Accelerator Achievements

    International Nuclear Information System (INIS)

    Chao, Y C; Drury, M; Hovater, C; Hutton, A; Krafft, G A; Poelker, M; Reece, C; Tiefenback, M

    2011-01-01

    In the past decade, nuclear physics users of Jefferson Lab's Continuous Electron Beam Accelerator Facility (CEBAF) have benefited from accelerator physics advances and machine improvements. As of early 2011, CEBAF operates routinely at 6 GeV, with a 12 GeV upgrade underway. This article reports highlights of CEBAF's scientific and technological evolution in the areas of cryomodule refurbishment, RF control, polarized source development, beam transport for parity experiments, magnets and hysteresis handling, beam breakup, and helium refrigerator operational optimization.

  8. Super High Energy Colliding Beam Accelerators

    International Nuclear Information System (INIS)

    Abdelaziz, M.E.

    2009-01-01

    This lecture presents a review of cyclic accelerators and their energy limitations. A description is given of the phase stability principle and evolution of the synchrotron, an accelerator without energy limitation. Then the concept of colliding beams emerged to yield doubling of the beam energy as in the Tevatron 2 trillion electron volts (TeV) proton collider at Fermilab and the Large Hadron Collider (LHC) which is now planned as a 14-TeV machine in the 27 kilometer tunnel of the Large Electron Positron (LEP) collider at CERN. Then presentation is given of the Superconducting Supercollider (SSC), a giant accelerator complex with energy 40-TeV in a tunnel 87 kilometers in circumference under the country surrounding Waxahachie in Texas, U.S.A. These superhigh energy accelerators are intended to smash protons against protons at energy sufficient to reveal the nature of matter and to consolidate the prevailing general theory of elementary particle.

  9. Evolution of control systems for accelerators

    International Nuclear Information System (INIS)

    Crowley-Milling, M.C.

    1983-01-01

    The author reviews the development of control systems for accelerators. After an historical survey and a general introduction the hardware and software of such systems is described. As example the control system of the CERN SP5 is considered. Finally an outlook is given to future developments with special regards to the LEP storage ring. (HSI)

  10. Accelerating parameter identification of proton exchange membrane fuel cell model with ranking-based differential evolution

    International Nuclear Information System (INIS)

    Gong, Wenyin; Cai, Zhihua

    2013-01-01

    Parameter identification of PEM (proton exchange membrane) fuel cell model is a very active area of research. Generally, it can be treated as a numerical optimization problem with complex nonlinear and multi-variable features. DE (differential evolution), which has been successfully used in various fields, is a simple yet efficient evolutionary algorithm for global numerical optimization. In this paper, with the objective of accelerating the process of parameter identification of PEM fuel cell models and reducing the necessary computational efforts, we firstly present a generic and simple ranking-based mutation operator for the DE algorithm. Then, the ranking-based mutation operator is incorporated into five highly-competitive DE variants to solve the PEM fuel cell model parameter identification problems. The main contributions of this work are the proposed ranking-based DE variants and their application to the parameter identification problems of PEM fuel cell models. Experiments have been conducted by using both the simulated voltage–current data and the data obtained from the literature to validate the performance of our approach. The results indicate that the ranking-based DE methods provide better results with respect to the solution quality, the convergence rate, and the success rate compared with their corresponding original DE methods. In addition, the voltage–current characteristics obtained by our approach are in good agreement with the original voltage–current curves in all cases. - Highlights: • A simple and generic ranking-based mutation operator is presented in this paper. • Several DE (differential evolution) variants are used to solve the parameter identification of PEMFC (proton exchange membrane fuel cells) model. • Results show that our method accelerates the process of parameter identification. • The V–I characteristics are in very good agreement with experimental data

  11. Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance.

    Science.gov (United States)

    Ferris, Elliott; Abegglen, Lisa M; Schiffman, Joshua D; Gregg, Christopher

    2018-03-06

    The identity of most functional elements in the mammalian genome and the phenotypes they impact are unclear. Here, we perform a genome-wide comparative analysis of patterns of accelerated evolution in species with highly distinctive traits to discover candidate functional elements for clinically important phenotypes. We identify accelerated regions (ARs) in the elephant, hibernating bat, orca, dolphin, naked mole rat, and thirteen-lined ground squirrel lineages in mammalian conserved regions, uncovering ∼33,000 elements that bind hundreds of different regulatory proteins in humans and mice. ARs in the elephant, the largest land mammal, are uniquely enriched near elephant DNA damage response genes. The genomic hotspot for elephant ARs is the E3 ligase subunit of the Fanconi anemia complex, a master regulator of DNA repair. Additionally, ARs in the six species are associated with specific human clinical phenotypes that have apparent concordance with overt traits in each species. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. Accelerated Evolution in Distinctive Species Reveals Candidate Elements for Clinically Relevant Traits, Including Mutation and Cancer Resistance

    Directory of Open Access Journals (Sweden)

    Elliott Ferris

    2018-03-01

    Full Text Available The identity of most functional elements in the mammalian genome and the phenotypes they impact are unclear. Here, we perform a genome-wide comparative analysis of patterns of accelerated evolution in species with highly distinctive traits to discover candidate functional elements for clinically important phenotypes. We identify accelerated regions (ARs in the elephant, hibernating bat, orca, dolphin, naked mole rat, and thirteen-lined ground squirrel lineages in mammalian conserved regions, uncovering ∼33,000 elements that bind hundreds of different regulatory proteins in humans and mice. ARs in the elephant, the largest land mammal, are uniquely enriched near elephant DNA damage response genes. The genomic hotspot for elephant ARs is the E3 ligase subunit of the Fanconi anemia complex, a master regulator of DNA repair. Additionally, ARs in the six species are associated with specific human clinical phenotypes that have apparent concordance with overt traits in each species.

  13. Pressure fluctuation caused by moderate acceleration

    Science.gov (United States)

    Tagawa, Yoshiyuki; Kurihara, Chihiro; Kiyama, Akihito

    2017-11-01

    Pressure fluctuation caused by acceleration of a liquid column is observed in various important technologies, e.g. water-hammer in a pipeline. The magnitude of fluctuation can be estimated by two different approaches: When the duration time of acceleration is much shorter than the propagation time for a pressure wave to travel the length of the liquid column, e.g. sudden valve closure for a long pipe, Joukowsky equation is applied. In contrast, if the acceleration duration is much longer, the liquid is modeled as a rigid column, ignoring compressibility of the fluid. However, many of practical cases exist between these two extremes. In this study we propose a model describing pressure fluctuation when the duration of acceleration is in the same order of the propagation time for a pressure wave, i.e. under moderate acceleration. The novel model considers both temporal and spatial evolutions of pressure propagation as well as gradual pressure rise during the acceleration. We conduct experiments in which we impose acceleration to a liquid with varying the length of the liquid column, acceleration duration, and properties of liquids. The ratio between the acceleration duration and the propagation time is in the range of 0.02 - 2. The model agrees well with measurement results. JSPS KAKENHI Grant Numbers 26709007 and 17H01246.

  14. Control of electron injection and acceleration in laser-wakefield accelerators

    International Nuclear Information System (INIS)

    Guillaume, E.

    2015-01-01

    Laser-plasma accelerators provide a promising compact alternative to conventional accelerators. Plasma waves with extremely strong electric fields are generated when a high intensity laser is focused into an underdense gas target. Electrons that are trapped in these laser-driven plasma waves can be accelerated up to energies of a few GeVs. Despite their great potential, laser-wakefield accelerators face some issues, regarding notably the stability and reproducibility of the beam when electrons are injected in the accelerating structure. In this manuscript, different techniques of electron injection are presented and compared, notably injection in a sharp density gradient and ionization injection. It is shown that combining these two methods allows for the generation of stable and tunable electron beams. We have also studied a way to manipulate the electron bunch in the phase-space in order to accelerate the bunch beyond the dephasing limit. Such a technique was used with quasi-monoenergetic electron beams to enhance their energy. Moreover, the origin of the evolution of the angular momentum of electrons observed experimentally was investigated. Finally, we demonstrated experimentally a new method - the laser-plasma lens - to strongly reduce the divergence of the electron beam. This laser-plasma lens consists of a second gas jet placed at the exit of the accelerator. The laser pulse drives a wakefield in this second jet whose focusing forces take advantage to reduce the divergence of the trailing electron bunch. A simple analytical model describing the principle is presented, underlining the major importance of the second jet length, density and distance from the first jet. Experimental demonstration of the laser-plasma lens shows a divergence reduction by a factor of 2.6 for electrons up to 300 MeV, in accordance with the model predictions

  15. EuCARD2: enhanced accelerator research and development in Europe

    Science.gov (United States)

    Romaniuk, Ryszard S.

    2013-10-01

    Accelerator science and technology is one of a key enablers of the developments in the particle physic, photon physics and also applications in medicine and industry. EuCARD2 is an European research project which will be realized during 2013-2017 inside the EC FP7 framework. The project concerns the development and coordination of European Accelerator Research and Development. The project is particularly important, to a number of domestic laboratories, due to some plans to build large accelerator infrastructure in Poland. Large accelerator infrastructure of fundamental and applied research character stimulates around it the development and industrial applications as well as biomedical of advanced accelerators, material research and engineering, cryo-technology, mechatronics, robotics, and in particular electronics - like networked measurement and control systems, sensors, computer systems, automation and control systems. The paper presents a digest of the European project EuCARD2 which is Enhanced European Coordination for Accelerator Research and Development. The paper presents a digest of the research results and assumptions in the domain of accelerator science and technology in Europe, shown during the final fourth annual meeting of the EuCARD - European Coordination of Accelerator R&D, and the kick-off meeting of the EuCARD2. There are debated a few basic groups of accelerator systems components like: measurement - control networks of large geometrical extent, multichannel systems for large amounts of metrological data acquisition, precision photonic networks of reference time, frequency and phase distribution, high field magnets, superconducting cavities, novel beam collimators, etc. The paper bases on the following materials: Internet and Intranet documents combined with EuCARD2, Description of Work FP7 EuCARD-2 DoW-312453, 2013-02-13, and discussions and preparatory materials worked on by Eucard-2 initiators.

  16. The FOX and the mutants in mature human B cells and DLBCL: The role of FOXP1 in mature human B cell biology and lymphomagenesis & prevalence of oncogenic MyD88 and CD79B mutations in diffuse large B cell lymphoma

    NARCIS (Netherlands)

    van Keimpema, M.

    2015-01-01

    The transcription factor FOXP1 is prominently expressed in mature B cells and is a potential oncogene in B cell non-Hodgkin lymphomas; however, the functions of FOXP1 in mature B cells and B cell lymphomagenesis have not yet been fully explored. In the first part of this thesis, the roles of FOXP1

  17. Myocardial Gene Expression of T-bet, GATA-3, Ror-γt, FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

    Directory of Open Access Journals (Sweden)

    Luciana Gabriel Nogueira

    2014-01-01

    Full Text Available Background. Chronic Chagas disease cardiomyopathy (CCC, a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC. Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13 or associated with Treg (TGF-β and IL-10 were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation.

  18. Detection of Tax-specific CTLs in lymph nodes of adult T-cell leukemia/lymphoma patients and its association with Foxp3 positivity of regulatory T-cell function.

    Science.gov (United States)

    Ichikawa, Ayako; Miyoshi, Hiroaki; Arakawa, Fumiko; Kiyasu, Junichi; Sato, Kensaku; Niino, Daisuke; Kimura, Yoshizo; Yoshida, Maki; Kawano, Riko; Muta, Hiroko; Sugita, Yasuo; Ohshima, Koichi

    2017-06-01

    Human T-cell lymphotropic virus type (HTLV)-1 Tax is a viral protein that has been reported to be important in the proliferation of adult T-cell leukemia/lymphoma (ATLL) cells and to be a target of HTLV-1-specific cytotoxic T lymphocytes (CTLs). However, it is not clear how Tax-specific CTLs behave in lymph nodes of ATLL patients. The present study analyzed the immunostaining of Tax-specific CTLs. Furthermore, ATLL tumor cells are known to be positive for forkhead box P3 (Foxp3)and to have a regulatory T (Treg)-cell-like function. The association between T-reg function and number and activity of Tax-specific CTLs was also investigated. A total of 15 ATLL lymphoma cases with human leukocyte antigen (HLA)-A24, for which Tax has a high affinity, were selected from the files of the Department of Pathology, School of Medicine, Kurume University (Kurume, Japan) using a polymerase chain reaction (PCR) method. Immunostaining was performed for cluster of differentiation (CD) 20, CD3, CD4, CD8, T-cell intracellular antigen-1 and Foxp3 in paraffin sections, and for Tax, interferon γ and HLA-A24 in frozen sections. In addition, the staining of Tax-specific CTLs (HLA-A24-restricted) was analyzed by MHC Dextramer ® assay in frozen sections. In addition, the messenger RNA expression of Tax and HTLV-1 basic leucine zipper factor were also evaluated by reverse transcription-PCR. Immunohistochemical staining of Tax protein in lymphoma tissue revealed the presence of positive lymphoma cells ranging from 5 to 80%, and immunohistochemical staining of HLA-A24 revealed the presence of positive lymphoma cells ranging from 1 to 95%. The expression of Tax and HLA-A24 was downregulated by viral function. Foxp3, a marker for Treg cells, was expressed in 0-90% of cells. Several cases exhibited Tax-specific CTL (HLA-A24-restricted)-positive cells, and there was an inverse correlation between Tax-specific CTLs and Foxp3. However, neither Tax nor HLA-A24 expression was associated with CTL or

  19. Hamburg Accelerator Conference (2)

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Edmund J.N. [CERN Accelerator School (Switzerland)

    1992-11-15

    From 20-24 July, Hamburg welcomed the Fifteenth International Conference on High Energy Accelerators (HEACC). The HEACC Conference traditionally reviews the status of all major accelerator projects whether they are already running like clockwork, still in the construction phase, or waiting impatiently for financial approval.

  20. Hamburg Accelerator Conference (2)

    International Nuclear Information System (INIS)

    Wilson, Edmund J.N.

    1992-01-01

    From 20-24 July, Hamburg welcomed the Fifteenth International Conference on High Energy Accelerators (HEACC). The HEACC Conference traditionally reviews the status of all major accelerator projects whether they are already running like clockwork, still in the construction phase, or waiting impatiently for financial approval

  1. 4-1BB Signaling in Conventional T Cells Drives IL-2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression.

    Directory of Open Access Journals (Sweden)

    Hampartsoum B Barsoumian

    Full Text Available Costimulation with the recombinant SA-4-1BBL agonist of 4-1BB receptor on conventional CD4+ T cells (Tconvs overcomes the suppression mediated by naturally occurring CD4+CD25+FoxP3+ T regulatory cells (Tregs. The mechanistic basis of this observation has remained largely unknown. Herein we show that Tconvs, but not Tregs, are the direct target of SA-4-1BBL-mediated evasion of Treg suppression. IL-2 produced by Tconvs in response to 4-1BB signaling is both necessary and sufficient for overcoming Treg suppression. Supernatant from Tconvs stimulated with SA-4-1BBL contains high levels of IL-2 and overcomes Treg suppression in ex vivo Tconv:Treg cocultures. Removal of IL-2 from such supernatant restores Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL-2 overcomes suppression. This study establishes 4-1BB signaling as a key circuit that regulates physical and functional equilibrium between Tregs and Tconvs with important implications for immunotherapy for indications where a fine balance between Tregs and Teffs plays a decisive role.

  2. Gas-filled capillaries for plasma-based accelerators

    International Nuclear Information System (INIS)

    Filippi, F; Anania, M P; Brentegani, E; Biagioni, A; Chiadroni, E; Ferrario, M; Pompili, R; Romeo, S; Cianchi, A; Zigler, A

    2017-01-01

    Plasma Wakefield Accelerators are based on the excitation of large amplitude plasma waves excited by either a laser or a particle driver beam. The amplitude of the waves, as well as their spatial dimensions and the consequent accelerating gradient depend strongly on the background electron density along the path of the accelerated particles. The process needs stable and reliable plasma sources, whose density profile must be controlled and properly engineered to ensure the appropriate accelerating mechanism. Plasma confinement inside gas filled capillaries have been studied in the past since this technique allows to control the evolution of the plasma, ensuring a stable and repeatable plasma density distribution during the interaction with the drivers. Moreover, in a gas filled capillary plasma can be pre-ionized by a current discharge to avoid ionization losses. Different capillary geometries have been studied to allow the proper temporal and spatial evolution of the plasma along the acceleration length. Results of this analysis obtained by varying the length and the number of gas inlets will be presented. (paper)

  3. Gas-filled capillaries for plasma-based accelerators

    Science.gov (United States)

    Filippi, F.; Anania, M. P.; Brentegani, E.; Biagioni, A.; Cianchi, A.; Chiadroni, E.; Ferrario, M.; Pompili, R.; Romeo, S.; Zigler, A.

    2017-07-01

    Plasma Wakefield Accelerators are based on the excitation of large amplitude plasma waves excited by either a laser or a particle driver beam. The amplitude of the waves, as well as their spatial dimensions and the consequent accelerating gradient depend strongly on the background electron density along the path of the accelerated particles. The process needs stable and reliable plasma sources, whose density profile must be controlled and properly engineered to ensure the appropriate accelerating mechanism. Plasma confinement inside gas filled capillaries have been studied in the past since this technique allows to control the evolution of the plasma, ensuring a stable and repeatable plasma density distribution during the interaction with the drivers. Moreover, in a gas filled capillary plasma can be pre-ionized by a current discharge to avoid ionization losses. Different capillary geometries have been studied to allow the proper temporal and spatial evolution of the plasma along the acceleration length. Results of this analysis obtained by varying the length and the number of gas inlets will be presented.

  4. SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

    Directory of Open Access Journals (Sweden)

    Shravan Madireddi

    Full Text Available Tumors convert conventional CD4(+ T cells into induced CD4(+CD25(+FoxP3(+ T regulatory (iTreg cells that serve as an effective means of immune evasion. Therefore, the blockade of conventional CD4(+ T cell conversion into iTreg cells represents an attractive target for improving the efficacy of various immunotherapeutic approaches. Using a novel form of 4-1BBL molecule, SA-4-1BBL, we previously demonstrated that costimulation via 4-1BB receptor renders both CD4(+and CD8(+ T effector (Teff cells refractory to inhibition by Treg cells and increased intratumoral Teff/Treg cell ratio that correlated with therapeutic efficacy in various preclinical tumor models. Building on these studies, we herein show for the first time, to our knowledge, that signaling through 4-1BB inhibits antigen- and TGF-β-driven conversion of naïve CD4(+FoxP3(- T cells into iTreg cells via stimulation of IFN-γ production by CD4(+FoxP3(- T cells. Importantly, treatment with SA-4-1BBL blocked the conversion of CD4(+FoxP3(- T cells into Treg cells by EG.7 tumors. Taken together with our previous studies, these results show that 4-1BB signaling negatively modulate Treg cells by two distinct mechanisms: i inhibiting the conversion of CD4(+FoxP3(- T cells into iTreg cells and ii endowing Teff cells refractory to inhibition by Treg cells. Given the dominant role of Treg cells in tumor immune evasion mechanisms, 4-1BB signaling represents an attractive target for favorably tipping the Teff:Treg balance toward Teff cells with important implications for cancer immunotherapy.

  5. Evolution of branched regulatory genetic pathways: directional selection on pleiotropic loci accelerates developmental system drift.

    Science.gov (United States)

    Johnson, Norman A; Porter, Adam H

    2007-01-01

    Developmental systems are regulated by a web of interacting loci. One common and useful approach in studying the evolution of development is to focus on classes of interacting elements within these systems. Here, we use individual-based simulations to study the evolution of traits controlled by branched developmental pathways involving three loci, where one locus regulates two different traits. We examined the system under a variety of selective regimes. In the case where one branch was under stabilizing selection and the other under directional selection, we observed "developmental system drift": the trait under stabilizing selection showed little phenotypic change even though the loci underlying that trait showed considerable evolutionary divergence. This occurs because the pleiotropic locus responds to directional selection and compensatory mutants are then favored in the pathway under stabilizing selection. Though developmental system drift may be caused by other mechanisms, it seems likely that it is accelerated by the same underlying genetic mechanism as that producing the Dobzhansky-Muller incompatibilities that lead to speciation in both linear and branched pathways. We also discuss predictions of our model for developmental system drift and how different selective regimes affect probabilities of speciation in the branched pathway system.

  6. JACoW Decoupling CERN accelerators

    CERN Document Server

    Dworak, Andrzej

    2018-01-01

    The accelerator complex at CERN is a living system. Accelerators are being dismantled, upgraded or change their purpose. New accelerators are built. The changes do not happen overnight, but when they happen they may require profound changes across the handling systems. Central timings (CT), responsible for sequencing and synchronization of accelerators, are good examples of such systems. This paper shows how over the past twenty years the changes and new requirements influenced the evolution of the CTs. It describes experience gained from using the Central Beam and Cycle Manager (CBCM) CT model, for strongly coupled accelerators, and how it led to a design of a new Dynamic Beam Negotiation (DBN) model for the AD and ELENA accelerators, which reduces the coupling, increasing accelerator independence. The paper ends with an idea how to merge strong points of both models in order to create a single generic system able to efficiently handle all CERN accelerators and provide more beam time to experiments and LHC.

  7. CAS CERN Accelerator School: Advanced accelerator physics. Proceedings. Vol. 2

    International Nuclear Information System (INIS)

    Turner, S.

    1987-01-01

    This advanced course on general accelerator physics is the second of the biennial series given by the CERN Accelerator School and follows on from the first basic course given at Gif-sur-Yvette, Paris, in 1984. Stress is placed on the mathematical tools of Hamiltonian mechanics and the Vlasov and Fokker-Planck equations, which are widely used in accelerator theory. The main topics treated in this present work include: nonlinear resonances, chromaticity, motion in longitudinal phase space, growth and control of longitudinal and transverse beam emittance, space-charge effects and polarization. The seminar programme treats some specific accelerator techniques, devices, projects and future possibilities. (orig.)

  8. Neutron induced activation in the EVEDA accelerator materials: Implications for the accelerator maintenance

    International Nuclear Information System (INIS)

    Sanz, J.; Garcia, M.; Sauvan, P.; Lopez, D.; Moreno, C.; Ibarra, A.; Sedano, L.

    2009-01-01

    The Engineering Validation and Engineering Design Activities (EVEDA) phase of the International Fusion Materials Irradiation Facility project should result in an accelerator prototype for which the analysis of the dose rates evolution during the beam-off phase is a necessary task for radioprotection and maintenance feasibility purposes. Important aspects of the computational methodology to address this problem are discussed, and dose rates for workers inside the accelerator vault are assessed and found to be not negligible.

  9. Neutron induced activation in the EVEDA accelerator materials: Implications for the accelerator maintenance

    Energy Technology Data Exchange (ETDEWEB)

    Sanz, J. [Department of Power Engineering, Universidad Nacional de Educacion a Distancia (UNED), C/Juan del Rosal 12, 28040 Madrid (Spain); Institute of Nuclear Fusion, UPM, 28006 Madrid (Spain)], E-mail: jsanz@ind.uned.es; Garcia, M.; Sauvan, P.; Lopez, D. [Department of Power Engineering, Universidad Nacional de Educacion a Distancia (UNED), C/Juan del Rosal 12, 28040 Madrid (Spain); Institute of Nuclear Fusion, UPM, 28006 Madrid (Spain); Moreno, C.; Ibarra, A.; Sedano, L. [CIEMAT, 28040 Madrid (Spain)

    2009-04-30

    The Engineering Validation and Engineering Design Activities (EVEDA) phase of the International Fusion Materials Irradiation Facility project should result in an accelerator prototype for which the analysis of the dose rates evolution during the beam-off phase is a necessary task for radioprotection and maintenance feasibility purposes. Important aspects of the computational methodology to address this problem are discussed, and dose rates for workers inside the accelerator vault are assessed and found to be not negligible.

  10. New developments in particle acceleration techniques. Proceedings. Vol. 2

    International Nuclear Information System (INIS)

    Turner, S.

    1987-01-01

    A Workshop organised jointly by the European Committee for Future Accelerators (ECFA), the CERN Accelerator School (CAS), the Institut National de Physique Nucleaire et de Physique des Particules (IN2P3), the Institut pour la Recherche Fondamentale/Commissariat a l'Energie Atomique (IRF/CEA) and the European Physical Society (EPS) was held at the Laboratoire de l'Accelerateur Lineaire (LAL), Orsay, from 29 June to 4 July 1987. Its purpose was to review current experimental and theoretical developments in charged-particle accelerator techniques and to address problems related to future very-high-energy machines. These proceedings contain the great majority of the papers presented at the Workshop, the corresponding questions and answers, and the round-table discussion. The principal topics were semi-conventional high-frequency linacs, transformer acceleration mechanisms, acceleration using plasma, e + e - sources, including low-emittance production and preservation, final focus and interaction point, and other new ideas. Among the latter were open accelerating structures, crystal X-ray accelerators, ferroelectrics, and acceleration using lasers. (orig.)

  11. Replication and fine mapping for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in the Chinese population.

    Directory of Open Access Journals (Sweden)

    Qing-Zhi Long

    Full Text Available Prostate cancer represents the leading cause of male death across the world. A recent genome-wide association study (GWAS identified five novel susceptibility loci for prostate cancer in the Japanese population. This study is to replicate and fine map the potential association of these five loci with prostate cancer in the Chinese Han population.In Phase I of the study, we tested the five single nucleotide polymorphisms (SNPs which showed the strongest association evidence in the original GWAS in Japanese. The study sample consists of 1,169 Chinese Hans, comprising 483 patients and 686 healthy controls. Then in phase II, flanking SNPs of the successfully replicated SNPs in Phase I were genotyped and tested for association with prostate cancer to fine map those significant association signals.We successfully replicated the association of rs13385191 (located in the C2orf43 gene, P = 8.60×10(-5, rs12653946 (P = 1.33×10(-6, rs1983891 (FOXP4, P = 6.22×10(-5, and rs339331 (GPRC6A/RFX6, P = 1.42×10(-5 with prostate cancer. The most significant odds ratio (OR was recorded as 1.41 (95% confidence interval 1.18-1.68 for rs12653946. Rs9600079 did not show significant association (P = 8.07×10(-2 with prostate cancer in this study. The Phase II study refined these association signals, and identified several SNPs showing more significant association with prostate cancer than the very SNPs tested in Phase I.Our results provide further support for association of the C2orf43, FOXP4, GPRC6A and RFX6 genes with prostate cancer in Eastern Asian populations. This study also characterized the novel loci reported in the original GWAS with more details. Further work is still required to determine the functional variations and finally clarify the underlying biological mechanisms.

  12. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin.

    Directory of Open Access Journals (Sweden)

    Theofilos Poutahidis

    Full Text Available Wound healing capability is inextricably linked with diverse aspects of physical fitness ranging from recovery after minor injuries and surgery to diabetes and some types of cancer. Impact of the microbiome upon the mammalian wound healing process is poorly understood. We discover that supplementing the gut microbiome with lactic acid microbes in drinking water accelerates the wound-healing process to occur in half the time required for matched control animals. Further, we find that Lactobacillus reuteri enhances wound-healing properties through up-regulation of the neuropeptide hormone oxytocin, a factor integral in social bonding and reproduction, by a vagus nerve-mediated pathway. Bacteria-triggered oxytocin serves to activate host CD4+Foxp3+CD25+ immune T regulatory cells conveying transplantable wound healing capacity to naive Rag2-deficient animals. This study determined oxytocin to be a novel component of a multi-directional gut microbe-brain-immune axis, with wound-healing capability as a previously unrecognized output of this axis. We also provide experimental evidence to support long-standing medical traditions associating diet, social practices, and the immune system with efficient recovery after injury, sustained good health, and longevity.

  13. C-w operation of a 2-MeV RFQ accelerator

    International Nuclear Information System (INIS)

    Cornelius, W.D.

    1986-01-01

    We have achieved reliable cw operation of the Fusion Materials Irradiation Test (FMIT) radio-frequency quadrupole (RFQ) accelerator and have accelerated 40 mA of H 2 + beam to an energy of 2 MeV. The technical considerations for future cw accelerator designs, based on our experience in achieving cw operation, will be presented. Also to be discussed are measurements of beam emittance, matching into the RFQ, and beam transmission through the accelerator. These measurements will be compared with results of theoretical simulations of the device. The diagnostics instrumentation developed for characterizing intense cw beams also will be discussed, as well as the performance of those devices

  14. Ion acceleration in the plasma focus

    International Nuclear Information System (INIS)

    Deutsch, R.

    1982-09-01

    Experimental informations are used to estimate the time dependence of the current density in the plasma focus and the electromagnetic field is determined from the Maxwell equations. The acceleration of the ions in these fields is studied. A detailed analysis of the acceleration in the compression phase, in the expansion phase and during the evolution of the m=O instability is made. It is shown, that the appearance of fast selffocused quasineutral electron beams, as a result of the betatron acceleration, has a decisive importance in the ion acceleration during the m=O constriction. Models for electromagnetic ion acceleration are described for each phase. A concordance with many experimental results can be observed. (orig.)

  15. Superconducting Magnets for Particle Accelerators

    CERN Document Server

    Bottura, Luca; Yamamoto, Akira; Zlobin, Alexander V

    2016-01-01

    In this paper we summarize the evolution and contributions of superconducting magnets to particle accelerators as chronicled over the last 50 years of Particle Accelerator Conferences (PAC, NA-PAC and IPAC). We begin with an historical overview based primarily on PAC Proceedings augmented with references to key milestones in the development of superconducting magnets for particle accelerators. We then provide some illustrative examples of applications that have occurred over the past 50 years, focusing on those that have either been realized in practice or provided technical development for other projects, with discussion of possible future applications.

  16. HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients

    DEFF Research Database (Denmark)

    Melsted, Wenna Nascimento; Johansen, Lasse Lindholm; Lock-Andersen, Jørgen

    2017-01-01

    HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM...

  17. Methionine enkephalin (MENK) inhibits tumor growth through regulating CD4+Foxp3+ regulatory T cells (Tregs) in mice.

    Science.gov (United States)

    Li, Xuan; Meng, Yiming; Plotnikoff, Nicolas P; Youkilis, Gene; Griffin, Noreen; Wang, Enhua; Lu, Changlong; Shan, Fengping

    2015-01-01

    Methionine enkephalin (MENK), an endogenous neuropeptide, plays an crucial role in both neuroendocrine and immune systems. CD4+Foxp3+ regulatory T cells (Tregs) are identified as a major subpopulation of T lymphocytes in suppressing immune system to keep balanced immunity. The aim of this research work was to elucidate the mechanisms via which MENK interacts with Tregs in cancer situation. The influence of MENK on transforming growth factor-β (TGF-β) mediated conversion from naïve CD4+CD25- T cells to CD4+CD25+ Tregs was determined and the data from flow cytometry (FCM) analysis indicated that MENK effectively inhibited the expression of Foxp3 during the process of TGF-βinduction. Furthermore, this inhibiting process was accompanied by diminishing phosphorylation and nuclear translocation of Smad2/3, confirmed by western blot (WB) analysis and immunofluorescence (IF) at molecular level. We established sarcoma mice model with S180 to investigate whether MENK could modulate Tregs in tumor circumstance. Our findings showed that MENK delayed the development of tumor in S180 tumor bearing mice and down-regulated level of Tregs. Together, these novel findings reached a conclusion that MENK could inhibit Tregs activity directly and retard tumor development through down-regulating Tregs in mice. This work advances the deepening understanding of the influence of MENK on Tregs in cancer situation, and relation of MENK with immune system, supporting the implication of MENK as a new strategy for cancer immunotherapy.

  18. Flux Rope Acceleration and Enhanced Magnetic Reconnection Rate

    International Nuclear Information System (INIS)

    C.Z. Cheng; Y. Ren; G.S. Choe; Y.-J. Moon

    2003-01-01

    A physical mechanism of flares, in particular for the flare rise phase, has emerged from our 2-1/2-dimensional resistive MHD simulations. The dynamical evolution of current-sheet formation and magnetic reconnection and flux-rope acceleration subject to continuous, slow increase of magnetic shear in the arcade are studied by employing a non-uniform anomalous resistivity in the reconnecting current sheet under gravity. The simulation results directly relate the flux rope's accelerated rising motion with an enhanced magnetic reconnection rate and thus an enhanced reconnection electric field in the current sheet during the flare rise phase. The simulation results provide good quantitative agreements with observations of the acceleration of flux rope, which manifests in the form of SXR ejecta or erupting filament or CMEs, in the low corona. Moreover, for the X-class flare events studied in this paper the peak reconnection electric field is about O(10 2 V/m) or larger, enough to accelerate p articles to over 100 keV in a field-aligned distance of 10 km. Nonthermal electrons thus generated can produce hard X-rays, consistent with impulsive HXR emission observed during the flare rise phase

  19. Adaptability and evolution.

    Science.gov (United States)

    Bateson, Patrick

    2017-10-06

    The capacity of organisms to respond in their own lifetimes to new challenges in their environments probably appeared early in biological evolution. At present few studies have shown how such adaptability could influence the inherited characteristics of an organism's descendants. In part, this has been because organisms have been treated as passive in evolution. Nevertheless, their effects on biological evolution are likely to have been important and, when they occurred, accelerated the pace of evolution. Ways in which this might have happened have been suggested many times since the 1870s. I review these proposals and discuss their relevance to modern thought.

  20. Heavy ion acceleration strategies in the AGS accelerator complex -- 1994 Status report

    International Nuclear Information System (INIS)

    Ahrens, L.A.; Benjamin, J.; Blaskiewicz, M.

    1995-01-01

    The strategies invoked to satisfy the injected beam specifications for the Brookhaven Relativistic Heavy Ion Collider (RHIC) continue to evolve, in the context of the yearly AGS fixed target heavy ion physics runs. The primary challenge is simply producing the required intensity. The acceleration flexibility available particularly in the Booster main magnet power supply and rf accelerating systems, together with variations in the charge state delivered from the Tandem van de Graaff, and accommodation by the AGS main magnet and rf systems allow the possibility for a wide range of options. The yearly physics run provides the opportunity for exploration of these options with the resulting significant evolution in the acceleration plan. This was particularly true in 1994 with strategies involving three different charge states and low and high acceleration rates employed in the Booster. The present status of this work will be presented

  1. Calycosin Inhibits the Migration and Invasion of Human Breast Cancer Cells by Down-Regulation of Foxp3 Expression

    Directory of Open Access Journals (Sweden)

    Shuangxi Li

    2017-12-01

    Full Text Available Background/Aims: Calycosin, a phytoestrogenic compound, has recently emerged as a promising antitumor drug. It has been shown that calycosin suppresses growth and induces apoptosis of breast cancer cells. However, the effect of calycosin on migration and invasion of breast cancer cells and the underlying molecular mechanisms have not been elucidated. Methods: Human breast cancer cells MCF-7 and T47D were treated with, or without, different doses (0, 6.25, 12.5, 25, 50, 100 or 150 μM of calycosin, and the viability of different groups was determined by MTT assay. Next, the inhibitory effect of higher doses (50, 100 or 150 μM of calycosin on migration and invasion of the two cell lines was determined by wound healing and transwell assay. The relative expression levels of forkhead box P3 (Foxp3, vascular endothelial growth factor (VEGF and matrix metalloproteinase-9 (MMP-9 in MCF-7 and T47D cells were determined by quantitative RT-PCR and Western blot. Results: Treatment with lower doses (6.25 or 12.5 μM promoted proliferation of breast cancer cells, but with higher doses significantly reduced the viability of MCF-7 and T47D cells. Furthermore, higher doses of calycosin were found to inhibit migration and invasion of the two cell lines in a dose-dependent manner. Additionally, treatment with a higher dose of calycosin significantly reduced the expression levels of Foxp3, followed by down-regulation of VEGF and MMP-9 in both MCF-7 and T47D breast cancer cells. Conclusion: Treatment with a higher dose of calycosin tends to reduce migration and invasion capacity of human breast cancer cells, by targeting Foxp3-mediated VEGF and MMP-9 expression.

  2. Particle acceleration and shock wave structure

    International Nuclear Information System (INIS)

    DRURY, L.O'C.

    1989-01-01

    A significant determinant in the large-scale structure and evolution of strong collisionless shocks under astrophysical conditions is probably the acceleration of charged particles. The reaction of these particles on the dynamical structure of the shock wave is discussed both theoretically and in the light of recent numerical calculations. Astrophysical implications for the evolution of supernova remnants, are considered. (author). 15 refs

  3. Dissecting the regulatory microenvironment of a large animal model of non-Hodgkin lymphoma: evidence of a negative prognostic impact of FOXP3+ T cells in canine B cell lymphoma.

    Directory of Open Access Journals (Sweden)

    Dammy Pinheiro

    Full Text Available The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL, proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3(+ T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01 and overall survival (hazard ratio 1.61; p = 0.01 when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.

  4. Differential effects of IL-2 and IL-21 on expansion of the CD4+ CD25+ Foxp3+ T regulatory cells with redundant roles in natural killer cell mediated antibody dependent cellular cytotoxicity in chronic lymphocytic leukemia.

    Science.gov (United States)

    Gowda, Aruna; Ramanunni, Asha; Cheney, Carolyn; Rozewski, Darlene; Kindsvogel, Wayne; Lehman, Amy; Jarjoura, David; Caligiuri, Michael; Byrd, John C; Muthusamy, Natarajan

    2010-01-01

    CD4(+) CD25(+) regulatory T cells are expanded in solid and hematological malignancies including chronic lymphocytic leukemia (CLL). Several cytokines and co-stimulatory molecules are required for generation, survival and maintenance of their suppressive effect. We and others have shown direct cytotoxic effect of the novel common gamma chain cytokine interleukin (IL)-21 on primary B cells from CLL patients. Since members of this family of cytokines are known to exhibit their effects on diverse immune cells, we have examined the effects of IL-21 on CLL patient derived regulatory T cell (Treg) induction, expansion and the inhibitory effect on natural killer cells in vitro. We demonstrate here the expression of IL-21 receptor in CD4(+)CD25(High) regulatory cells from CLL patients. In contrast to IL-2, the IL-21 cytokine failed to mediate expansion of regulatory T cells or induced expression of Foxp3 in CD4(+)CD25(Intermediate) or CD4(+)CD25(Dim/-) T cells in whole blood derived from CLL patients. Interestingly, in contrast to their differential effects on expansion of the CD4(+)CD25(+)Foxp3(+)T cells, IL-2 and IL-21 exhibited a redundant role in Treg mediated suppression of NK cell mediated antibody dependent cytotoxicity function. Given the infusion related toxicities and pro-survival effect of IL-2 in CLL, these studies provide a rationale to explore IL-21 as an alternate gamma chain cytokine in CLL therapy.

  5. In situ acceleration in extragalactic radio jets

    International Nuclear Information System (INIS)

    Bicknell, G.V.; Melrose, D.B.

    1982-01-01

    We have examined the energy dissipated by large-scale turbulence in an extragalactic jet. The turbulence is driven by a shear instability which does not disrupt the jet. Fluid theory should be used to treat the evolution of the turbulence, and this allows us to estimate the rate of dissipation without detailed knowledge of the dissipation process. Dissipation occurs due to Fermi acceleration at a scale length approx.10 -3 R and that resonant acceleration plays no role. The Alfvenic component in the turbulent spectrum is dissipated by first being converted into magneto-acoustic waves. An alternative dissipation process due to formation of weak shocks is shown to be equivalent in some respects to Fermi acceleration. Dissipation in the thermal gas should not exceed that due to Fermi acceleration. The effect of Fermi acceleration, adiabatic losses, and radiative losses on an initial power-law distribution with an upper cutoff is studied. Radio emission extending to at least 100 GHz is shown to be possible, and no spectral index gradients are introduced by the acceleration. The upper cutoff can increase due to the acceleration alone or when the acceleration is balanced by radiative losses. The northern jet in NGC 315 is studied in detail. Using our model for the acceleration, we estimate a jet velocity > or approx. =5000 km s -1 with Mach number not much greater than 1, and a density -4 f -1 cm -3 at the turn-on of the jet at 6 cm, where 0.05 5 yr, and it is predicted that the radius of the jet at the turn-on point should vary with frequency either as ν/sup 2/3/ or as ν/sup 3/2/, or there may be no frequency dependence, contingent upon the details of the acceleration

  6. Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.

    Science.gov (United States)

    Kehrmann, Jan; Tatura, Roman; Zeschnigk, Michael; Probst-Kepper, Michael; Geffers, Robert; Steinmann, Joerg; Buer, Jan

    2014-07-01

    The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage-specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells. © 2014 John Wiley & Sons Ltd.

  7. Chronic lymphocytic thyroiditis (CLT) has a positive prognostic value in papillary thyroid cancer (PTC) patients: the potential key role of Foxp3+ T lymphocytes.

    Science.gov (United States)

    Pilli, T; Toti, P; Occhini, R; Castagna, M G; Cantara, S; Caselli, M; Cardinale, S; Barbagli, L; Pacini, F

    2017-12-11

    An impact of chronic lymphocytic thyroiditis (CLT) on papillary thyroid cancer (PTC) outcome has long been advocated but it is still controversial. The aim of this study was to evaluate the prognostic value of CLT in a retrospective cohort of PTC patients and to characterize the lymphocytic subpopulations and infiltrate (LI). We assessed 375 PTC patients, aged 45.2 ± 16.4 years, and treated with thyroidectomy and radioiodine remnant ablation, with a mean follow-up of 6.28 ± 3.86 years. In a subgroup of patients (n = 81) tissue sections were reviewed for the presence of CLT or lymphocytes associated with tumor in absence of background thyroiditis (TAL); cytotoxic CD8+/regulatory Foxp3+ T lymphocyte (CD8+/Foxp3+) ratio was characterized by immunohistochemistry: a low ratio is suggestive of a less effective anti tumor immune response. Seventy-five/375 patients (20%) had a histological diagnosis of CLT and showed at the last follow-up a significantly better outcome compared to those with no CLT (cure rate: 91.8 versus 76.3%, p = 0.003). LI was characterized in 81 PTC patients (24 with CLT and 57 with TAL): the peri-tumoral CD8+/Foxp3+ ratio was lower in patients not cured at the final evaluation. Our data suggest that concurrent CLT has a protective effect on PTC outcome and that the imbalance between cytotoxic and regulatory T lymphocytes in the peri-tumoral TAL may affect the tumor-specific immune response favoring a more aggressive behavior of cancer.

  8. Accelerator developments since the ZGS by ZGS people

    International Nuclear Information System (INIS)

    Cho, Y.

    1994-01-01

    The ZGS was a facility, as well as an organization, where people got together to pursue a common goal of doing exciting science of the day. In this note, the authors describe notable events related to accelerators and accelerator people since the closing of the ZGS program some 15 years ago. Many of the same ZGS people have been carrying out the state-of-the art accelerator work around the Laboratory with the same dedication that characterized their work in the earlier days. First the authors describe how the activities were re-organized after the closing of the ZGS, the migration of people, and the organizational evolution since that time. Doing this shows the similarity between the birth of the ZGS and the birth of the Advanced Photon Source (APS). Then, some of the accelerator work by the former ZGS people are described. These include: (1) Intense Pulsed Neutron Source (IPNS), (2) GeV Electron Microtron (GEM), (3) Wake Field Accelerator Test Facility, (4) Advanced Photon Source, and (5) IPNS Upgrade

  9. Accelerating Generalized Polygon Beams and Their Propagation

    International Nuclear Information System (INIS)

    Zhang Yun-Tian; Zhang Zhi-Gang; Cheng Teng; Zhang Qing-Chuan; Wu Xiao-Ping

    2015-01-01

    Accelerating beams with intensity cusps and exotic topological properties are drawing increasing attention as they have extensive uses in many intriguing fields. We investigate the structural features of accelerating polygon beams, show their generalized mathematical form theoretically, and discuss the even-numbered polygon beams. Furthermore, we also carry out the experiment and observe the intensity evolution during their propagation

  10. Evolution of optically selected quasars with z<2.2 and B<20

    International Nuclear Information System (INIS)

    Marshall, H.L.

    1985-01-01

    Several complete samples of optically selected quasars are combined to give details of the quasar luminosity function and its evolution for redshifts less than 2.2. Sufficient coverage of the Hubble diagram is obtained that luminosity-dependent density evolution models can be tested and compared against pure luminosity evolution models. Although luminosity-dependent evolution is indicated if the evolution function has an exponential form, the data are consistent with a power-law evolution model that is independent of luminosity. When the sample is split into halves by redshift, a better fit is obtained with a power-law evolution model than with an exponential model. Furthermore, the luminosity function is consistent with a power-law shape whose slope is independent of redshift. Pure luminosity evolution models wherein luminosities evolve as (1+z)/sup 3.5/ and the luminosity functioin is given by dN/dLproportionalL/sup -3.6/ are consistent with these results and fit the data very well. These results suggest that the same mass supply and energy generation mechanisms apply over several decades of optical luminosity and for z<2.2

  11. An Adaptive Laboratory Evolution Method to Accelerate Autotrophic Metabolism

    DEFF Research Database (Denmark)

    Zhang, Tian; Tremblay, Pier-Luc

    2018-01-01

    Adaptive laboratory evolution (ALE) is an approach enabling the development of novel characteristics in microbial strains via the application of a constant selection pressure. This method is also an efficient tool to acquire insights on molecular mechanisms responsible for specific phenotypes. ALE...... autotrophically and reducing CO2 into acetate more efficiently. Strains developed via this ALE method were also used to gain knowledge on the autotrophic metabolism of S. ovata as well as other acetogenic bacteria....

  12. General accelerator physics. Proceedings. Vol. 2

    International Nuclear Information System (INIS)

    Bryant, P.; Turner, S.

    1985-01-01

    This course on accelerator physics is the first in a series of two, which is planned by the CERN Accelerator School. Starting at the level of a science graduate, this course covers mainly linear theory. The topics include: transverse and longitudinal beam dynamics, insertions, coupling, transition, dynamics of radiating particles, space-charge forces, neutralization, beam profiles, luminosity calculations in colliders, longitudinal phase-space stacking, phase-displacement acceleration, transfer lines, injection and extraction. Some more advanced topics are also introduced: coherent instabilities in coasting beams, general collective phenomena, quantum lifetime, and intra-beam scattering. The seminar programme is based on two themes: firstly, the sub-systems of an accelerator and, secondly, the uses to which accelerators are put. (orig.)

  13. How adaptive learning affects evolution: reviewing theory on the Baldwin effect

    NARCIS (Netherlands)

    Sznajder, B.; Sabelis, M.W.; Egas, M.

    2012-01-01

    We review models of the Baldwin effect, i.e., the hypothesis that adaptive learning (i.e., learning to improve fitness) accelerates genetic evolution of the phenotype. Numerous theoretical studies scrutinized the hypothesis that a non-evolving ability of adaptive learning accelerates evolution of

  14. The hunt for FOXP5 a genomic mystery novel

    CERN Document Server

    Kaufman, Wallace

    2016-01-01

    Genetics professor Michelle Murphy loses her husband under mysterious circumstances and without warning, while their brilliant eight year old daughter Avalon, adopted in Kazakhstan, stubbornly believes she is a mutant. As if this were not enough she soon finds herself thrown into the middle of a quickly thickening plot, where the legacy of Genghis Khan meets the hunt for FOXP5, a genetic transcription factor that could herald the dawn of new human species. Initially caught helplessly between well-meaning fellow scientists, the government and more sinister agents, Michelle, with the help of a host of unlikely heroes, eventually takes control and finds the courage to confront the decision of whether to save human lives or humanity. The scientific and technical aspects underlying the plot - in particular aspects of FOX proteins, genetic mutations, viruses and cancer as well as the relation between intelligence and cortical complexity - are introduced and discussed by the authors in an extensive non-technical a...

  15. Advanced turbine/CO2 pellet accelerator

    International Nuclear Information System (INIS)

    Foster, C.A.; Fisher, P.W.

    1994-01-01

    An advanced turbine/CO 2 pellet accelerator is being evaluated as a depaint technology at Oak Ridge National Laboratory. The program, sponsored by Warner Robins Air Logistics Center, Robins Air Force Base, Georgia, has developed a robot-compatible apparatus that efficiently accelerates pellets of dry ice with a high-speed rotating wheel. In comparison to the more conventional compressed air sandblast pellet accelerators, the turbine system can achieve higher pellet speeds, has precise speed control, and is more than ten times as efficient. A preliminary study of the apparatus as a depaint technology has been undertaken. Depaint rates of military epoxy/urethane paint systems on 2024 and 7075 aluminum panels as a function of pellet speed and throughput have been measured. In addition, methods of enhancing the strip rate by combining infra-red heat lamps with pellet blasting have also been studied. The design and operation of the apparatus will be discussed along with data obtained from the depaint studies. Applications include removal of epoxy-based points from aircraft and the cleaning of surfaces contaminated with toxic, hazardous, or radioactive substances. The lack of a secondary contaminated waste stream is of great benefit

  16. EFFECT OF LIPOSOMAL CLODRONATE-DEPENDENT DEPLETION OF PROFESSIONAL ANTIGEN PRESENTING CELLS ON NUMBERS AND PHENOTYPE OF CANINE CD4+CD25+FOXP3+ REGULATORY T CELLS

    Science.gov (United States)

    Weaver, Kriston F.; Stokes, John V.; Gunnoe, Sagen A.; Follows, Joyce S.; Shafer, Lydia; Ammari, Mais G.; Archer, Todd M.; Thomason, John M.; Mackin, Andrew J.; Pinchuk, Lesya M.

    2015-01-01

    Regulatory T cells (Tregs) are known to control autoreactivity during and subsequent to the development of the peripheral immune system. Professional antigen presenting cells (APCs), dendritic cells (DCs) and monocytes, have an important role in inducing Tregs. For the first time, this study evaluated proportions and phenotypes of Tregs in canine peripheral blood depleted of professional APCs, utilizing liposomal clodronate (LC) and multicolor flow cytometry analysis. Our results demonstrate that LC exposure promoted short term decreases followed by significant increases in the proportions or absolute numbers of CD4+CD25+FOXP3+ Tregs in dogs. In general, the LC-dependent Treg fluctuations were similar to the changes in the levels of CD14+ monocytes in Walker hounds. However, the proportions of monocytes showed more dramatic changes compared to the proportions of Tregs that were visually unchanged after LC treatment over the study period. At the same time, absolute Treg numbers showed, similarly to the levels of CD14+ monocytes, significant compensatory gains as well as the recovery during the normalization period. We confirm the previous data that CD4+ T cells with the highest CD25 expression were highly enriched for FOXP3. Furthermore, for the first time, we report that CD4+CD25lowFOXP3+ is the major regulatory T cell subset affected by LC exposure. The increases within the lowest CD25 expressers of CD4+FOXP3+ cells together with compensatory gains in the proportion of CD14+ monocytes during compensatory and normalization periods suggest the possible direct or indirect roles of monocytes in active recruitment and generation of Tregs from naïve CD4+ T cells. PMID:25950023

  17. Nonlinear evolution of broad-bandwidth, laser-imprinted nonuniformities in planar targets accelerated by 351-nm laser light

    International Nuclear Information System (INIS)

    Smalyuk, V.A.; Boehly, T.R.; Bradley, D.K.; Goncharov, V.N.; Delettrez, J.A.; Knauer, J.P.; Meyerhofer, D.D.; Oron, D.; Shvarts, D.; Srebro, Y.; Town, R.P.

    1999-01-01

    Planar, 20 and 40 μm thick CH targets have been accelerated by 351 nm laser beams of the OMEGA laser system [Opt. Commun. 133, 495 (1997)]. Different beam-smoothing techniques were employed including distributed phase plates, smoothing by spectral dispersion, and distributed polarization rotators. The Rayleigh - Taylor evolution of three-dimensional (3D) broadband planar-target perturbations seeded by laser nonuniformities was measured using x-ray radiography at ∼1.3 keV. Fourier analysis shows that the perturbations evolve to longer wavelengths and the shorter wavelengths saturate. The saturation amplitudes and rates of growth of these features are consistent with the predictions of Haan [Phys. Rev. A 39, 5812 (1989)]. copyright 1999 American Institute of Physics

  18. Induction Acceleration of a Single RF Bunch in the KEK PS

    CERN Document Server

    Takayama, Ken; Arakida, Yoshio; Horioka, Kazuhiko; Igarashi, Susumu; Iwashita, Taiki; Kawasaki, Atsushi; Kishiro, Junichi; Kono, Tadaaki; Koseki, Kunio; Nakamura, Eiji; Sakuda, Makoto; Sato, Hikaru; Shiho, Makoto; Shimosaki, Yoshito; Shirakata, Masashi; Sueno, Tsuyoshi; Tokuchi, Akira; Torikai, Kota; Toyama, Takeshi; Wake, Masayoshi; Watanabe, Masao; Yamane, Isao

    2005-01-01

    A single bunch trapped in an RF bucket was accelerated by induction devices from 500 MeV to 8GeV beyond transition energy in the KEK-PS. This is the first demonstration of induction acceleration in a high energy circular ring. The acceleration was confirmed by measuring a temporal evolution of the RF phase through an entire acceleration.* Key devices in an induction acceleration system are an induction accelerating cavity capable of generating an induced voltage of 2kV/cell, a pulse modulator to drive the cavity (switching driver), and a DSP system to control gate signals for switching. Their remarkable characteristics are its repetition ratio of about 1MHz and duty factor of 50%. All devices have been newly developed at KEK so as to meet this requirement. The pulse modulator employing MOSFETs as switching elements is connected with the accelerating cavity through a long transmission cable in order to avoid a high-dose irradiation in the accelerator tunnel. The induction system has been running beyond more th...

  19. Increase of Circulating CD4(+)CD25(high)Foxp3(+) Regulatory T Cells in Patients With Metastatic Renal Cell Carcinoma During Treatment With Dendritic Cell Vaccination and Low-Dose Interleukin-2

    DEFF Research Database (Denmark)

    Berntsen, Annika; Brimnes, M.K.; Straten, P.T.

    2010-01-01

    Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2...... in patients with metastatic renal cell carcinoma on the frequency of CD4(+) CD25(high)Foxp3(+) Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P cells decreased when patients...... had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads...

  20. Technogical spinoff from accelerators-2

    Energy Technology Data Exchange (ETDEWEB)

    Barbalat, Oscar

    1994-07-15

    This is the second of two articles on the technological benefits arising from the central tool of particle physics - the particle accelerator. It is based on a report initially prepared at the request of a special panel set up by the International Committee for Future Accelerators (ICFA)

  1. Technogical spinoff from accelerators-2

    International Nuclear Information System (INIS)

    Barbalat, Oscar

    1994-01-01

    This is the second of two articles on the technological benefits arising from the central tool of particle physics - the particle accelerator. It is based on a report initially prepared at the request of a special panel set up by the International Committee for Future Accelerators (ICFA)

  2. CAS CERN accelerator school: 5. general accelerator physics course. Vol. 2. Proceedings

    International Nuclear Information System (INIS)

    Turner, S.

    1994-01-01

    The fifth CERN Accelerator School (CAS) basic course on General Accelerator Physics was given at the University of Jyvaeskylae, Finland, from 7 to 18 September 1992. Its syllabus was based on the previous similar courses held at Gif-sur-Yvette in 1984, Aarhus 1986, Salamanca 1988 and Juelich 1990, and whose proceedings were published as CERN Reports 85-19, 87-10, 89-05 and 91-04, respectively. However, certain topics were treated in a different way, improved or extended, while new subjects were introduced. As far as the proceedings of this school are concerned the opportunity was taken not only to include the lectures presented but also to select and revise the most appropriate chapters from the previous similar schools. In this way the present volumes constitute a rather complete introduction to all aspects of the design and construction of particle accelerators, including optics, emittance, luminosity, longitudinal and transverse beam dynamics, insertions, chromaticity, transfer lines, resonances, accelerating structures, tune shifts, coasting beams, lifetime, synchrotron radiation, radiation damping, beam-beam effects, diagnostics, cooling, ion and positron sources, RF and vacuum systems, injection and extraction, conventional, permanent and superconducting magnets, cyclotrons, RF linear accelerators, microtrons, as well as applications of particle accelerators (including therapy) and the history of accelerators. See hints under the relevant topics. (orig.)

  3. Suppression of X-radiation from 2 MeV ion electrostatic accelerator

    International Nuclear Information System (INIS)

    Ignat'ev, I.G.; Miroshnichenko, V.I.; Sirenko, A.M.; Storizhko, V.E.

    2008-01-01

    The paper presents results concerning studies of X-radiation from 2 MeV ion electrostatic accelerator 'Sokol' used for nuclear microprobe analysis. The radiation protection system of the accelerator was developed and tested. Tests of the system of the accelerator show that it reduces doses rate by two orders of magnitude

  4. Accelerator-tem interface facility and application

    International Nuclear Information System (INIS)

    Li Ming; He Jun; Yang Zheng; Zhou Lin; Liu Chuansheng; Guo Liping; Jiang Changzhong; Yang Shibo; Fu Dejun; Fan Xiangjun; Liu Jiarui; Lee, J.C.

    2010-01-01

    An accelerator-TEM interface facility has been established at Wuhan University. The system consists of an H800 TEM linked to a 200 kV ion implanter and a 2 x 1.7 MV tandetron accelerator. Measures were taken to isolate the TEM from mechanical vibration transmitted from the ion beam lines and good resolution was maintained with the TEM machine when operated under high zoom modes during the ion implantation. Nitrogen ions at 115 keV were successfully transported from the implanter into the TEM chamber through the interface system, and the ion currents measured at the entrance of the TEM column were between 20 and 180 nA. Structural evolution caused by ion irradiation in Si, GaAs, nanocrystal Ag were observed in situ. The TEM sample could be tilted by 52 degree and for low energy ion irradiation, real time observation was realized. The in situ observation showed that the critical implant dose for amorphization of Si is 2 x 10 14 cm -2 and it became fully amorphized at 3 x 10 15 cm -2 . Amorphization of GaAs started at 1 x 10 14 cm -2 , whereas for nanocrystal Ag, the starting dose was 6 x 10 14 cm -2 . The nuclear material C276 samples implanted with 115 keV Ar+ was also studied and dislocation loops with sizes of 3-12 nm were clearly observed after implantation to doses higher than 1 x 10 15 cm -2 . The density of the loops increased with the increase in the implant dose and evolution to polycrystalline and amorphous structures were observed at 5 x 10 15 cm -2 and 3 x 10 16 cm -2 , respectively. An in situ RBS/C chamber has been installed on the transport line of the accelerator-TEM interface system. This makes it possible to in situ measure composition and location of impurities in the lattice of the implanted samples. In addition, a 50 kV low-energy gaseous ion generator was installed close to the TEM chamber, which facilitates in situ TEM observation of helium bubbles formed in materials by helium implantation. (authors)

  5. Bulk viscous matter and recent acceleration of the universe

    Energy Technology Data Exchange (ETDEWEB)

    Sasidharan, Athira; Mathew, Titus K. [Cochin University of Science and Technology, Department of Physics, Kochi (India)

    2015-07-15

    We consider a cosmological model dominated by bulk viscous matter with a total bulk viscosity coefficient proportional to the velocity and acceleration of the expansion of the universe in such a way that ζ = ζ{sub 0} + ζ{sub 1}(a)/(a) + ζ{sub 2}(a)/(a). We show that there exist two limiting conditions in the bulk viscous coefficients (ζ{sub 0}, ζ{sub 1}, ζ{sub 2}) which correspond to a universe having a Big Bang at the origin, followed by an early decelerated epoch and then making a smooth transition into an accelerating epoch. We have constrained the model using the type Ia Supernovae data, evaluated the best estimated values of all the bulk viscous parameters and the Hubble parameter corresponding to the two limiting conditions. We found that even though the evolution of the cosmological parameters are in general different for the two limiting cases, they show identical behavior for the best estimated values of the parameters from both limiting conditions. A recent acceleration would occur if ζ{sub 0} + ζ{sub 1} > 1 for the first limiting conditions and if ζ{sub 0} + ζ{sub 1} < 1 for the second limiting conditions. The age of the universe predicted by this model is found to be less than that predicted from the oldest galactic globular clusters. The total bulk viscosity seems to be negative in the past and becomes positive when z ≤ 0.8. So the model violates the local second law of thermodynamics. However, the model satisfies the generalized second law of thermodynamics at the apparent horizon throughout the evolution of the universe. We also made a statefinder analysis of the model and found that it is distinguishably different from the standard ΛCDM model at present, but it shows a de Sitter type behavior in the far future of the evolution. (orig.)

  6. The Genotype of the Donor for the (GTn Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

    Directory of Open Access Journals (Sweden)

    Víctor Noriega

    Full Text Available The FOXP3 gene encodes for a protein (Foxp3 involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+, which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT15 for the (GTn polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08-0.82, p = 0.021; without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

  7. Systematic analysis of immune infiltrates in high-grade serous ovarian cancer reveals CD20, FoxP3 and TIA-1 as positive prognostic factors.

    Directory of Open Access Journals (Sweden)

    Katy Milne

    Full Text Available BACKGROUND: Tumor-infiltrating T cells are associated with survival in epithelial ovarian cancer (EOC, but their functional status is poorly understood, especially relative to the different risk categories and histological subtypes of EOC. METHODOLOGY/PRINCIPAL FINDINGS: Tissue microarrays containing high-grade serous, endometrioid, mucinous and clear cell tumors were analyzed immunohistochemically for the presence of lymphocytes, dendritic cells, neutrophils, macrophages, MHC class I and II, and various markers of activation and inflammation. In high-grade serous tumors from optimally debulked patients, positive associations were seen between intraepithelial cells expressing CD3, CD4, CD8, CD45RO, CD25, TIA-1, Granzyme B, FoxP3, CD20, and CD68, as well as expression of MHC class I and II by tumor cells. Disease-specific survival was positively associated with the markers CD8, CD3, FoxP3, TIA-1, CD20, MHC class I and class II. In other histological subtypes, immune infiltrates were less prevalent, and the only markers associated with survival were MHC class II (positive association in endometrioid cases and myeloperoxidase (negative association in clear cell cases. CONCLUSIONS/SIGNIFICANCE: Host immune responses to EOC vary widely according to histological subtype and the extent of residual disease. TIA-1, FoxP3 and CD20 emerge as new positive prognostic factors in high-grade serous EOC from optimally debulked patients.

  8. The formation of kappa-distribution accelerated electron populations in solar flares

    Energy Technology Data Exchange (ETDEWEB)

    Bian, Nicolas H.; Stackhouse, Duncan J.; Kontar, Eduard P. [School of Physics and Astronomy, University of Glasgow, Glasgow G12 8QQ (United Kingdom); Emslie, A. Gordon, E-mail: n.bian@physics.gla.ac.uk, E-mail: d.stackhouse.1@research.gla.ac.uk, E-mail: eduard@astro.gla.ac.uk, E-mail: emslieg@wku.edu [Department of Physics and Astronomy, Western Kentucky University, Bowling Green, KY 42101 (United States)

    2014-12-01

    Driven by recent RHESSI observations of confined loop-top hard X-ray sources in solar flares, we consider stochastic acceleration of electrons in the presence of Coulomb collisions. If electron escape from the acceleration region can be neglected, the electron distribution function is determined by a balance between diffusive acceleration and collisions. Such a scenario admits a stationary solution for the electron distribution function that takes the form of a kappa distribution. We show that the evolution toward this kappa distribution involves a 'wave front' propagating forward in velocity space, so that electrons of higher energy are accelerated later; the acceleration timescales with energy according to τ{sub acc} ∼ E {sup 3/2}. At sufficiently high energies escape from the finite-length acceleration region will eventually dominate. For such energies, the electron velocity distribution function is obtained by solving a time-dependent Fokker-Planck equation in the 'leaky-box' approximation. Solutions are obtained in the limit of a small escape rate from an acceleration region that can effectively be considered a thick target.

  9. Evolution of the Argonne Tandem Linear Accelerator System (ATLAS) control system

    International Nuclear Information System (INIS)

    Power, M.; Munson, F.

    2012-01-01

    Given that the Argonne Tandem Linear Accelerator System (ATLAS) recently celebrated its 25. anniversary, this paper will explore the past, present, and future of the ATLAS Control System, and how it has evolved along with the accelerator and control system technology. ATLAS as we know it today, originated with a Tandem Van de Graff in the sixties. With the addition of the Booster section in the late seventies, came the first computerized control. ATLAS itself was placed into service on June 25, 1985, and was the world's first superconducting linear accelerator for ions. Since its dedication as a National User Facility, more than a thousand experiments by more than 2,000 users worldwide, have taken advantage of the unique capabilities it provides. Today, ATLAS continues to be a user facility for physicists who study the particles that form the heart of atoms. Its most recent addition, CARIBU (Californium Rare Isotope Breeder Upgrade), creates special beams that feed into ATLAS. ATLAS is similar to a living organism, changing and responding to new technological challenges and research needs. As it continues to evolve, so does the control system: from the original days using a DEC PDP-11/34 computer and two CAMAC crates, to a DEC Alpha computer running Vsystem software and more than twenty CAMAC crates, to distributed computers and VME systems. Future upgrades are also in the planning stages that will continue to evolve the control system. (authors)

  10. Programming cells by multiplex genome engineering and accelerated evolution.

    Science.gov (United States)

    Wang, Harris H; Isaacs, Farren J; Carr, Peter A; Sun, Zachary Z; Xu, George; Forest, Craig R; Church, George M

    2009-08-13

    The breadth of genomic diversity found among organisms in nature allows populations to adapt to diverse environments. However, genomic diversity is difficult to generate in the laboratory and new phenotypes do not easily arise on practical timescales. Although in vitro and directed evolution methods have created genetic variants with usefully altered phenotypes, these methods are limited to laborious and serial manipulation of single genes and are not used for parallel and continuous directed evolution of gene networks or genomes. Here, we describe multiplex automated genome engineering (MAGE) for large-scale programming and evolution of cells. MAGE simultaneously targets many locations on the chromosome for modification in a single cell or across a population of cells, thus producing combinatorial genomic diversity. Because the process is cyclical and scalable, we constructed prototype devices that automate the MAGE technology to facilitate rapid and continuous generation of a diverse set of genetic changes (mismatches, insertions, deletions). We applied MAGE to optimize the 1-deoxy-D-xylulose-5-phosphate (DXP) biosynthesis pathway in Escherichia coli to overproduce the industrially important isoprenoid lycopene. Twenty-four genetic components in the DXP pathway were modified simultaneously using a complex pool of synthetic DNA, creating over 4.3 billion combinatorial genomic variants per day. We isolated variants with more than fivefold increase in lycopene production within 3 days, a significant improvement over existing metabolic engineering techniques. Our multiplex approach embraces engineering in the context of evolution by expediting the design and evolution of organisms with new and improved properties.

  11. Particle acceleration in the interplanetary space

    International Nuclear Information System (INIS)

    Tverskoj, B.A.

    1983-01-01

    A review on the problem of particle acceleration in the interplanetary space is given. The main lationship attention is paid to the problem of the re/ between the impact- and turbulent acceleration when an undisturbed magnetic field forms not too small angle THETA > 10 deg with the shock wave front. The following conclusions are drawn. Particle acceleration at the shock wave front is manifested in the explicit form, if the shock wave propagates along a homogeneous (in the 11 cm range) solar wind. The criterion of such an acceleration is the exponential distribution function F approximately vsup(-ν) (v is the particle velocity and ν is the accelerated particle spectrum index) in the low energy range and the conservation of this function at considerable distances behind the front. The presence of an additional turbulent acceleration behind the front is manifested in decreasing ν down to approximately 3.5 in the low energy range and in the spectrum evolution behind the front

  12. Salmon cartilage proteoglycan suppresses mouse experimental colitis through induction of Foxp3+ regulatory T cells

    International Nuclear Information System (INIS)

    Mitsui, Toshihito; Sashinami, Hiroshi; Sato, Fuyuki; Kijima, Hiroshi; Ishiguro, Yoh; Fukuda, Shinsaku; Yoshihara, Shuichi; Hakamada, Ken-Ichi; Nakane, Akio

    2010-01-01

    Research highlights: → Salmon proteoglycan suppresses IL-10 -/- cell transfer-induced colitis progression. → Salmon proteoglycan suppresses Th1- and Th17-related factors in colitis mice. → Salmon proteoglycan enhances Foxp3 expression. -- Abstract: Proteoglycans (PGs) are complex glycohydrates which are widely distributed in extracellular matrix (ECM). PGs are involved in the construction of ECM, cell proliferation and differentiation. ECM components are involved in transduction of proinflammatory responses, but it is still unknown whether PGs are involved in inflammatory response. In this study, we investigated the effect of PG extracted from salmon cartilage on the progression of experimental colitis-induced in severe combined immunodeficiency mice by cell transfer from interleukin-10 (IL-10) -/- mice. IL-10 -/- cell-transferred mice showed weight loss, colon shortening and histological appearance of mild colitis. Daily oral administration of PG attenuated the clinical progression of colitis in a dose-dependent manner. Colitis-induced mice showed the elevated expression of IFN-γ, IL-12, TNF-α, IL-21, IL-23p19, IL-6, IL-17A and retinoic acid-related orphan receptor γt (RORγt) in lamina propria mononuclear cells (LPMCs) and oral administration of PG suppressed the expression of these factors. Conversely, expression of Foxp3 that induces CD4 + CD25 + regulatory T cells in LPMCs was enhanced by PG administration. These findings suggested that salmon PG attenuated the progression of colitis due to suppression of inflammatory response by enhancement of regulatory T cell induction.

  13. Evolution of complex dynamics

    Science.gov (United States)

    Wilds, Roy; Kauffman, Stuart A.; Glass, Leon

    2008-09-01

    We study the evolution of complex dynamics in a model of a genetic regulatory network. The fitness is associated with the topological entropy in a class of piecewise linear equations, and the mutations are associated with changes in the logical structure of the network. We compare hill climbing evolution, in which only mutations that increase the fitness are allowed, with neutral evolution, in which mutations that leave the fitness unchanged are allowed. The simple structure of the fitness landscape enables us to estimate analytically the rates of hill climbing and neutral evolution. In this model, allowing neutral mutations accelerates the rate of evolutionary advancement for low mutation frequencies. These results are applicable to evolution in natural and technological systems.

  14. The Living Eye “Disarms” Uncommitted Autoreactive T Cells by Converting Them to FoxP3+ Regulatory Cells Following Local Antigen Recognition

    Science.gov (United States)

    Zhou, Ru; Horai, Reiko; Silver, Phyllis B; Mattapallil, Mary J; Zárate-Bladés, Carlos R; Chong, Wai Po; Chen, Jun; Rigden, Rachael C; Villasmil, Rafael; Caspi, Rachel R

    2011-01-01

    Immune privilege is used by the eye, brain, reproductive organs and gut to preserve structural and functional integrity in the face of inflammation. The eye is arguably the most vulnerable, and therefore also the most “privileged” of tissues, but paradoxically, remains subject to destructive autoimmunity. It has been proposed, although never proven in vivo, that the eye can induce T regulatory cells (Tregs) locally. Using FoxP3-GFP reporter mice expressing a retina-specific T cell receptor, we now show that uncommitted T cells rapidly convert in the living eye to FoxP3+ Tregs in a process involving retinal antigen recognition, de novo FoxP3 induction and proliferation. This takes place within the ocular tissue and is supported by retinoic acid, which is normally present in the eye due to its function in the chemistry of vision. Non-converted T cells showed evidence of priming, but appeared restricted from expressing effector function in the eye. Preexisting ocular inflammation impeded conversion of uncommitted T cells into Tregs. Importantly, retina-specific T cells primed in vivo before introduction into the eye were resistant to Treg conversion in the ocular environment, and instead caused severe uveitis. Thus, uncommitted T cells can be disarmed, but immune privilege is unable to protect from uveitogenic T cells that have acquired effector function prior to entering the eye. These findings shed new light on the phenomenon of immune privilege and on its role, as well as its limitations, in actively controlling immune responses in the tissue. PMID:22238462

  15. Particle Accelerators: Activities and Developments in the CIEMAT

    International Nuclear Information System (INIS)

    Garcia Tabares, L.; Toral Fernandez, F.

    2010-01-01

    Although they have been in use for many years, particle accelerators are machines in constant evolution with a growing number of applications. They are not only used in basic science to understand the structure of matter, but they also have multiple technological, medical and analytical applications, etc. This fact led the CIEMAT to create the Accelerator Unit in late 2008, as part of the Technology department. Although the group had been carrying out accelerator-related activities for some time, the aim of creating the Unit was to develop not only accelerator components but also complete systems. This article contains a brief introduction to accelerators and also describes the current activities in our Unit. (Author) 8 refs.

  16. Rapid acceleration leads to rapid weakening in earthquake-like laboratory experiments

    Science.gov (United States)

    Chang, J. C.; Lockner, D. A.; Reches, Z.

    2012-12-01

    We simulated the slip of a fault-patch during a large earthquake by rapidly loading an experimental, ring-shaped fault with energy stored in a spinning flywheel. The flywheel abruptly delivers a finite amount of energy by spinning the fault-patch that spontaneously dissipates the energy without operator intervention. We conducted 42 experiments on Sierra White granite (SWG) samples, and 24 experiments on Kasota dolomite (KD) samples. Each experiment starts by spinning a 225 kg disk-shaped flywheel to a prescribed angular velocity. We refer to this experiment as an "earthquake-like slip-event" (ELSE). The strength-evolution in ELSE experiments is similar to the strength-evolution proposed for earthquake models and observed in stick-slip experiments. Further, we found that ELSE experiments are similar to earthquakes in at least three ways: (1) slip driven by the release of a finite amount of stored energy; (2) pattern of fault strength evolution; and (3) seismically observed values, such as average slip, peak-velocity and rise-time. By assuming that the measured slip, D, in ELSE experiments is equivalent to the average slip during an earthquake, we found that ELSE experiments (D = 0.003-4.6 m) correspond to earthquakes in moment-magnitude range of Mw = 4-8. In ELSE experiments, the critical-slip-distance, dc, has mean values of 2.7 cm and 1.2 cm for SWG and KD, that are much shorter than the 1-10 m in steady-state classical experiments in rotary shear systems. We attribute these dc values, to ELSE loading in which the fault-patch is abruptly loaded by impact with a spinning flywheel. Under this loading, the friction-velocity relations are strikingly different from those under steady-state loading on the same rock samples with the same shear system (Reches and Lockner, Nature, 2010). We further note that the slip acceleration in ELSE evolves systematically with fault strength and wear-rate, and that the dynamic weakening is restricted to the period of intense

  17. An extended car-following model considering the acceleration derivative in some typical traffic environments

    Science.gov (United States)

    Zhou, Tong; Chen, Dong; Liu, Weining

    2018-03-01

    Based on the full velocity difference and acceleration car-following model, an extended car-following model is proposed by considering the vehicle’s acceleration derivative. The stability condition is given by applying the control theory. Considering some typical traffic environments, the results of theoretical analysis and numerical simulation show the extended model has a more actual acceleration of string vehicles than that of the previous models in starting process, stopping process and sudden brake. Meanwhile, the traffic jams more easily occur when the coefficient of vehicle’s acceleration derivative increases, which is presented by space-time evolution. The results confirm that the vehicle’s acceleration derivative plays an important role in the traffic jamming transition and the evolution of traffic congestion.

  18. Acceleration of runaway electrons in solar flares

    Science.gov (United States)

    Moghaddam-Taaheri, E.; Goertz, C. K.

    1990-01-01

    The dc electric field acceleration of electrons out of a thermal plasma and the evolution of the runaway tail are studied numerically, using a relativistic quasi-linear code based on the Ritz-Galerkin method and finite elements. A small field-aligned electric field is turned on at a certain time. The resulting distribution function from the runaway process is used to calculate the synchrotron emission during the evolution of the runaway tail. It is found that, during the runaway tail formation, which lasts a few tens of seconds for typical solar flare conditions, the synchrotron emission level is low, almost ot the same order as the emission from the thermal plasma, at the high-frequency end of the spectrum. However, the emission is enhanced explosively in a few microseconds by several orders of magnitude at the time the runaway tail stops growing along the magnetic field and tends toward isotropy due to the pitch-angle scattering of the fast particles. Results indicate that, in order to account for the observed synchrotron emission spectrum of a typical solar flare, the electric field acceleration phase must be accompanied or preceded by a heating phase which yields an enhanced electron temperature of about 2-15 keV in the flare region if the electric field is 0.1-0.2 times the Dreicer field and cyclotron-to-plasma frequency ratios are of order 1-2.

  19. Final Report for 'Modeling Electron Cloud Diagnostics for High-Intensity Proton Accelerators'

    International Nuclear Information System (INIS)

    Veitzer, Seth A.

    2009-01-01

    Electron clouds in accelerators such as the ILC degrade beam quality and limit operating efficiency. The need to mitigate electron clouds has a direct impact on the design and operation of these accelerators, translating into increased cost and reduced performance. Diagnostic techniques for measuring electron clouds in accelerating cavities are needed to provide an assessment of electron cloud evolution and mitigation. Accurate numerical modeling of these diagnostics is needed to validate the experimental techniques. In this Phase I, we developed detailed numerical models of microwave propagation through electron clouds in accelerating cavities with geometries relevant to existing and future high-intensity proton accelerators such as Project X and the ILC. Our numerical techniques and simulation results from the Phase I showed that there was a high probability of success in measuring both the evolution of electron clouds and the effects of non-uniform electron density distributions in Phase II.

  20. The History and Role of Accelerators in Radiation Oncology

    Science.gov (United States)

    Smith, Alfred

    2003-04-01

    Over one million people are diagnosed with cancer (excluding skin cancer) each year in the United States - about half of those patients will receive radiation as part of their treatment. Radiation Oncology is the field of medicine that specializes in the treatment of cancer with radiation. The evolution of Radiation Oncology, and its success as a cancer treatment modality, has generally paralleled developments in imaging and accelerator technologies. Accelerators, the topic of this paper, have proven to be highly reliable, safe and efficient sources of radiation for cancer treatment. Advances in accelerator technology, especially those that have provided higher energies and dose rates, and more localized (to the tumor volume) dose distributions, have enabled significant improvements in the outcomes of cancer treatments. The use of Cobalt 60 beams has greatly declined in the past decade. Radiation beams used in cancer treatment include x-rays, electrons, protons, negative pions, neutrons, and ions of helium, carbon, neon and silicon. X-rays and electrons, produced by linear electron accelerators, have been the most widely used. The history of medical accelerators can be traced from Roentgen's discovery of x-rays in 1895. The evolution of medical electron accelerators will be discussed and the use of x-ray tubes, electrostatic accelerators, betatrons, and linear accelerators will be described. Heavy particle cancer treatments began in 1955 using proton beams from the Berkeley 184-inch cyclotron. Accelerators that have been used for heavy particle therapy include the Berkeley Bevalac, Los Alamos Pion Facility, Fermi Laboratory, and various research and medical cyclotrons and synchrotrons. Heavy particle accelerators and their application for cancer treatment will be discussed.

  1. Relativity matters from Einstein's EMC2 to laser particle acceleration and quark-gluon plasma

    CERN Document Server

    Rafelski, Johann

    2017-01-01

    Rafelski presents Special Relativity in a language deemed accessible to students without any topical preparation - avoiding the burden of geometry, tensor calculus, and space-time symmetries – and yet advancing in highly contemporary context all the way to research frontiers. Special Relativity is presented such that nothing remains a paradox or just apparent, but rather is explained. A text of similar character, content, and scope, has not been available before. This book describes Special Relativity when rigid material bodies are introduced describing the reality of body contraction; it shows the relevance of acceleration and the necessary evolution of the theoretical framework when acceleration is critical. This book also presents the evolving views of Einstein about the aether. In addition to a careful and elementary introduction to relativity complete with exercises, worked examples and many discussions, this volume connects to current research topics so that readers can explore Special Relativity fr...

  2. Association between forkhead-box P2 gene polymorphism and clinical symptoms in chronic schizophrenia in a Chinese population.

    Science.gov (United States)

    Rao, Wenwang; Du, Xiangdong; Zhang, Yingyang; Yu, Qiong; Hui, Li; Yu, Yaqin; Kou, Changgui; Yin, Guangzhong; Zhu, Xiaomin; Man, Lijuan; Soares, Jair C; Zhang, Xiang Yang

    2017-07-01

    The forkhead-box P2 (FOXP2) gene polymorphism has been reported to be involved in the susceptibility to schizophrenia; however, few studies have investigated the association between FOXP2 gene polymorphism and clinical symptoms in schizophrenia. This study investigated whether the FOXP2 gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese population. The FOXP2 rs10447760 polymorphism was genotyped in 1069 schizophrenia inpatients and 410 healthy controls using a case-control design. The patients' psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the genotype and allele distributions between the patient and control groups. Interestingly, we found significant differences in PANSS total, positive symptom, and general psychopathology scores between genotypic subgroups in patients, with the higher score in patients with CC genotype than those with CT genotype (all p schizophrenia, but may contribute to the clinical symptoms of schizophrenia among Han Chinese.

  3. S2 synthetic acceleration scheme for the one-dimensional S/sub n/ equations

    International Nuclear Information System (INIS)

    Lorence, L.J. Jr.; Larsen, E.W.; Morel, J.E.

    1986-01-01

    The authors have developed an S 2 synthetic acceleration method for the one-dimensional S/sub n/ equations with linear-discontinuous (LD) spatial differencing, and implemented it in a new version of the ONETRAN code. As in the diffusion-synthetic acceleration (DSA) of Morel, both the zeroth and first moments of the scattering source are accelerated. This is done by using the S 2 equations with Gauss quadrature rather than the diffusion equation as the low-order operator in the synthetic acceleration scheme

  4. IFNy+ and IFNy- Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function.

    Science.gov (United States)

    Trojan, Karina; Unterrainer, Christian; Aly, Mostafa; Zhu, Li; Weimer, Rolf; Bulut, Nuray; Morath, Christian; Opelz, Gerhard; Daniel, Volker

    2016-10-29

    Treg are a heterogenous cell population. In the present study we attempted to identify Treg subsets that might contribute to stable and good long-term graft function. Lymphocyte and Treg subsets were studied in 136 kidney transplant recipients with good long-term graft function and in 52 healthy control individuals using eight-color-fluorescence flow cytometry. Foxp3 TSDR methylation status was investigated in enriched IFNy+ and IFNy- Treg preparations using high resolution melt analysis. Compared with healthy controls, patients showed strong associations of IFNy secreting Helios+ and Helios- Treg with Treg that co-expressed perforin and/or CTLA4 (CD152; pterm graft function possess IFNy+ and IFNy- Treg with stable and unstable Foxp3 expression in the blood. They co-express CD28, HLADR, CTLA4, CXCR3, Lselectin, TGFβ, perforin and FasL and might contribute to the establishment and maintenance of good long-term graft function. Copyright © 2016. Published by Elsevier B.V.

  5. EFFECTS OF HISTONE DEACETYLASE INHIBITOR, SAHA, ON EFFECTOR AND FOXP3+ REGULATORY T CELLS IN RHESUS MACAQUES

    OpenAIRE

    Johnson, Jennifer; Pahuja, Anil; Graham, Melanie; Hering, Bernhard; Hancock, Wayne W.; Pratima, Bansal-Pakala

    2008-01-01

    SAHA, a histone deacetylase inhibitor (HDACi), is clinically approved for treatment of cutaneous T-cell lymphoma. Although the exact underlying mechanisms are unknown, HDACi arrest the cell cycle in rapidly proliferating tumor cells and promote their apoptosis. HDACi were also recently shown to enhance the production and suppressive functions of Foxp3+ regulatory T (Treg) cells in rodents, leading us to begin to investigate the actions of HDACi on rhesus monkey T cells for the sake of potenti...

  6. Microwave Accelerated Polymerization of 2-Phenyl-2-Oxazoline: Microwave or Temperature Effects?

    NARCIS (Netherlands)

    Hoogenboom, R.; Leenen, M.A.M.; Wiesbrock, F.D.; Schubert, U.S.

    2005-01-01

    Summary: Investigations regarding the cationic ring-opening polymerization of 2-phenyl-2-oxazoline under microwave irradiation and conventional heating are reported. This study was inspired by contradictory reports of the (non-)existence of non-thermal microwave effects that might accelerate the

  7. Diagnostics for studies of novel laser ion acceleration mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Senje, Lovisa; Aurand, Bastian; Wahlström, Claes-Göran [Department of Physics, Lund University, P. O. Box 118, S-221 00 Lund (Sweden); Yeung, Mark; Kuschel, Stephan; Rödel, Christian [Helmholtz-Institut Jena, D-07743 Jena (Germany); Wagner, Florian; Roth, Markus [Technische Universität Darmstadt, D-64289 Darmstadt (Germany); Li, Kun; Neumayer, Paul [ExtreMe Matter Institut, D-64291 Darmstadt (Germany); Dromey, Brendan; Jung, Daniel [Department of Physics and Astronomy, Queen' s University, Belfast BT7 1NN (United Kingdom); Bagnoud, Vincent [Helmholtz-Institut Jena, D-07743 Jena (Germany); GSI Helmholtzzentrum für Schwerionenforschung GmbH, D-64291 Darmstadt (Germany); Zepf, Matthew [Helmholtz-Institut Jena, D-07743 Jena (Germany); Department of Physics and Astronomy, Queen' s University, Belfast BT7 1NN (United Kingdom); Kuehl, Thomas [ExtreMe Matter Institut, D-64291 Darmstadt (Germany); GSI Helmholtzzentrum für Schwerionenforschung GmbH, D-64291 Darmstadt (Germany); Universität Mainz, D-55099 Mainz (Germany)

    2014-11-15

    Diagnostic for investigating and distinguishing different laser ion acceleration mechanisms has been developed and successfully tested. An ion separation wide angle spectrometer can simultaneously investigate three important aspects of the laser plasma interaction: (1) acquire angularly resolved energy spectra for two ion species, (2) obtain ion energy spectra for multiple species, separated according to their charge to mass ratio, along selected axes, and (3) collect laser radiation reflected from and transmitted through the target and propagating in the same direction as the ion beam. Thus, the presented diagnostic constitutes a highly adaptable tool for accurately studying novel acceleration mechanisms in terms of their angular energy distribution, conversion efficiency, and plasma density evolution.

  8. Diagnostics for studies of novel laser ion acceleration mechanisms

    International Nuclear Information System (INIS)

    Senje, Lovisa; Aurand, Bastian; Wahlström, Claes-Göran; Yeung, Mark; Kuschel, Stephan; Rödel, Christian; Wagner, Florian; Roth, Markus; Li, Kun; Neumayer, Paul; Dromey, Brendan; Jung, Daniel; Bagnoud, Vincent; Zepf, Matthew; Kuehl, Thomas

    2014-01-01

    Diagnostic for investigating and distinguishing different laser ion acceleration mechanisms has been developed and successfully tested. An ion separation wide angle spectrometer can simultaneously investigate three important aspects of the laser plasma interaction: (1) acquire angularly resolved energy spectra for two ion species, (2) obtain ion energy spectra for multiple species, separated according to their charge to mass ratio, along selected axes, and (3) collect laser radiation reflected from and transmitted through the target and propagating in the same direction as the ion beam. Thus, the presented diagnostic constitutes a highly adaptable tool for accurately studying novel acceleration mechanisms in terms of their angular energy distribution, conversion efficiency, and plasma density evolution

  9. Fast acceleration of 2D wave propagation simulations using modern computational accelerators.

    Directory of Open Access Journals (Sweden)

    Wei Wang

    Full Text Available Recent developments in modern computational accelerators like Graphics Processing Units (GPUs and coprocessors provide great opportunities for making scientific applications run faster than ever before. However, efficient parallelization of scientific code using new programming tools like CUDA requires a high level of expertise that is not available to many scientists. This, plus the fact that parallelized code is usually not portable to different architectures, creates major challenges for exploiting the full capabilities of modern computational accelerators. In this work, we sought to overcome these challenges by studying how to achieve both automated parallelization using OpenACC and enhanced portability using OpenCL. We applied our parallelization schemes using GPUs as well as Intel Many Integrated Core (MIC coprocessor to reduce the run time of wave propagation simulations. We used a well-established 2D cardiac action potential model as a specific case-study. To the best of our knowledge, we are the first to study auto-parallelization of 2D cardiac wave propagation simulations using OpenACC. Our results identify several approaches that provide substantial speedups. The OpenACC-generated GPU code achieved more than 150x speedup above the sequential implementation and required the addition of only a few OpenACC pragmas to the code. An OpenCL implementation provided speedups on GPUs of at least 200x faster than the sequential implementation and 30x faster than a parallelized OpenMP implementation. An implementation of OpenMP on Intel MIC coprocessor provided speedups of 120x with only a few code changes to the sequential implementation. We highlight that OpenACC provides an automatic, efficient, and portable approach to achieve parallelization of 2D cardiac wave simulations on GPUs. Our approach of using OpenACC, OpenCL, and OpenMP to parallelize this particular model on modern computational accelerators should be applicable to other

  10. Induction of Foxp3-expressing regulatory T-cells by donor blood transfusion is required for tolerance to rat liver allografts.

    Directory of Open Access Journals (Sweden)

    Yuta Abe

    Full Text Available BACKGROUND: Donor-specific blood transfusion (DST prior to solid organ transplantation has been shown to induce long-term allograft survival in the absence of immunosuppressive therapy. Although the mechanisms underlying DST-induced allograft tolerance are not well defined, there is evidence to suggest DST induces one or more populations of antigen-specific regulatory cells that suppress allograft rejection. However, neither the identity nor the regulatory properties of these tolerogenic lymphocytes have been reported. Therefore, the objective of this study was to define the kinetics, phenotype and suppressive function of the regulatory cells induced by DST alone or in combination with liver allograft transplantation (LTx. METHODOLOGY/PRINCIPAL FINDINGS: Tolerance to Dark Agouti (DA; RT1(a rat liver allografts was induced by injection (iv of 1 ml of heparinized DA blood to naïve Lewis (LEW; RT1(l rats once per week for 4 weeks prior to LTx. We found that preoperative DST alone generates CD4(+ T-cells that when transferred into naïve LEW recipients are capable of suppressing DA liver allograft rejection and promoting long-term survival of the graft and recipient. However, these DST-generated T-cells did not express the regulatory T-cell (Treg transcription factor Foxp3 nor did they suppress alloantigen (DA-induced activation of LEW T-cells in vitro suggesting that these lymphocytes are not fully functional regulatory Tregs. We did observe that DST+LTx (but not DST alone induced the time-dependent formation of CD4(+Foxp3(+ Tregs that potently suppressed alloantigen-induced activation of naïve LEW T-cells in vitro and liver allograft rejection in vivo. Finally, we present data demonstrating that virtually all of the Foxp3-expressing Tregs reside within the CD4(+CD45RC(- population whereas in which approximately 50% of these Tregs express CD25. CONCLUSIONS/SIGNIFICANCE: We conclude that preoperative DST, in the absence of liver allograft

  11. Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7

    Science.gov (United States)

    Bi, Enguang; Ma, Xingzhe; Lu, Yong; Yang, Maojie; Wang, Qiang; Xue, Gang; Qian, Jianfei; Wang, Siqing; Yi, Qing

    2018-01-01

    Tumor-specific CD4+ T helper 9 (TH9) cells, so-called because of their production of the cytokine interleukin-9 (IL-9), are a powerful effector T cell subset for cancer immunotherapy. We found that pretreatment of naïve CD4+ T cells with IL-7 further enhanced their differentiation into TH9 cells and augmented their antitumor activity. IL-7 markedly increased the abundance of the histone acetyltransferase p300 by activating the STAT5 and PI3K-AKT-mTOR signaling pathways and promoting the acetylation of histones at the Il9 promoter. As a result, the transcriptional regulator Foxo1 was dephosphorylated and translocated to the nucleus, bound to the Il9 promoter, and induced the production of IL-9 protein. In contrast, Foxp1, which bound to the Il9 promoter in naïve CD4+ T cells and inhibited Il9 expression, was outcompeted for binding to the Il9 promoter by Foxo1 and translocated to the cytoplasm. Furthermore, forced expression of Foxo1 or a deficiency in Foxp1 in CD4+ T cells markedly increased the production of IL-9, whereas a deficiency in Foxo1 inhibited the ability of IL-7 to enhance the differentiation and antitumor activity of TH9 cells. Thus, we identified the roles of Foxo1 as a positive regulator and Foxp1 as a negative regulator of TH9 cell differentiation and antitumor activity, which may provide potential targets for cancer immunotherapy. PMID:29018172

  12. CAS CERN Accelerator School. 5. Advanced accelerator physics course. Proceedings. Vol. 2

    International Nuclear Information System (INIS)

    Turner, S.

    1995-01-01

    The fifth CERN Accelerator School (CAS) advanced course on Accelerator Physics was given at the Paradise Hotel, Rhodes, Greece from 20 September to 1 October 1993. Its syllabus was based on the previous similar courses held at Oxford 1985, Berlin 1987, Uppsala 1989 and Noordwijkerhout 1991, and whose proceedings were published as CERN Reports 97-03, 89-01, 90-04 and 92-01, respectively. The present volumes are intended to replace and to bring up to date all the material in earlier publications. They contain not only all the lectures given in the Rhodes course but a number of important contributions to previous courses which are thought to be essential for a complete understanding of all aspects of the design and construction of particle accelerators at an advanced level. They include sections on Hamiltonian equations and accelerator optics, chromaticity and dynamic beam aperture, particle tracking, the kinetic theory, longitudinal beam optics, coherent instabilities, beam-beam dynamics, intra-beam scattering, beam cooling, Schottky noise, beam radiation, neutralisation, beam polarisation, radio-frequency quadrupoles, as well as chapters on space charge, superconducting magnets, crystal bending, beam-beam measurement and accelerator medical applications. (orig.)

  13. CAS CERN Accelerator School. 5. Advanced accelerator physics course. Proceedings. Vol. 2

    Energy Technology Data Exchange (ETDEWEB)

    Turner, S [ed.

    1995-11-22

    The fifth CERN Accelerator School (CAS) advanced course on Accelerator Physics was given at the Paradise Hotel, Rhodes, Greece from 20 September to 1 October 1993. Its syllabus was based on the previous similar courses held at Oxford 1985, Berlin 1987, Uppsala 1989 and Noordwijkerhout 1991, and whose proceedings were published as CERN Reports 97-03, 89-01, 90-04 and 92-01, respectively. The present volumes are intended to replace and to bring up to date all the material in earlier publications. They contain not only all the lectures given in the Rhodes course but a number of important contributions to previous courses which are thought to be essential for a complete understanding of all aspects of the design and construction of particle accelerators at an advanced level. They include sections on Hamiltonian equations and accelerator optics, chromaticity and dynamic beam aperture, particle tracking, the kinetic theory, longitudinal beam optics, coherent instabilities, beam-beam dynamics, intra-beam scattering, beam cooling, Schottky noise, beam radiation, neutralisation, beam polarisation, radio-frequency quadrupoles, as well as chapters on space charge, superconducting magnets, crystal bending, beam-beam measurement and accelerator medical applications. (orig.).

  14. Accelerator mass spectrometry programme at BARC-TIFR pelletron accelerator. PD-1-2

    International Nuclear Information System (INIS)

    Bhagwat, P.V.

    2007-01-01

    Accelerator mass spectrometry (AMS) is an ultra sensitive means of counting individual atoms having sufficiently long half-life and available in small amount. The 14 UD Pelletron Accelerator is an ideal machine to carry out AMS studies with heavy isotopes like 36 Cl and 129 I. Cosmogenic radioisotope 36 Cl is widely being detected using AMS as it has got applications in ground water research, radioactive waste management, atmospheric 36 Cl transport mechanism studies of Arctic Alpine ice core etc . The AMS programme at the 14 UD Mumbai Pelletron Accelerator has taken off with the installation of the state of the art Terminal Potential Stabilizer setup and operation of the accelerator in Generating Volt Meter (GVM) mode. Feasibility studies have been carried out for detection/identification of 14 C from a charcoal sample and 3 He in natural Helium. As the primary interest of AMS programme at Mumbai Pelletron Accelerator is related to the cosmogenic nuclei, 36 Cl and 129 I, a segmented gas detector developed for identification of 36 Cl was tested for performance. Recently a beam chopper required for this measurement has also been developed

  15. Accelerating the culture change!

    Science.gov (United States)

    Klunk, S W; Panetta, J; Wooten, J

    1996-11-01

    Exide Electronics, a major supplier of uninterruptible power system equipment, embarked on a journey of changing a culture to improve quality, enhance customer responsiveness, and reduce costs. This case study examines the evolution of change over a period of seven years, with particular emphasis on the most recent years, 1992 through 1995. The article focuses on the Raleigh plant operations and describes how each succeeding year built on the successes and fixed the shortcomings of the prior years to accelerate the culture change, including corrective action and continuous improvement processes, organizational structures, expectations, goals, achievements, and pitfalls. The real challenge to changing the culture was structuring a dynamic approach to accelerate change! The presentation also examines how the evolutionary process itself can be created and accelerated through ongoing communication, regular feedback of progress and goals, constant evaluation and direction of the process, and measuring and paying for performance.

  16. Early Increases in Superantigen-Specific Foxp3+ Regulatory T Cells during Mouse Mammary Tumor Virus Infection▿ †

    Science.gov (United States)

    Cabrera, Gabriel; Burzyn, Dalia; Mundiñano, Juliana; Courreges, M. Cecilia; Camicia, Gabriela; Lorenzo, Daniela; Costa, Héctor; Ross, Susan R.; Nepomnaschy, Irene; Piazzon, Isabel

    2008-01-01

    Mouse mammary tumor virus (MMTV) is a milk-borne betaretrovirus that has developed strategies to exploit and subvert the host immune system. Here, we show in a natural model of MMTV infection that the virus causes early and progressive increases in superantigen (SAg)-specific Foxp3+ regulatory T cells (Treg) in Peyer's patches (PP). These increases were shown to be dependent on the presence of dendritic cells. CD4+ CD25+ T cells from the PP of infected mice preferentially suppress the proliferative response of T cells to SAg-expressing antigen-presenting cells ex vivo. We investigated the influence of the depletion of CD25+ cells at different stages of the infection. When CD25+ cells were depleted before MMTV infection, an increase in the number of PP SAg-cognate Foxp3− T cells was found at day 6 of infection. Since the SAg response is associated with viral amplification, the possibility exists that Treg cells attenuate the increase in viral load at the beginning of the infection. In contrast, depletion of CD25+ cells once the initial SAg response has developed caused a lower viral load, suggesting that at later stages Treg cells may favor viral persistence. Thus, our results indicated that Treg cells play an important and complex role during MMTV infection. PMID:18495774

  17. Ion response to relativistic electron bunches in the blowout regime of laser-plasma accelerators.

    Science.gov (United States)

    Popov, K I; Rozmus, W; Bychenkov, V Yu; Naseri, N; Capjack, C E; Brantov, A V

    2010-11-05

    The ion response to relativistic electron bunches in the so called bubble or blowout regime of a laser-plasma accelerator is discussed. In response to the strong fields of the accelerated electrons the ions form a central filament along the laser axis that can be compressed to densities 2 orders of magnitude higher than the initial particle density. A theory of the filament formation and a model of ion self-compression are proposed. It is also shown that in the case of a sharp rear plasma-vacuum interface the ions can be accelerated by a combination of three basic mechanisms. The long time ion evolution that results from the strong electrostatic fields of an electron bunch provides a unique diagnostic of laser-plasma accelerators.

  18. Effects of Forsythia suspensa on expression of NF-κB and Foxp3 during liver injury in rats with severe acute pancreatitis

    Directory of Open Access Journals (Sweden)

    FAN Xiaobin

    2013-07-01

    Full Text Available ObjectiveTo investigate the roles of nuclear factor-kappa B (NF-κB and forkhead box P3 (Foxp3 during liver injury in rats with severe acute pancreatitis (SAP and the effects of Forsythia suspensa on their expression. MethodsEighty male Wistar rats were randomly allocated into sham operation (SO group, SAP group, and intervention group. The intervention group was further divided into high-dose, middle-dose, and low-dose Forsythia suspensa subgroups and positive control (PDTC subgroup. A rat model was induced by injecting sodium taurocholate into the bile-pancreatic duct. The rats in SO and SAP groups were sacrificed at 3, 6, and 12 h after operation, and those in intervention group were sacrificed at 12 h after operation. The serum levels of amylase (Amy, alanine aminotransferase (ALT, and tumor necrosis factor (TNFα were measured. The endotoxin content in plasma was determined using a limulus reagent. The percentage of Treg cells among peripheral blood lymphocytes was measured by flow cytometry. The pathological examination and scoring of the liver and pancreas were performed. The mRNA expression levels of NF-κB and Foxp3 in liver tissue were measured by RT-PCR. One-way analysis of variance was used for comparison among groups; multiple comparison was performed by LSD test; the indices were subjected to linear correlation analysis. ResultsCompared with those in the SO group, all the indices in the SAP group increased over time and reached the peak levels at 12 h after operation. Compared with the rats in SAP group that were sacrificed at 12 h after operation, the intervention group (mortality = 0 had significantly decreased mRNA expression of NF-κB and Foxp3 in liver tissue (P<0.01. The NF-κB mRNA level was positively correlated with the percentage of Treg cells (r=0.738, P<0.01. As the dose of Forsythia suspensa rose, Amy, ALT, and TNFα levels decreased significantly, and the inflammation of liver and pancreas was significantly

  19. SPECTRAL EVOLUTION OF THE 2010 SEPTEMBER GAMMA-RAY FLARE FROM THE CRAB NEBULA

    International Nuclear Information System (INIS)

    Vittorini, V.; Tavani, M.; Donnarumma, I.; Trois, A.; Del Monte, E.; Evangelista, Y.; Lazzarotto, F.; Pacciani, L.; Pucella, G.; Striani, E.; Caraveo, P.; Giuliani, A.; Mereghetti, S.; Pellizzoni, A.; Ferrari, A.; Barbiellini, G.; Bulgarelli, A.; Cattaneo, P. W.; Colafrancesco, S.; Pilia, M.

    2011-01-01

    Strong gamma-ray flares from the Crab Nebula have been recently discovered by AGILE and confirmed by Fermi-LAT. We study here the spectral evolution in the gamma-ray energy range above 50 MeV of the 2010 September flare that was simultaneously detected by AGILE and Fermi-LAT. We revisit the AGILE spectral data and present an emission model based on rapid (within 1 day) acceleration followed by synchrotron cooling. We show that this model successfully explains both the published AGILE and Fermi-LAT spectral data showing a rapid rise and a decay within 2 and 3 days. Our analysis constrains the acceleration timescale and mechanism, the properties of the particle distribution function, and the local magnetic field. The combination of very rapid acceleration, emission well above 100 MeV, and the spectral evolution consistent with synchrotron cooling contradicts the idealized scenario predicting an exponential cutoff at photon energies above 100 MeV. We also consider a variation of our model based on even shorter acceleration and decay timescales, which can be consistent with the published averaged properties.

  20. Molecular ion acceleration using tandem accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Saito, Yuichi; Mizuhashi, Kiyoshi; Tajima, Satoshi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

    1996-12-01

    In TIARA compound beam radiation system, cluster beams have been produced using 3 MV tandem accelerator (9SDH-2) to supply them to various radiation on injection experiments. Till now, productions of C{sub 2-8}, Si{sub 2-4} and O{sub 2} and their accelerations up to 6 MeV have been succeeded. This study aimed at production and acceleration of B{sub 2-4} and LiF. Anion clusters were produced using the conventional ion source of cesium sputter type. The proportions of atoms, molecules and clusters elicited from the ion source were varied depending on the material`s properties and the operating conditions of ion source such as sample temperature, sputter voltage and the shape of sample. The anion clusters were accelerated toward the high voltage terminal in the center of tandem accelerator, leading to cations through losing their electrons by the collision to N{sub 2} gas in a charge conversion cell at the terminal. Positively charged cluster ions could be obtained by modulating the pressure of N{sub 2} gas. Thus, B{sub 2} (64 nA), B{sub 3} (4.4 nA) and B{sub 4} (2.7 nA) have been produced and their maximum survival probabilities were higher than those of carbon or silicon clusters. In addition, the relationship between beam current and gas pressure was investigated for Bn (n = 2-4) and LiF. (M.N.)

  1. Dynamics of electron acceleration in laser-driven wakefields. Acceleration limits and asymmetric plasma waves

    Energy Technology Data Exchange (ETDEWEB)

    Popp, Antonia

    2011-12-16

    The experiments presented in this thesis study several aspects of electron acceleration in a laser-driven plasma wave. High-intensity lasers can efficiently drive a plasma wave that sustains electric fields on the order of 100 GV/m. Electrons that are trapped in this plasma wave can be accelerated to GeV-scale energies. As the accelerating fields in this scheme are 3-4 orders of magnitude higher than in conventional radio-frequency accelerators, the necessary acceleration distance can be reduced by the same factor, turning laser-wakefield acceleration (LWFA) into a promising compact, and potentially cheaper, alternative. However, laser-accelerated electron bunches have not yet reached the parameter standards of conventional accelerators. This work will help to gain better insight into the acceleration process and to optimize the electron bunch properties. The 25 fs, 1.8 J-pulses of the ATLAS laser at the Max-Planck-Institute of Quantum Optics were focused into a steady-state flow gas cell. This very reproducible and turbulence-free gas target allows for stable acceleration of electron bunches. Thus the sensitivity of electron parameters to subtle changes of the experimental setup could be determined with meaningful statistics. At optimized experimental parameters, electron bunches of {approx}50 pC total charge were accelerated to energies up to 450 MeV with a divergence of {approx}2 mrad FWHM. As, in a new design of the gas cell, its length can be varied from 2 to 14 mm, the electron bunch energy could be evaluated after different acceleration distances, at two different electron densities. From this evolution important acceleration parameters could be extracted. At an electron density of 6.43. 10{sup 18} cm{sup -3} the maximum electric field strength in the plasma wave was determined to be {approx}160 GV/m. The length after which the relativistic electrons outrun the accelerating phase of the electric field and are decelerated again, the so-called dephasing length

  2. Dynamics of electron acceleration in laser-driven wakefields. Acceleration limits and asymmetric plasma waves

    International Nuclear Information System (INIS)

    Popp, Antonia

    2011-01-01

    The experiments presented in this thesis study several aspects of electron acceleration in a laser-driven plasma wave. High-intensity lasers can efficiently drive a plasma wave that sustains electric fields on the order of 100 GV/m. Electrons that are trapped in this plasma wave can be accelerated to GeV-scale energies. As the accelerating fields in this scheme are 3-4 orders of magnitude higher than in conventional radio-frequency accelerators, the necessary acceleration distance can be reduced by the same factor, turning laser-wakefield acceleration (LWFA) into a promising compact, and potentially cheaper, alternative. However, laser-accelerated electron bunches have not yet reached the parameter standards of conventional accelerators. This work will help to gain better insight into the acceleration process and to optimize the electron bunch properties. The 25 fs, 1.8 J-pulses of the ATLAS laser at the Max-Planck-Institute of Quantum Optics were focused into a steady-state flow gas cell. This very reproducible and turbulence-free gas target allows for stable acceleration of electron bunches. Thus the sensitivity of electron parameters to subtle changes of the experimental setup could be determined with meaningful statistics. At optimized experimental parameters, electron bunches of ∼50 pC total charge were accelerated to energies up to 450 MeV with a divergence of ∼2 mrad FWHM. As, in a new design of the gas cell, its length can be varied from 2 to 14 mm, the electron bunch energy could be evaluated after different acceleration distances, at two different electron densities. From this evolution important acceleration parameters could be extracted. At an electron density of 6.43. 10 18 cm -3 the maximum electric field strength in the plasma wave was determined to be ∼160 GV/m. The length after which the relativistic electrons outrun the accelerating phase of the electric field and are decelerated again, the so-called dephasing length, was found to be 4.9 mm

  3. Modernization of the electrostatic accelerator ESA-2 used for fundamental and applied investigations

    International Nuclear Information System (INIS)

    Komarov, F.F.; Kamyshan, A.S.; Lagutin, A.E.

    2005-01-01

    The directions of indispensable modernization of the Van de Graaff electrostatic accelerator ESA-2 are indicated. Design and results of reconstruction of the electrostatic accelerator are described and discussed. The ion source constructed is described too. Design of the new acceleration tube with flat electrodes was investigated. There are many characteristics for the electrostatic accelerator tube presented. The main attention was paid to the upgrading of the charging system. There are many characteristics for the electrostatic accelerator charging belt discussed as well. (authors)

  4. Cosmological evolution of p-brane networks

    International Nuclear Information System (INIS)

    Sousa, L.; Avelino, P. P.

    2011-01-01

    In this paper we derive, directly from the Nambu-Goto action, the relevant components of the acceleration of cosmological featureless p-branes, extending previous analysis based on the field theory equations in the thin-brane limit. The component of the acceleration parallel to the velocity is at the core of the velocity-dependent one-scale model for the evolution of p-brane networks. We use this model to show that, in a decelerating expanding universe in which the p-branes are relevant cosmologically, interactions cannot lead to frustration, except for fine-tuned nonrelativistic networks with a dimensionless curvature parameter k<<1. We discuss the implications of our findings for the cosmological evolution of p-brane networks.

  5. Feature-Based Analysis of Plasma-Based Particle Acceleration Data

    Energy Technology Data Exchange (ETDEWEB)

    Rubel, Oliver [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Geddes, Cameron G. R. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Chen, Min [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Cormier-Michel, Estelle [Tech-X Corp., Boulder, CO (United States); Bethel, E. Wes [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2014-02-01

    Plasma-based particle accelerators can produce and sustain thousands of times stronger acceleration fields than conventional particle accelerators, providing a potential solution to the problem of the growing size and cost of conventional particle accelerators. To facilitate scientific knowledge discovery from the ever growing collections of accelerator simulation data generated by accelerator physicists to investigate next-generation plasma-based particle accelerator designs, we describe a novel approach for automatic detection and classification of particle beams and beam substructures due to temporal differences in the acceleration process, here called acceleration features. The automatic feature detection in combination with a novel visualization tool for fast, intuitive, query-based exploration of acceleration features enables an effective top-down data exploration process, starting from a high-level, feature-based view down to the level of individual particles. We describe the application of our analysis in practice to analyze simulations of single pulse and dual and triple colliding pulse accelerator designs, and to study the formation and evolution of particle beams, to compare substructures of a beam and to investigate transverse particle loss.

  6. Vacuum laser acceleration using a radially polarized CO sub 2 laser beam

    CERN Document Server

    Liu, Y; He, P

    1999-01-01

    Utilizing the high-power, radially polarized CO sub 2 laser and high-quality electron beam at the Brookhaven Accelerator Test Facility, a vacuum laser acceleration scheme is proposed. In this scheme, optics configuration is simple, a small focused beam spot size can be easily maintained, and optical damage becomes less important. At least 0.5 GeV/m acceleration gradient is achievable by 1 TW laser power.

  7. CD4~+Foxp3~+ regulatory T cells converted by rapamycin from peripheral CD4~+ CD25~-naive T cells display more potent regulatory ability in vitro

    Institute of Scientific and Technical Information of China (English)

    CHEN Jian-fei; GAO Jie; ZHANG Dong; WANG Zi-han; ZHU Ji-ye

    2010-01-01

    Background Rapamycin (RAPA) is a relatively new immunosuppressant drug that functions as a serine/threonine kinase inhibitor to prevent rejection in organ transplantation. RAPA blocks activation of T-effector (Teff) cells by inhibiting the response to interleukin-2. Recently, RAPA was also shown to selectively expand the T-regulator (Treg) cell population. To date, no studies have examined the mechanism by which RAPA converts Teff cells to Treg cells. Methods Peripheral CD4~+CD25~- naive T cells were cultivated with RAPA and B cells as antigen-presenting cells (APCs) in vitro. CD4~+CD25~- T cells were harvested after 6 days and analyzed for expression of forkhead box protein 3 (Foxp3) using flow cytometry. CD4~+CD25~+CD127~- subsets as the converted Tregs were isolated from the mixed lymphocyte reactions (MLR) with CD127 negative selection, followed by CD4 and CD25 positive selection using microbeads and magnetic separation column (MSC). Moreover, mRNA was extracted from converted Tregs and C57BL/6 naive CD4~+CD25~+ T cells and Foxp3 levels were examined by quantitative real-time polymerase chain reaction (rt-PCR). A total of 1×10~5 carboxyfluorescein succinimidyl ester (CFSE)-labeled naive CD4~+CD25~- T cells/well from C57BL/6 mice were cocultured with DBA/2 or C3H maturation of dendritic cells (mDCs) (0.25×10~5/well) in 96-well round-bottom plates for 6 days. Then 1×10~5 or 0.25×10~5 converted Treg cells were added to every well as regulatory cells. Cells were harvested after 6 days of culture and analyzed for proliferation of CFSE-labeled naive CD4~+CD25~- T cells using flow cytometry. Data were analyzed using CellQuest software.Results We found that RAPA can convert peripheral CD4~+CD25~- naive T Cells to CD4~+Foxp3~+ Treg cells using B cells as APCs, and this subtype of Treg can potently suppress Teff proliferation and maintain antigenic specificity. Conclusion Our findings provide evidence that RAPA induces Treg cell conversion from Teff cells and

  8. From inflation to recent cosmic acceleration: the fermionic Elko field driving the evolution of the universe

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, S.H.; Guimarães, T.M., E-mail: shpereira@feg.unesp.br, E-mail: thiago.mogui@gmail.com [Universidade Estadual Paulista (Unesp), Faculdade de Engenharia, Guaratinguetá, Departamento de Física e Química, Av. Dr. Ariberto Pereira da Cunha 333, 12516-410, Guaratinguetá, SP (Brazil)

    2017-09-01

    In this paper we construct the complete evolution of the universe driven by the mass dimension one dark spinor called Elko, starting with inflation, passing by the matter dominated era and finishing with the recent accelerated expansion. The dynamic of the fermionic Elko field with a symmetry breaking type potential can reproduce all phases of the universe in a natural and elegant way. The dynamical equations in general case and slow roll conditions in the limit H || m {sub pl} are also presented for the Elko system. Numerical analysis for the number of e-foldings during inflation, energy density after inflation and for present time and also the actual size of the universe are in good agreement with the standard model of cosmology. An interpretation of the inflationary phase as a result of Pauli exclusion principle is also possible if the Elko field is treated as an average value of its quantum analogue.

  9. Transverse emittance studies of an induction accelerator of heavy ions

    International Nuclear Information System (INIS)

    Garvey, T.; Eylon, S.; Fessenden, T.J.; Hahn, K.; Henestroza, E.

    1991-01-01

    Current amplification of heavy ion beams is an integral feature of the induction linac approach to heavy ion fusion. As part of the Heavy Ion Fusion Accelerator Research program at LBL the authors have been studying the evolution of the transverse emittance of ion beams while they are undergoing current amplification, achieved by longitudinal bunch compression and acceleration. Experiments are conducted on MBE-4, a four beam Cs + induction linac. The space-charge dominated beams of MBE-4 are focused by electrostatic quadrupoles while they are accelerated from nominally 200 keV up to ∼ 1 MEV by 24 accelerating gaps. Initially the beams have currents of typically 4 mA to 10 mA per beam. Early experimental results showed a growth of the normalized emittance by a factor of 2 while the beam current was amplified by up to 9 times its initial value. The authors will discuss the results of recent experiments in which a mild bunch length compression rate, more typical of that required by a fusion driver, has shown that the normalized emittance can be maintained at its injection value (0.03 mm-mr) during acceleration

  10. Foxp3+ regulatory T cells control persistence of viral CNS infection.

    Directory of Open Access Journals (Sweden)

    Dajana Reuter

    Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

  11. (99) Tc-methylene diphosphonate improves rheumatoid arthritis disease activity by increasing the frequency of peripheral γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs.

    Science.gov (United States)

    Su, Dinglei; Shen, Minning; Gu, Bingjie; Wang, Xiaoqin; Wang, Dandan; Li, Xia; Sun, Lingyun

    2016-06-01

    γδ T cells exhibit important functions in the pathogenesis of rheumatoid arthritis (RA). In recent years, numerous studies harnessed the γδ T cell-activating capacity of aminobiphosphonates for the treatment of malignant tumors. As (99) Tc-methylene diphosphonate ((99) Tc-MDP) has long been widely used for the treatment of RA in China with good efficacy, we are interested in whether this drug exerts its therapeutic effect on RA by modulating peripheral γδ T cells of RA patients. To investigate the effect of (99) Tc-MDP on the frequency of γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs in the peripheral blood of patients with active RA. Nineteen patients with active RA were treated with (99) Tc-MDP intravenously at a dose of 20 μg/day consecutively for 10-14 days. Before and after treatment, the main clinical and laboratory parameters for each patient were evaluated. The frequency of CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs was detected by flow cytometry. Serum levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-β were measured with enzyme-linked immunosorbent assay. After intravenous (99) Tc-MDP therapy, the frequency of peripheral CD3(+) γδ(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs were significantly elevated, paralleled with decreased serum levels of TNF-α and IL-6 and increased level of serum TGF-β. The elevation of peripheral CD3(+) γδ(+) T cells was positively correlated with increased serum TGF-β and decreased disease activity. (99) Tc-MDP may improve the activity of RA through upregulating the frequency of peripheral γδ T cells and CD4(+) CD25(+) Foxp3(+) Tregs as well as affecting the serum cytokine environment by increasing TGF-β and decreasing TNF-α and IL-6. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  12. Salmon cartilage proteoglycan suppresses mouse experimental colitis through induction of Foxp3{sup +} regulatory T cells

    Energy Technology Data Exchange (ETDEWEB)

    Mitsui, Toshihito [Department of Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Zaifu-cho 5, Hirosaki, Aomori 036-8562 (Japan); Department of Digestive Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562 (Japan); Sashinami, Hiroshi [Department of Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Zaifu-cho 5, Hirosaki, Aomori 036-8562 (Japan); Sato, Fuyuki; Kijima, Hiroshi [Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562 (Japan); Ishiguro, Yoh; Fukuda, Shinsaku [Department of Digestive Internal Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562 (Japan); Yoshihara, Shuichi [Department of Glycomedicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562 (Japan); Hakamada, Ken-Ichi [Department of Digestive Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562 (Japan); Nakane, Akio, E-mail: a27k03n0@cc.hirosaki-u.ac.jp [Department of Microbiology and Immunology, Hirosaki University Graduate School of Medicine, Zaifu-cho 5, Hirosaki, Aomori 036-8562 (Japan)

    2010-11-12

    Research highlights: {yields} Salmon proteoglycan suppresses IL-10{sup -/-} cell transfer-induced colitis progression. {yields} Salmon proteoglycan suppresses Th1- and Th17-related factors in colitis mice. {yields} Salmon proteoglycan enhances Foxp3 expression. -- Abstract: Proteoglycans (PGs) are complex glycohydrates which are widely distributed in extracellular matrix (ECM). PGs are involved in the construction of ECM, cell proliferation and differentiation. ECM components are involved in transduction of proinflammatory responses, but it is still unknown whether PGs are involved in inflammatory response. In this study, we investigated the effect of PG extracted from salmon cartilage on the progression of experimental colitis-induced in severe combined immunodeficiency mice by cell transfer from interleukin-10 (IL-10){sup -/-} mice. IL-10{sup -/-} cell-transferred mice showed weight loss, colon shortening and histological appearance of mild colitis. Daily oral administration of PG attenuated the clinical progression of colitis in a dose-dependent manner. Colitis-induced mice showed the elevated expression of IFN-{gamma}, IL-12, TNF-{alpha}, IL-21, IL-23p19, IL-6, IL-17A and retinoic acid-related orphan receptor {gamma}t (ROR{gamma}t) in lamina propria mononuclear cells (LPMCs) and oral administration of PG suppressed the expression of these factors. Conversely, expression of Foxp3 that induces CD4{sup +}CD25{sup +} regulatory T cells in LPMCs was enhanced by PG administration. These findings suggested that salmon PG attenuated the progression of colitis due to suppression of inflammatory response by enhancement of regulatory T cell induction.

  13. Computer codes for particle accelerator design and analysis: A compendium. Second edition

    International Nuclear Information System (INIS)

    Deaven, H.S.; Chan, K.C.D.

    1990-05-01

    The design of the next generation of high-energy accelerators will probably be done as an international collaborative efforts and it would make sense to establish, either formally or informally, an international center for accelerator codes with branches for maintenance, distribution, and consultation at strategically located accelerator centers around the world. This arrangement could have at least three beneficial effects. It would cut down duplication of effort, provide long-term support for the best codes, and provide a stimulating atmosphere for the evolution of new codes. It does not take much foresight to see that the natural evolution of accelerator design codes is toward the development of so-called Expert Systems, systems capable of taking design specifications of future accelerators and producing specifications for optimized magnetic transport and acceleration components, making a layout, and giving a fairly impartial cost estimate. Such an expert program would use present-day programs such as TRANSPORT, POISSON, and SUPERFISH as tools in the optimization process. Such a program would also serve to codify the experience of two generations of accelerator designers before it is lost as these designers reach retirement age. This document describes 203 codes that originate from 10 countries and are currently in use. The authors feel that this compendium will contribute to the dialogue supporting the international collaborative effort that is taking place in the field of accelerator physics today

  14. Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease.

    Science.gov (United States)

    Massoud, Amir H; Kaufman, Gabriel N; Xue, Di; Béland, Marianne; Dembele, Marieme; Piccirillo, Ciriaco A; Mourad, Walid; Mazer, Bruce D

    2017-04-01

    IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyperresponsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3 + regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chromatin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags. Copyright © 2017 by The American Association of Immunologists, Inc.

  15. Tropics accelerate the evolution of hybrid male sterility in Drosophila.

    Science.gov (United States)

    Yukilevich, Roman

    2013-06-01

    Understanding the evolutionary mechanisms that facilitate speciation and explain global patterns of species diversity has remained a challenge for decades. The most general pattern of species biodiversity is the latitudinal gradient, whereby species richness increases toward the tropics. Although such a global pattern probably has a multitude of causes, recent attention has focused on the hypothesis that speciation and the evolution of reproductive isolation occur faster in the tropics. Here, I tested this prediction using a dataset on premating and postzygotic isolation between recently diverged Drosophila species. Results showed that while the evolution of premating isolation was not greater between tropical Drosophila relative to nontropical species, postzygotic isolation evolved faster in the tropics. In particular, hybrid male sterility was much greater among tropical Drosophila compared to nontropical species pairs of similar genetic age. Several testable explanations for the novel pattern are discussed, including greater role for sterility-inducing bacterial endosymbionts in the tropics and more intense sperm-sperm competition or sperm-egg sexual conflict in the tropics. The results imply that processes of speciation in the tropics may evolve at different rates or may even be somewhat different from those at higher latitudes. © 2013 The Author(s). Evolution © 2013 The Society for the Study of Evolution.

  16. Catalyst Stability Benchmarking for the Oxygen Evolution Reaction: The Importance of Backing Electrode Material and Dissolution in Accelerated Aging Studies.

    Science.gov (United States)

    Geiger, Simon; Kasian, Olga; Mingers, Andrea M; Nicley, Shannon S; Haenen, Ken; Mayrhofer, Karl J J; Cherevko, Serhiy

    2017-09-18

    In searching for alternative oxygen evolution reaction (OER) catalysts for acidic water splitting, fast screening of the material intrinsic activity and stability in half-cell tests is of vital importance. The screening process significantly accelerates the discovery of new promising materials without the need of time-consuming real-cell analysis. In commonly employed tests, a conclusion on the catalyst stability is drawn solely on the basis of electrochemical data, for example, by evaluating potential-versus-time profiles. Herein important limitations of such approaches, which are related to the degradation of the backing electrode material, are demonstrated. State-of-the-art Ir-black powder is investigated for OER activity and for dissolution as a function of the backing electrode material. Even at very short time intervals materials like glassy carbon passivate, increasing the contact resistance and concealing the degradation phenomena of the electrocatalyst itself. Alternative backing electrodes like gold and boron-doped diamond show better stability and are thus recommended for short accelerated aging investigations. Moreover, parallel quantification of dissolution products in the electrolyte is shown to be of great importance for comparing OER catalyst feasibility. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. The control computer for the Chalk River electron test accelerator

    International Nuclear Information System (INIS)

    McMichael, G.E.; Fraser, J.S.; McKeown, J.

    1978-02-01

    A versatile control and data acquisition system has been developed for a modest-sized linear accelerator using mainly process I/O hardware and software. This report describes the evolution of the present system since 1972, the modifications needed to satisfy the changing requirements of the various accelerator physics experiments and the limitations of such a system in process control. (author)

  18. High power beam test and measurement of emittance evolution of a 1.6-cell photocathode RF gun at Pohang Accelerator Laboratory

    International Nuclear Information System (INIS)

    Park, Jang-Ho; Park, Sung-Ju; Kim, Changbum; Huang, Jung-Yun; Ko, In Soo; Parc, Yong-Woon; Hong, Ju-Ho; Xiang Dao; Wang, Xijie

    2007-01-01

    A Brookhaven National Laboratory (BNL) GUN-IV type photocathode rf gun has been fabricated to use in femtosecond electron diffraction (FED), femtosecond far infrared radiation (fs-FIR) facility, and X-ray free electron laser (XFEL) facilities at the Pohang Accelerator Laboratory (PAL). The gun consists of a 1.6-cell cavity with a copper cathode, a solenoid magnet, beam diagnostic components and auxiliary systems. We report here the measurement of the basic beam parameters which confirm a successful fabrication of the photocathode RF gun system. The emittance evolution is measured by an emittance meter and compared with the PARMELA simulation, which shows a good agreement. (author)

  19. 2D electron density profile measurement in tokamak by laser-accelerated ion-beam probe.

    Science.gov (United States)

    Chen, Y H; Yang, X Y; Lin, C; Wang, L; Xu, M; Wang, X G; Xiao, C J

    2014-11-01

    A new concept of Heavy Ion Beam Probe (HIBP) diagnostic has been proposed, of which the key is to replace the electrostatic accelerator of traditional HIBP by a laser-driven ion accelerator. Due to the large energy spread of ions, the laser-accelerated HIBP can measure the two-dimensional (2D) electron density profile of tokamak plasma. In a preliminary simulation, a 2D density profile was reconstructed with a spatial resolution of about 2 cm, and with the error below 15% in the core region. Diagnostics of 2D density fluctuation is also discussed.

  20. Cosmic ray acceleration by shock waves in a diffusion medium. Research of high energies

    International Nuclear Information System (INIS)

    Lagage, P.O.

    1982-06-01

    The problem of galactic cosmic-ray acceleration is presented with the study of a new acceleration mechanism by supernova shock waves in a diffusive medium. The question is: do supernova shocks have enough time to accelerate cosmic rays beyond 10 4 -10 5 GeV. A firm upper limit to the energy that can be acquired by particles is established and it is considered that the mean free path of the particle has its lowest possible value and the most favorable model of supernova evolution. The diffusion coefficients which are relevant for the determination of the high energy cut off are investigated. The effect of the spatial dependence of the diffusion coefficient on the rate of acceleration of particles is examined. A more realistic cut off energy is calculated. We find E max = 2 10 4 GeV [fr

  1. Particle acceleration in relativistic magnetic flux-merging events

    Science.gov (United States)

    Lyutikov, Maxim; Sironi, Lorenzo; Komissarov, Serguei S.; Porth, Oliver

    2017-12-01

    Using analytical and numerical methods (fluid and particle-in-cell simulations) we study a number of model problems involving merger of magnetic flux tubes in relativistic magnetically dominated plasma. Mergers of current-carrying flux tubes (exemplified by the two-dimensional `ABC' structures) and zero-total-current magnetic flux tubes are considered. In all cases regimes of spontaneous and driven evolution are investigated. We identify two stages of particle acceleration during flux mergers: (i) fast explosive prompt X-point collapse and (ii) ensuing island merger. The fastest acceleration occurs during the initial catastrophic X-point collapse, with the reconnection electric field of the order of the magnetic field. During the X-point collapse, particles are accelerated by charge-starved electric fields, which can reach (and even exceed) values of the local magnetic field. The explosive stage of reconnection produces non-thermal power-law tails with slopes that depend on the average magnetization . For plasma magnetization 2$ the spectrum power-law index is 2$ ; in this case the maximal energy depends linearly on the size of the reconnecting islands. For higher magnetization, 2$ , the spectra are hard, , yet the maximal energy \\text{max}$ can still exceed the average magnetic energy per particle, , by orders of magnitude (if is not too close to unity). The X-point collapse stage is followed by magnetic island merger that dissipates a large fraction of the initial magnetic energy in a regime of forced magnetic reconnection, further accelerating the particles, but proceeds at a slower reconnection rate.

  2. Nitrogen evolution during rapid hydropyrolysis of coal

    Energy Technology Data Exchange (ETDEWEB)

    Xu, W.-C.; Kumagai, M. [Institute of Research and Innovation, Kashiwa (Japan)

    2002-12-01

    The behavior of nitrogen evolution during rapid hydropyrolysis of coal has been investigated at temperatures ranging from 923 to 1123 K and hydrogen pressure up to 5 MPa using a continuous free fall pyrolyzer. Three coals have been tested in this study. The dominant nitrogen gaseous species is ammonia, together with a little amount of HCN because most of HCN is converted to NH{sub 3} through secondary reactions. The results show that the evolution of nitrogen in coal is caused mainly by devolatilization at temperatures below 973 K, while the evolution of volatile nitrogen in char is accelerated with increasing temperature and hydrogen pressure. The mineral matter in coal act as catalysts to promote the evolution of volatile nitrogen in char to N{sub 2} apparently at high temperatures of 1123 K, as found during pyrolysis of coal by Ohtsuka et al. A pseudo-first-order kinetic model was applied to the evolution of nitrogen in coal during rapid hydropyrolysis. The model shows the activation energy for the nitrogen evolution from coal is 36.6 58.6 kJ/mol while the rate of the nitrogen evolution depends on hydrogen pressure in the order of 0.16 0.24. 41 refs., 11 figs., 3 tabs.

  3. Centralized digital control of accelerators

    International Nuclear Information System (INIS)

    Melen, R.E.

    1983-09-01

    In contrasting the title of this paper with a second paper to be presented at this conference entitled Distributed Digital Control of Accelerators, a potential reader might be led to believe that this paper will focus on systems whose computing intelligence is centered in one or more computers in a centralized location. Instead, this paper will describe the architectural evolution of SLAC's computer based accelerator control systems with respect to the distribution of their intelligence. However, the use of the word centralized in the title is appropriate because these systems are based on the use of centralized large and computationally powerful processors that are typically supported by networks of smaller distributed processors

  4. Model for evolution of grain size in the rim region of high burnup UO{sub 2} fuel

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Hongxing, E-mail: xiaohongxing2003@163.com; Long, Chongsheng; Chen, Hongsheng

    2016-04-01

    The restructuring process of the high burnup structure (HBS) formation in UO{sub 2} fuel results in sub-micron size grains that accelerate the fission gas swelling, which will raise some concern over the safety of extended the nuclear fuel operation life in the reactor. A mechanistic and engineering model for evolution of grain size in the rim region of high burnup UO{sub 2} fuel based on the experimental observations of the HBS in the literature is presented. The model takes into account dislocations evolution under irradiation and the grain subdivision occur successively at increasing local burnup. It is assumed that the original driving force for subdivision of grain in the HBS of UO{sub 2} fuel is the production and accumulation of dislocation loops during irradiation. The dislocation loops can also be annealed through thermal diffusion when the temperature is high enough. The capability of this model is validated by the comparison with the experimental data of temperature threshold of subdivision, dislocation density and sub-grain size as a function of local burnup. It is shown that the calculated results of the dislocation density and subdivided grain size as a function of local burnup are in good agreement with the experimental results. - Highlights: • A model for evolution of dislocation density and grain size in HBS is proposed. • The dislocation can also be annealed when the temperature is high enough. • Original driving force for subdivision is mostly accumulation of dislocation loops. • The temperature threshold of the subdivision is predicted at 1300–1400 K.

  5. Manufacturing and Testing of Accelerator Superconducting Magnets

    CERN Document Server

    Rossi, L

    2014-01-01

    Manufacturing of superconducting magnet for accelerators is a quite complex process that is not yet fully industrialized. In this paper, after a short history of the evolution of the magnet design and construction, we review the main characteristics of the accelerator magnets having an impact on the construction technology. We put in evidence how the design and component quality impact on construction and why the final product calls for a total-quality approach. LHC experience is widely discussed and main lessons are spelled out. Then the new Nb$_{3}$Sn technology, under development for the next generation magnet construction, is outlined. Finally, we briefly review the testing procedure of accelerator superconducting magnets, underlining the close connection with the design validation and with the manufacturing process.

  6. Manufacturing and Testing of Accelerator Superconducting Magnets

    International Nuclear Information System (INIS)

    Rossi, L

    2014-01-01

    Manufacturing of superconducting magnet for accelerators is a quite complex process that is not yet fully industrialized. In this paper, after a short history of the evolution of the magnet design and construction, we review the main characteristics of the accelerator magnets having an impact on the construction technology. We put in evidence how the design and component quality impact on construction and why the final product calls for a total-quality approach. LHC experience is widely discussed and main lessons are spelled out. Then the new Nb3Sn technology, under development for the next generation magnet construction, is outlined. Finally, we briefly review the testing procedure of accelerator superconducting magnets, underlining the close connection with the design validation and with the manufacturing process

  7. Manufacturing and Testing of Accelerator Superconducting Magnets

    Energy Technology Data Exchange (ETDEWEB)

    Rossi, L [European Organization for Nuclear Research, Geneva (Switzerland)

    2014-07-01

    Manufacturing of superconducting magnet for accelerators is a quite complex process that is not yet fully industrialized. In this paper, after a short history of the evolution of the magnet design and construction, we review the main characteristics of the accelerator magnets having an impact on the construction technology. We put in evidence how the design and component quality impact on construction and why the final product calls for a total-quality approach. LHC experience is widely discussed and main lessons are spelled out. Then the new Nb3Sn technology, under development for the next generation magnet construction, is outlined. Finally, we briefly review the testing procedure of accelerator superconducting magnets, underlining the close connection with the design validation and with the manufacturing process.

  8. Cosmological evolution in vector-tensor theories of gravity

    International Nuclear Information System (INIS)

    Beltran Jimenez, Jose; Maroto, Antonio L.

    2009-01-01

    We present a detailed study of the cosmological evolution in general vector-tensor theories of gravity without potential terms. We consider the evolution of the vector field throughout the expansion history of the Universe and carry out a classification of models according to the behavior of the vector field in each cosmological epoch. We also analyze the case in which the Universe is dominated by the vector field, performing a complete analysis of the system phase map and identifying those attracting solutions which give rise to accelerated expansion. Moreover, we consider the evolution in a universe filled with a pressureless fluid in addition to the vector field and study the existence of attractors in which we can have a transition from matter domination to vector domination with accelerated expansion so that the vector field may play the role of dark energy. We find that the existence of solutions with late-time accelerated expansion is a generic prediction of vector-tensor theories and that such solutions typically lead to the presence of future singularities. Finally, limits from local gravity tests are used to get constraints on the value of the vector field at small (Solar System) scales.

  9. N2-fixing red alder indirectly accelerates ecosystem nitrogen cycling

    Science.gov (United States)

    Perakis, Steven S.; Matkins, Joselin J.; Hibbs, David E.

    2012-01-01

    Symbiotic N2-fixing tree species can accelerate ecosystem N dynamics through decomposition via direct pathways by producing readily decomposed leaf litter and increasing N supply to decomposers, as well as via indirect pathways by increasing tissue and detrital N in non-fixing vegetation. To evaluate the relative importance of these pathways, we compared three-year decomposition and N dynamics of N2-fixing red alder leaf litter (2.34 %N) to both low-N (0.68 %N) and high-N (1.21 %N) litter of non-fixing Douglas-fir, and decomposed each litter source in four forests dominated by either red alder or Douglas-fir. We also used experimental N fertilization of decomposition plots to assess elevated N availability as a potential mechanism of N2-fixer effects on litter mass loss and N dynamics. Direct effects of N2-fixing red alder on decomposition occurred primarily as faster N release from red alder than Douglas-fir litter, but direct increases in N supply to decomposers via fertilization did not stimulate decomposition of any litter. Fixed N indirectly influenced detrital dynamics by increasing Douglas-fir tissue and litter N concentrations, which accelerated litter N release without accelerating mass loss. By increasing soil N, tissue N, and the rate of N release from litter of non-fixers, we conclude that N2-fixing vegetation can indirectly foster plant-soil feedbacks that contribute to the persistence of elevated N availability in terrestrial ecosystems.

  10. Uniform laser ablative acceleration of targets at 1014 W/cm2

    International Nuclear Information System (INIS)

    Obenschain, S.P.; Whitlock, R.R.; McLean, E.A.; Ripin, B.H.; Price, R.H.; Phillion, D.W.; Campbell, E.M.; Rosen, M.D.

    1982-01-01

    We present the first detailed investigations of the ablative acceleration of planar targets while simultaneously using high irradiance (10 14 W/cm 2 ), large focal diameters (1 mm) and long laser pulse duration (3 nsec). Included are measurements of target preheat, ablation pressures and uniformity achieved under these conditions. Targets were accelerated to high velocities with velocity profile uniformity approaching that required for high gain pellet implosions

  11. Distribution uniformity of laser-accelerated proton beams

    Science.gov (United States)

    Zhu, Jun-Gao; Zhu, Kun; Tao, Li; Xu, Xiao-Han; Lin, Chen; Ma, Wen-Jun; Lu, Hai-Yang; Zhao, Yan-Ying; Lu, Yuan-Rong; Chen, Jia-Er; Yan, Xue-Qing

    2017-09-01

    Compared with conventional accelerators, laser plasma accelerators can generate high energy ions at a greatly reduced scale, due to their TV/m acceleration gradient. A compact laser plasma accelerator (CLAPA) has been built at the Institute of Heavy Ion Physics at Peking University. It will be used for applied research like biological irradiation, astrophysics simulations, etc. A beamline system with multiple quadrupoles and an analyzing magnet for laser-accelerated ions is proposed here. Since laser-accelerated ion beams have broad energy spectra and large angular divergence, the parameters (beam waist position in the Y direction, beam line layout, drift distance, magnet angles etc.) of the beamline system are carefully designed and optimised to obtain a radially symmetric proton distribution at the irradiation platform. Requirements of energy selection and differences in focusing or defocusing in application systems greatly influence the evolution of proton distributions. With optimal parameters, radially symmetric proton distributions can be achieved and protons with different energy spread within ±5% have similar transverse areas at the experiment target. Supported by National Natural Science Foundation of China (11575011, 61631001) and National Grand Instrument Project (2012YQ030142)

  12. Accelerator Service

    International Nuclear Information System (INIS)

    Champelovier, Y.; Ferrari, M.; Gardon, A.; Hadinger, G.; Martin, J.; Plantier, A.

    1998-01-01

    Since the cessation of the operation of hydrogen cluster accelerator in July 1996, four electrostatic accelerators were in operation and used by the peri-nuclear teams working in multidisciplinary collaborations. These are the 4 MV Van de Graaff accelerator, 2,5 MV Van de Graaff accelerator, 400 kV ion implanter as well as the 120 kV isotope separator

  13. TIME-DEPENDENT STOCHASTIC ACCELERATION MODEL FOR FERMI BUBBLES

    Energy Technology Data Exchange (ETDEWEB)

    Sasaki, Kento; Asano, Katsuaki; Terasawa, Toshio, E-mail: kentos@icrr.u-tokyo.ac.jp, E-mail: asanok@icrr.u-tokyo.ac.jp, E-mail: terasawa@icrr.u-tokyo.ac.jp [Institute for Cosmic Ray Research, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8582 (Japan)

    2015-12-01

    We study stochastic acceleration models for the Fermi bubbles. Turbulence is excited just behind the shock front via Kelvin–Helmholtz, Rayleigh–Taylor, or Richtmyer–Meshkov instabilities, and plasma particles are continuously accelerated by the interaction with the turbulence. The turbulence gradually decays as it goes away from the shock fronts. Adopting a phenomenological model for the stochastic acceleration, we explicitly solve the temporal evolution of the particle energy distribution in the turbulence. Our results show that the spatial distribution of high-energy particles is different from those for a steady solution. We also show that the contribution of electrons that escaped from the acceleration regions significantly softens the photon spectrum. The photon spectrum and surface brightness profile are reproduced by our models. If the escape efficiency is very high, the radio flux from the escaped low-energy electrons can be comparable to that of the WMAP haze. We also demonstrate hadronic models with the stochastic acceleration, but they are unlikely in the viewpoint of the energy budget.

  14. CERN Accelerator School: Intensity Limitations in Particle Beams | 2-11 November

    CERN Multimedia

    2015-01-01

    Registration is now open for the CERN Accelerator School’s specialised course on Intensity Limitations in Particle Beams, to be held at CERN between 2 and 11 November 2015.   This course will mainly be of interest to staff in accelerator laboratories, university departments and companies manufacturing accelerator equipment. Many accelerators and storage rings, whether intended for particle physics experiments, synchrotron light sources or industrial applications, require beams of high brightness and the highest possible intensities. A good understanding of the possible limitations is required to achieve the desired performance. The programme for this course will cover the interaction of beams with their surroundings, with other beams and further collective effects. Lectures on the effects and possible mitigations will be complemented by tutorials. Further information can be found at: http://cas.web.cern.ch/cas/Intensity-Limitations-2015/IL-advert.html   http:/...

  15. Characteristics of KUMM Tandem Electrostatic Accelerator 5SDH-2

    International Nuclear Information System (INIS)

    Kitamura, Akira; Furuyama, Yuichi; Taniike, Akira; Kubota, Naoyoshi

    1998-01-01

    The KUMM Tandem Electrostatic Accelerator was heavily damaged by the Hanshin Earthquake in Jan. 1995, and the renewed version 5SDH-2 was installed in 1996. The fundamental characteristics of the renewed system is reported together with the system composition. (author)

  16. Evaluating secular acceleration in geomagnetic field model GRIMM-3

    Science.gov (United States)

    Lesur, V.; Wardinski, I.

    2012-12-01

    Secular acceleration of the magnetic field is the rate of change of its secular variation. One of the main results of studying magnetic data collected by the German survey satellite CHAMP was the mapping of field acceleration and its evolution in time. Questions remain about the accuracy of the modeled acceleration and the effect of the applied regularization processes. We have evaluated to what extent the regularization affects the temporal variability of the Gauss coefficients. We also obtained results of temporal variability of the Gauss coefficients where alternative approaches to the usual smoothing norms have been applied for regularization. Except for the dipole term, the secular acceleration of the Gauss coefficients is fairly well described up to spherical harmonic degree 5 or 6. There is no clear evidence from observatory data that the spectrum of this acceleration is underestimated at the Earth surface. Assuming a resistive mantle, the observed acceleration supports a characteristic time scale for the secular variation of the order of 11 years.

  17. Transmission electron microscope interfaced with ion accelerators and its application to materials science

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hiroaki; Naramoto, Hiroshi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment; Hojou, Kiichi; Furuno, Shigemi; Tsukamoto, Tetsuo

    1997-03-01

    We have developed the transmission/analytical electron microscope interfaced with two sets of ion accelerators (TEM-Accelerators Facility) at JAERI-Takasaki. The facility is expected to provide quantitative insights into radiation effects, such as damage evolution, irradiation-induced phase transformation and their stability, through in-situ observation and analysis under ion and/or electron irradiation. The TEM-Accelerators Facility and its application to materials research are reviewed. (author)

  18. Evolution 2.0

    DEFF Research Database (Denmark)

    Andersen, Casper; Bek-Thomsen, Jakob; Clasen, Mathias

    2013-01-01

    Studies in the history of science and education have documented that the reception and understanding of evolutionary theory is highly contingent on local factors such as school systems, cultural traditions, religious beliefs, and language. This has important implications for teaching evolution...... audiences readily available. As more and more schools require teachers to use low cost or free web-based materials, in the research community we need to take seriously how to facilitate that demand in communication strategies on evolution. This article addresses this challenge by presenting the learning...

  19. Function and regulation of AUTS2, a gene implicated in autism and human evolution.

    Directory of Open Access Journals (Sweden)

    Nir Oksenberg

    Full Text Available Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.

  20. History and Technology Developments of Radio Frequency (RF) Systems for Particle Accelerators

    Science.gov (United States)

    Nassiri, A.; Chase, B.; Craievich, P.; Fabris, A.; Frischholz, H.; Jacob, J.; Jensen, E.; Jensen, M.; Kustom, R.; Pasquinelli, R.

    2016-04-01

    This article attempts to give a historical account and review of technological developments and innovations in radio frequency (RF) systems for particle accelerators. The evolution from electrostatic field to the use of RF voltage suggested by R. Wideröe made it possible to overcome the shortcomings of electrostatic accelerators, which limited the maximum achievable electric field due to voltage breakdown. After an introduction, we will provide reviews of technological developments of RF systems for particle accelerators.

  1. 2. 5 MV Van de Graaff accelerator (VdG) and associated experimental equipments

    Energy Technology Data Exchange (ETDEWEB)

    Hasai, Hiromi; Iwatani, Kazuo; Shizuma, Kiyoshi; Nishiyama, Fumitaka

    1984-12-01

    A 2.5 MV VdG accelerator was recently installed in Saijo new campus, Higashi-Hiroshima and started into operation. This paper reports specifications of the accelerator and associated experimental equipments. Available ion beams are hydrogen, helium, nitrogen and, in addition, electrons by means of quick-conversion kit. A switching magnet, a beam transport tube with two beam slits and a vacuum chamber are connected to the accelerator. This VdG accelerator will be used not only for nuclear physics but also for researches of atomic, solid-state physics and microanalysis of elements of enviromental samples. (author).

  2. The clinical and pathogenetic value of Foxp3+ T regulatory cells in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    A. S. Avdeeva

    2016-01-01

    Full Text Available T regulatory cells (Tregs play a key role in the immune system due to the suppression of a hyperimmune response to autoantigens and opportunistic enteric microorganisms. In recent years, there has been evidence that Tregs can suppress various immunoinflammatory responses to a wide range of physiological and pathological stimuli, including microorganisms, tumor cells, allogeneic grafts, and fetal cells.Tregs express a broad spectrum of membrane molecules that determine their functional activity and make it possible to identify these cells; however, none has discovered a universal surface marker that would distinguish this cell subpopulation from a pool of T lymphocytes. The most specific intracellular marker for Tregs is the nuclear transcription factor Foxp3 that is of fundamental importance in the development of Tregs and their inhibitory function.The results of the vast majority of studies indicate that there are increased numbers of Tregs in the synovial fluid of patients with rheumatoid arthritis (RA; however, the data on the level of this cell population in their peripheral blood are very contradictory. The majority of investigators have observed a decrease in the percentage of circulating Tregs while other studies have revealed its increase or no differences from the corresponding value of healthy donors or patients with osteoarthritis. It is believed that a quantitative defect in CD4+CD25+Foxp3+CD127 regulatory cells is especially characteristic of early RA and associated with the risk of the latter in asymptomatic patients positive for anti-cyclic citrullinated peptide antibodies. The use of disease-modifying antirheumatic drugs and biologic agents is accompanied by a certain change in the level and functional activity of Tregs, which is responsible for the therapeutic effect of the medicaments.Thus, an important part is assigned to Tregs in the pathogenesis of autoimmune rheumatic diseases, RA in particular. The decrease in the level

  3. The acceleration intermediate phase (NiS and Ni3S2) evolution by nanocrystallization in Li/NiS2 thermal batteries with high specific capacity

    Science.gov (United States)

    Jin, Chuanyu; Zhou, Lingping; Fu, Licai; Zhu, Jiajun; Li, Deyi; Yang, Wulin

    2017-06-01

    The intermediate phase of NiS2 is thought to be a bottleneck currently to improve the overall performance of Li/NiS2 thermal batteries because of its low conductivity and close formation enthalpy between NiS2 and the intermediate phase (NiS, Ni3S2, etc). For improving the discharge performances of Li/NiS2 thermal batteries, the nano NiS2 with an average size of 85 ± 5 nm is designated as a cathode material. The electrochemical measurements show that the specific capacity of nano NiS2 cathode is higher than micro NiS2. The nano NiS2 cathode exhibits excellent electrochemical performances with high specific capacities of 794 and 654 mAh g-1 at current density of 0.1 and 0.5 A cm-2 under a cut-off voltage of 0.5 V, respectively. These results show that the rapid intermediate phase evolution from the nanocrystallization can obviously enhance use efficiency of NiS2 and improve discharge performances of thermal batteries.

  4. Applications of accelerator mass spectrometry: advances and innovation

    International Nuclear Information System (INIS)

    Fifield, L.K.

    2004-01-01

    Emerging trends in the applications of accelerator mass spectrometry (AMS) are identified and illustrated with specific examples. Areas of application covered include rapid landscape evolution, calibration of the radiocarbon time scale, compound-specific radiocarbon studies, tracing of nuclear discharges, and searches for extraterrestrial isotopes

  5. Evolution and development of the Oak Ridge 25URC tandem accelerator control system

    International Nuclear Information System (INIS)

    Juras, R.C.; Ziegler, N.F.; Meigs, M.J.; McPherson, R.L.; Hoglund, D.E.; Biggerstaff, J.A.

    1987-01-01

    Since acceptance of the 25URC accelerator in 1982, we have continued to develop and improve both the accelerator control system and associated software. In this paper, we describe these improvements and also discuss how our experience with the present system would influence the architecture and design of future, similar systems

  6. 2 MeV, 60 kW dual-beam type electron accelerator irradiation facility

    International Nuclear Information System (INIS)

    Yotsumoto, Keiichi; Kanazawa, Takao; Haruyama, Yasuyuki; Agematsu, Takashi; Mizuhashi, Kiyoshi; Sunaga, Hiromi; Washino, Masamitsu; Tamura, Naoyuki

    1984-02-01

    The specification of new irradiation facility which has been constructed from 1978 through 1981 as the replacement of 1st Accelerator of JAERI, TRCRE are described. The accelerator is the Cockcroft-Walton type and both vertical and horizontal accelerating tubes are arranged on a single high voltage generator. Transferring of the high voltage to the horizontal accelerating tube is performed with the high voltage changing system in the pressure vessel. The output ratings of the accelerator are 2 MV of acceleration voltage and 30 mA of beam current. By providing the dual beam system, two irradiation rooms, one for vertical and the other for horizontal beam, are independently operationable. Persons can enter the horizontal irradiation room for experimental setting even when the vertical irradiation room is in operation. The specification of the buildings, the exhaust air treatment system, the irradiation conveyor and the safety observation system are also described. (author)

  7. Parallel Evolution of Sperm Hyper-Activation Ca2+ Channels.

    Science.gov (United States)

    Cooper, Jacob C; Phadnis, Nitin

    2017-07-01

    Sperm hyper-activation is a dramatic change in sperm behavior where mature sperm burst into a final sprint in the race to the egg. The mechanism of sperm hyper-activation in many metazoans, including humans, consists of a jolt of Ca2+ into the sperm flagellum via CatSper ion channels. Surprisingly, all nine CatSper genes have been independently lost in several animal lineages. In Drosophila, sperm hyper-activation is performed through the cooption of the polycystic kidney disease 2 (pkd2) Ca2+ channel. The parallels between CatSpers in primates and pkd2 in Drosophila provide a unique opportunity to examine the molecular evolution of the sperm hyper-activation machinery in two independent, nonhomologous calcium channels separated by > 500 million years of divergence. Here, we use a comprehensive phylogenomic approach to investigate the selective pressures on these sperm hyper-activation channels. First, we find that the entire CatSper complex evolves rapidly under recurrent positive selection in primates. Second, we find that pkd2 has parallel patterns of adaptive evolution in Drosophila. Third, we show that this adaptive evolution of pkd2 is driven by its role in sperm hyper-activation. These patterns of selection suggest that the evolution of the sperm hyper-activation machinery is driven by sexual conflict with antagonistic ligands that modulate channel activity. Together, our results add sperm hyper-activation channels to the class of fast evolving reproductive proteins and provide insights into the mechanisms used by the sexes to manipulate sperm behavior. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  8. Accelerated expansion of the universe driven by tachyonic matter

    International Nuclear Information System (INIS)

    Padmanabhan, T.

    2002-01-01

    It is an accepted practice in cosmology to invoke a scalar field with a potential V(φ) when the observed evolution of the universe cannot be reconciled with theoretical prejudices. Since one function degree of freedom in the expansion factor a(t) can be traded off for the function V(φ), it is always possible to find a scalar field potential which will reproduce a given evolution. I provide a recipe for determining V(φ) from a(t) in two cases: (i) a normal scalar field with the Lagrangian L=(1/2)∂ a φ∂ a φ-V(φ) used in quintessence or dark energy models; (ii) a tachyonic field with the Lagrangian L=-V(φ)[1-∂ a φ∂ a φ] 1/2 , motivated by recent string theoretic results. In the latter case, it is possible to have accelerated expansion of the universe during the late phase in certain cases

  9. Yogurt Feeding Induced the Prolongation of Fully Major Histocompatibility Complex-Mismatched Murine Cardiac Graft Survival by Induction of CD4+Foxp3+ Cells.

    Science.gov (United States)

    Uchiyama, M; Yin, E; Yanagisawa, T; Jin, X; Hara, M; Matsuyama, S; Imazuru, T; Uchida, K; Kawamura, M; Niimi, M

    Yogurt is a nutrient-rich food and the beneficial effects of yogurt on both health and immunomodulatory effects are well documented. In this pilot study, we investigated the effects of commercially produced yogurt R-1 on alloimmune responses in a murine cardiac transplantation model. The R-1 is produced by Meiji Co., Ltd., and contains live and active lactic acid bacteria (lactobacillus bulgaricus OLL1073R-1) mainly. CBA (H2 k ) mice underwent transplantation of a C57BL/6 (H2 b ; B6) heart and received oral administration of 1 mL, 0.1 mL, and 0.01 mL of R-1 from the day of transplantation until 7 days afterward. Additionally, we prepared one group of CBA recipients given 1 mL of R-1 sterilized by microwave for 7 days. Histological and immunohistochemical studies were performed. Naïve CBA mice rejected B6 cardiac graft acutely (median survival time [MST]: 7 days). CBA recipients given of 1 mL of R-1 had significantly prolonged B6 allograft survival (MST, 27 days). However, other doses of 0.1 mL and 0.01 mL of R-1 did not prolonged allograft survival (MSTs, 9 days and 8.5 days, respectively). Also, CBA recipients administered microwaved R-1 had no prolongation of B6 allograft (MST, 9 days). Histological and immunohistochemical studies showed the cardiac allograft from R-1-exposed CBA recipients had preserved graft and vessel structure and the number of infiltrated CD4 + , CD8 + , and Foxp3 + cells in R-1-exposed CBA recipients increased, respectively. In conclusion, our findings imply that yogurt containing active lactic acid bacteria could change alloimmune responses partially and induce the prolongation of cardiac allograft survival via CD4 + Foxp3 + regulatory cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Summary report: working group 2 on 'Plasma Based Acceleration Concepts'

    International Nuclear Information System (INIS)

    Esarey, E.; Leemans, W.P.

    1998-01-01

    A summary of the talks, papers and discussion sessions presented in the Working Group on Plasma Based Acceleration Concepts is given within the context of the progress towards a 1 GeV laser driven accelerator module. The topics covered within the Working Group were self-modulated laser wakefield acceleration, standard laser wakefield acceleration, plasma beat wave acceleration, laser guiding and wake excitation in plasma channels, plasma wakefield acceleration, plasma lenses and optical injection techniques for laser wakefield accelerators. An overview will be given of the present status of experimental and theoretical progress as well as an outlook towards the future physics and technological challenges for the development of an optimized accelerator module

  11. Can the Stephani model be an alternative to FRW accelerating models?

    International Nuclear Information System (INIS)

    Godlowski, Wlodzimierz; Stelmach, Jerzy; Szydlowski, Marek

    2004-01-01

    A class of Stephani cosmological models as a prototype of a non-homogeneous universe is considered. The non-homogeneity can lead to accelerated evolution, which is now observed from the SNe Ia data. Three samples of type Ia supernovae obtained by Perlmutter et al, Tonry et al and Knop et al are taken into account. Different statistical methods (best fits as well as maximum likelihood method) to obtain estimation for the model parameters are used. The Stephani model is considered as an alternative to the ΛCDM model in the explanation of the present acceleration of the universe. The model explains the acceleration of the universe at the same level of accuracy as the ΛCDM model (χ 2 statistics are comparable). From the best fit analysis it follows that the Stephani model is characterized by a higher value of density parameter Ω m0 than the ΛCDM model. It is also shown that the model is consistent with the location of CMB peaks

  12. Accelerator Technology: Geodesy and Alignment for Particle Accelerators

    CERN Document Server

    Missiaen, D

    2013-01-01

    This document is part of Subvolume C 'Accelerators and Colliders' of Volume 21 'Elementary Particles' of Landolt-Börnstein - Group I 'Elementary Particles, Nuclei and Atoms'. It contains the the Section '8.9 Geodesy and Alignment for Particle Accelerators' of the Chapter '8 Accelerator Technology' with the content: 8.9 Geodesy and Alignment for Particle Accelerators 8.9.1 Introduction 8.9.2 Reference and Co-ordinate Systems 8.9.3 Definition of the Beam Line on the Accelerator Site 8.9.4 Geodetic Network 8.9.5 Tunnel Preliminary Works 8.9.6 The Alignment References 8.9.7 Alignment of Accelerator Components 8.9.8 Permanent Monitoring and Remote Alignment of Low Beta Quadrupoles 8.9.9 Alignment of Detector Components

  13. Cosmic-ray acceleration and the radio evolution of Cassiopeia A

    International Nuclear Information System (INIS)

    Chevalier, R.A.; Robertson, J.W.; Scott, J.S.

    1976-01-01

    A more detailed analysis of the Scott and Chevalier model for production of galactic cosmic rays in supernova remnants is presented. Particles are accelerated by second-order Fermi acceleration with turbulent vortices (produced by the motions of the supernova ejecta through the remnant) acting as moving scattering centers. The time-dependent equation of continuity in particle energy space is solved numerically. The results of the calculations are in substantial agreement with all time-dependent observations of the radio emission from Cas A. This mechanism implies an dependent solution yields a cosmic ray spectrum with the same slope as galactic cosmic rays. The results of our calculations and new work on γ-rays by, e.g., Stecker and by Lingenfelter and Higdon and cosmic ray composition by, e.g., Hainebach, Norman, and Schramm support our hypothesis that galactic cosmic rays are produced in supernova remnants by the mechanism proposed by Scott and Chevalier

  14. The design and commissioning of large particle accelerators

    International Nuclear Information System (INIS)

    Wilson, E.J.N.

    1981-01-01

    The design and development of synchrotrons and storage rings for proton and electron acceleration are discussed. Having traced the evolution of designs from those for the early cyclotrons, the present generation of synchrotrons are described and the running in of such component systems is considered. (U.K.)

  15. Coastal Foredune Evolution, Part 2: Modeling Approaches for Meso-Scale Morphologic Evolution

    Science.gov (United States)

    2017-03-01

    for Meso-Scale Morphologic Evolution by Margaret L. Palmsten1, Katherine L. Brodie2, and Nicholas J. Spore2 PURPOSE: This Coastal and Hydraulics ...managers because foredunes provide ecosystem services and can reduce storm damages to coastal infrastructure, both of which increase the resiliency...MS 2 U.S. Army Engineer Research and Development Center, Coastal and Hydraulics Laboratory, Duck, NC ERDC/CHL CHETN-II-57 March 2017 2 models of

  16. Acceleration of 100 keV protons using a 5SDH-2 Pelletron

    CERN Document Server

    Hollerman, W A; Ruzycki, N

    1999-01-01

    The authors successfully accelerated a 100 keV proton beam using a model 5SDH-2 Pelletron accelerator, manufactured by National Electrostatics Corporation (NEC). A pseudo-stable 1-2 nA beam was delivered on target with a net energy variation of less than 6%. However, the small terminal potential made it impossible to use standard stabilization techniques. Minor adjustments in terminal potential were required every 15 min to maintain beam current and energy. This level of stability is sufficient to deliver a proton fluence of 10 sup 1 sup 1 -10 sup 1 sup 2 cm sup - sup 2 to any desired target.

  17. Energy cascading in the beat-wave accelerator

    International Nuclear Information System (INIS)

    McKinstrie, C.J.; Batha, S.H.

    1987-01-01

    A review is given of energy cascading in the beat-wave accelerator. The properties of the electromagnetic cascade and the corresponding plasma-wave evolution are well understood within the framework of an approximate analytic model. Based on this model, idealized laser-plasma coupling efficiencies of the order of 10% do not seem unreasonable. 28 refs

  18. Stochastic spin evolution of neutron stars

    OpenAIRE

    Popov, S. B.; Prokhorov, M. E.; Khoperskov, A. V.; Lipunov, V. M.

    2001-01-01

    In this paper we present calculations of period distribution for old accreting isolated neutron stars (INSs). At the age about a few billions years low velocity INSs come to the stage of accretion. At that stage their period evolution is governed by magnetic breaking and accreted angular momentum. Due to turbulence of the interstellar medium (ISM) accreted momentum can both accelerate and decelerate rotation of an INS and spin evolution has chaotic character. Calculations show that for consta...

  19. CD4+ FOXP3+ Regulatory T Cells Exhibit Impaired Ability to Suppress Effector T Cell Proliferation in Patients with Turner Syndrome.

    Directory of Open Access Journals (Sweden)

    Young Ah Lee

    Full Text Available We investigated whether the frequency, phenotype, and suppressive function of CD4+ FOXP3+ regulatory T cells (Tregs are altered in young TS patients with the 45,X karyotype compared to age-matched controls.Peripheral blood mononuclear cells from young TS patients (n = 24, 17.4-35.9 years and healthy controls (n = 16 were stained with various Treg markers to characterize their phenotypes. Based on the presence of thyroid autoimmunity, patients were categorized into TS (- (n = 7 and TS (+ (n = 17. Tregs sorted for CD4+ CD25bright were co-cultured with autologous CD4+ CD25- target cells in the presence of anti-CD3 and -CD28 antibodies to assess their suppressive function.Despite a lower frequency of CD4+ T cells in the TS (- and TS (+ patients (mean 30.8% and 31.7%, vs. 41.2%; P = 0.003 and P < 0.001, respectively, both groups exhibited a higher frequency of FOXP3+ Tregs among CD4+ T cells compared with controls (means 1.99% and 2.05%, vs. 1.33%; P = 0.029 and P = 0.004, respectively. There were no differences in the expression of CTLA-4 and the frequency of Tregs expressing CXCR3+, and CCR4+ CCR6+ among the three groups. However, the ability of Tregs to suppress the in vitro proliferation of autologous CD4+ CD25- T cells was significantly impaired in the TS (- and TS (+ patients compared to controls (P = 0.003 and P = 0.041. Meanwhile, both the TS (- and TS (+ groups had lower frequencies of naïve cells (P = 0.001 for both but higher frequencies of effector memory cells (P = 0.004 and P = 0.002 than did the healthy control group.The Tregs of the TS patients could not efficiently suppress the proliferation of autologous effector T cells, despite their increased frequency in peripheral CD4+ T cells.

  20. Dynamic Monte Carlo simulations of radiatively accelerated GRB fireballs

    Science.gov (United States)

    Chhotray, Atul; Lazzati, Davide

    2018-05-01

    We present a novel Dynamic Monte Carlo code (DynaMo code) that self-consistently simulates the Compton-scattering-driven dynamic evolution of a plasma. We use the DynaMo code to investigate the time-dependent expansion and acceleration of dissipationless gamma-ray burst fireballs by varying their initial opacities and baryonic content. We study the opacity and energy density evolution of an initially optically thick, radiation-dominated fireball across its entire phase space - in particular during the Rph matter-dominated fireballs due to Thomson scattering. We quantify the new phases by providing analytical expressions of Lorentz factor evolution, which will be useful for deriving jet parameters.

  1. Subcutaneous administration of polymerized type I collagen downregulates interleukin (IL)-17A, IL-22 and transforming growth factor-β1 expression, and increases Foxp3-expressing cells in localized scleroderma.

    Science.gov (United States)

    Furuzawa-Carballeda, J; Ortíz-Ávalos, M; Lima, G; Jurado-Santa Cruz, F; Llorente, L

    2012-08-01

    Localized scleroderma (LS) is a disfiguring inflammatory autoimmune disease of the skin and underlying tissue. As in systemic sclerosis, a key feature is the presence of T cells in inflammatory lesions. To evaluate the effect of polymerized type I collagen vs. methylprednisolone (MP) in LS, and to determine the influence of this polymerized collagen (PC) on CD4+ peripheral T cells expressing interleukin (IL)-4, IL-17A, interferon-γ and Forkhead box protein (Foxp)3, and on cells expressing transforming growth factor (TGF)-β1, IL-17A, IL-22 and Foxp3 in the skin. In total, 16 patients with LS were treated for 3 months with monthly subcutaneous intralesional injections of 0.1 mL MP (giving a total dose of 20 mg/mL each month) and 15 patients were treated, with weekly subcutaneous intralesional injections of PC, ranging from 0.2 mL (equivalent to 1.66 mg collagen) for a lesion of 50 mm in size, up to a maximum of 1.0 mL (8.3 mg collagen) for a lesion > 100 mm in size, and followed up for a further 6 months. Skin biopsies were obtained from lesions at baseline (before treatment) and 9 months later (6 months after treatment end). Tissue sections were evaluated by histology and immunohistochemistry (IL-17A, IL-22, TGF-β1 and Foxp3). CD4+ T-cell subsets were determined in peripheral blood by flow cytometry. Abnormal tissue architecture was seen in the biopsies taken from patients treated with MP, whereas the PC treatment restored normal skin architecture. PC downregulated pro-inflammatory/profibrotic cytokine expression in peripheral cells, and upregulated the number of regulatory T cells (Tregs) in skin. PC was safe and well tolerated. PC is not only an antifibrotic/fibrolytic agent but also an immunomodulator biodrug that restores the balance between T helper (Th)1, Th2, Th17 and Tregs, downregulates production of pro-inflammatory or profibrogenic cytokines (IL-17A, IL-22 and TGF-β1), and renews skin architecture, without adverse effects. © The Author(s). CED

  2. 2016 Accelerators meeting

    International Nuclear Information System (INIS)

    Spiro, Michel; Revol, Jean-Luc; Biarrotte, Jean-Luc; Napoly, Olivier; Jardin, Pascal; Chautard, Frederic; Thomas, Jean Charles; Petit, Eric

    2016-09-01

    The Accelerators meeting is organised every two years by the Accelerators division of the French Society of Physics (SFP). It brings together about 50 participants during a one-day meeting. The morning sessions are devoted to scientific presentations while the afternoon is dedicated to technical visits of facilities. This document brings together the available presentations (slides): 1 - Presentation of the Ganil - Grand accelerateur national d'ions lourds/Big national heavy-ion accelerator, Caen (Jardin, Pascal); 2 - Presentation of the Accelerators division of the French Society of Physics (Revol, Jean-Luc); 3 - Forward-looking and Prospective view (Napoly, Olivier); 4 - Accelerators at the National Institute of Nuclear and particle physics, situation, Forward-looking and Prospective view (Biarrotte, Jean-Luc); 5 - GANIL-SPIRAL2, missions and goals (Thomas, Jean Charles); 6 - The SPIRAL2 project (Petit, Eric)

  3. 2-D emittance equation with acceleration and compression

    International Nuclear Information System (INIS)

    Hahn, K.D.; Smith, L.

    1988-10-01

    Since both acceleration and compression are required for an Inertial Fusion Driver, the understanding of their effect on the beam quality, emittance, is important. This report attempts to generalize the usual emittance formula for the drifting beam to include these effects. The derivation of the 2-D emittance equation is carried out and a comparison with the particle code results is given. The 2-D emittance at a given axial location is reasonable to consider for a long beam, particularly with velocity tilt; transverse emittance averaged over the entire bunch is not a useful quantity. 6 refs., 2 figs., 1 tab

  4. Structure of period-2 step-1 accelerator island in area preserving maps

    International Nuclear Information System (INIS)

    Hirose, K.; Ichikawa, Y.H.; Saito, S.

    1996-03-01

    Since the multi-periodic accelerator modes manifest their contribution even in the region of small stochastic parameters, analysis of such regular motion appears to be critical to explore the stochastic properties of the Hamiltonian system. Here, structure of period-2 step-1 accelerator mode is analyzed for the systems described by the Harper map and by the standard map. The stability criterions have been analyzed in detail in comparison with numerical analyses. The period-3 squeezing around the period-2 step-1 islands is identified in the standard map. (author)

  5. Energy-driven surface evolution in beta-MnO2 structures

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Wentao; Yuan, Yifei; Asayesh-Ardakani, Hasti; Huang, Zhennan; Long, Fei; Friedrich, Craig; Amine, Khalil; Lu, Jun; Shahbazian-Yassar, Reza

    2018-01-01

    Exposed crystal facets directly affect the electrochemical/catalytic performance of MnO2 materials during their applications in supercapacitors, rechargeable batteries, and fuel cells. Currently, the facet-controlled synthesis of MnO2 is facing serious challenges due to the lack of an in-depth understanding of their surface evolution mechanisms. Here, combining aberration-corrected scanning transmission electron microscopy (STEM) and high-resolution TEM, we revealed a mutual energy-driven mechanism between beta-MnO2 nanowires and microstructures that dominated the evolution of the lateral facets in both structures. The evolution of the lateral surfaces followed the elimination of the {100} facets and increased the occupancy of {110} facets with the increase in hydrothermal retention time. Both self-growth and oriented attachment along their {100} facets were observed as two different ways to reduce the surface energies of the beta-MnO2 structures. High-density screw dislocations with the 1/2 < 100 > Burgers vector were generated consequently. The observed surface evolution phenomenon offers guidance for the facet-controlled growth of beta-MnO2 materials with high performances for its application in metal-air batteries, fuel cells, supercapacitors, etc.

  6. Accelerator development

    International Nuclear Information System (INIS)

    Anon.

    1975-01-01

    Because the use of accelerated heavy ions would provide many opportunities for new and important studies in nuclear physics and nuclear chemistry, as well as other disciplines, both the Chemistry and Physics Divisions are supporting the development of a heavy-ion accelerator. The design of greatest current interest includes a tandem accelerator with a terminal voltage of approximately 25 MV injecting into a linear accelerator with rf superconducting resonators. This combined accelerator facility would be capable of accelerating ions of masses ranging over the entire periodic table to an energy corresponding to approximately 10 MeV/nucleon. This approach, as compared to other concepts, has the advantages of lower construction costs, lower operating power, 100 percent duty factor, and high beam quality (good energy resolution, good timing resolution, small beam size, and small beam divergence). The included sections describe the concept of the proposed heavy-ion accelerator, and the development program aiming at: (1) investigation of the individual questions concerning the superconducting accelerating resonators; (2) construction and testing of prototype accelerator systems; and (3) search for economical solutions to engineering problems. (U.S.)

  7. Particle Acceleration, Magnetic Field Generation and Emission from Relativistic Jets and Supernova Remnants

    Science.gov (United States)

    Nishikawa, K.-I.; Hartmann, D. H.; Hardee, P.; Hededal, C.; Mizunno, Y.; Fishman, G. J.

    2006-01-01

    We performed numerical simulations of particle acceleration, magnetic field generation, and emission from shocks in order to understand the observed emission from relativistic jets and supernova remnants. The investigation involves the study of collisionless shocks, where the Weibel instability is responsible for particle acceleration as well as magnetic field generation. A 3-D relativistic particle-in-cell (RPIC) code has been used to investigate the shock processes in electron-positron plasmas. The evolution of theWeibe1 instability and its associated magnetic field generation and particle acceleration are studied with two different jet velocities (0 = 2,5 - slow, fast) corresponding to either outflows in supernova remnants or relativistic jets, such as those found in AGNs and microquasars. Slow jets have intrinsically different structures in both the generated magnetic fields and the accelerated particle spectrum. In particular, the jet head has a very weak magnetic field and the ambient electrons are strongly accelerated and dragged by the jet particles. The simulation results exhibit jitter radiation from inhomogeneous magnetic fields, generated by the Weibel instability, which has different spectral properties than standard synchrotron emission in a homogeneous magnetic field.

  8. Idh2 deficiency accelerates renal dysfunction in aged mice.

    Science.gov (United States)

    Lee, Su Jeong; Cha, Hanvit; Lee, Seoyoon; Kim, Hyunjin; Ku, Hyeong Jun; Kim, Sung Hwan; Park, Jung Hyun; Lee, Jin Hyup; Park, Kwon Moo; Park, Jeen-Woo

    2017-11-04

    The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP + -dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2 -/- ) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2 -/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2 -/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Art as A Playground for Evolution

    DEFF Research Database (Denmark)

    Beloff, Laura

    2016-01-01

    Art works which engage with the topic of human enhancement and evolution have begun appearing parallel to increased awareness about anthropogenic changes to our environment and acceleration of the speed of technological developments that impact us and our biological environment. The article...... and related topics is proposed as play activity for adults, which simultaneously experiments directly with ideas concerning evolution and human development. The author proposes that these kinds of experimental art projects support our mental adaptation to evolutionary changes....

  10. Research in accelerator physics (theory)

    International Nuclear Information System (INIS)

    Ohnuma, Shoroku.

    1991-01-01

    This report discusses the following topics: beam-beam interaction in colliders with momentum oscillation; isolated difference resonance and evolution of the particle distribution; study of magnet sorting for the SSC High Energy Booster; development of a discrete HESQ; beam dynamics in compact synchrotrons; theoretical problems in multi-stage FEL for two-beam acceleration; operation of Tevatron near integer tunes; and detailed examination of coupling impedance of various devices in storage rings; impact on beams from the insertion devices

  11. Investigation of beam transmission in A 9SDH-2 3.0 MV NEC pelletron tandem accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Deoli, Naresh T.; Kummari, Venkata C.; Pacheco, Jose L.; Duggan, Jerome L.; Glass, Gary A.; McDaniel, Floyd D.; Reinert, Tilo; Rout, Bibhudutta; Weathers, Duncan L. [Ion Beam Modification And Analysis Laboratory, Department of Physics, University of North Texas, Denton, Texas 76203 (United States)

    2013-04-19

    Electrostatic tandem accelerators are widely used to accelerate ions for experiments in materials science such as high energy ion implantation, materials modification, and analyses. Many applications require high beam current as well as high beam brightness at the target; thus, maximizing the beam transmission through such electrostatic accelerators becomes important. The Ion Beam Modification and Analysis Laboratory (IBMAL) at University of North Texas is equipped with four accelerators, one of which is a 9SDH-2 3.0 MV National Electrostatic Corporation (NEC) Pelletron Registered-Sign tandem accelerator. The tandem accelerator is equipped with three ion sources: one radio frequency-He ion source (Alphatross) and two ion sources of Cs-sputter type, the SNICS II (Source of Negative Ions by Cesium Sputtering) and a Cs-sputter source for trace-element accelerator based mass spectrometry. This work presents a detailed study of the beam transmission of hydrogen, silicon, and silver ions through the accelerator using the SNICS ion source with injection energies ranging from 20 keV to 70 keV. The beam transmission is quantified for three different terminal voltages: 1.5 MV, 2.0 MV and 2.5 MV. For a given terminal voltage, it has been found that beam transmission is strongly dependent on the ion source injector potential. Details of experiments and data analysis are presented.

  12. Accelerator mass spectrometry at the Rossendorf 5 MV tandem accelerator

    International Nuclear Information System (INIS)

    Friedrich, M.; Buerger, W.; Curian, H.; Hartmann, B.; Hentschel, E.; Matthes, H.; Probst, W.; Seidel, M.; Turuc, S.; Hebert, D.; Rothe, T.; Stolz, W.

    1992-01-01

    The Rossendorf electrostatic accelerators (5 MV tandem accelerator and single ended 2 MV van de Graaff accelerator) are already used for ion beam analysis. The existing methods (RBS, PIXE, ERDA, NRA, nuclear microprobe and external beam) will be completed by introduction of Accelerator Mass Spectrometry (AMS). A short description of the Rossendorf AMS system is given and first experimental results are presented. (R.P.) 4 refs.; 6 figs

  13. Development of bipolar pulse accelerator for intense pulsed ion beam acceleration

    International Nuclear Information System (INIS)

    Fujioka, Y.; Mitsui, C.; Kitamura, I.; Takahashi, T.; Masugata, K.; Tanoue, H.; Arai, K.

    2003-01-01

    To improve the purity of an intense pulsed ion beams a new type of pulsed ion beam accelerator named 'bipolar pulse accelerator (BPA)' was proposed. In the accelerator purity of the beam is expected. To confirm the principle of the accelerator experimental system was developed. The system utilizes B y type magnetically insulated acceleration gap and operated with single polar negative pulse. A coaxial gas puff plasma gun placed in the grounded anode was used as an ion source, and source plasma (nitrogen) of current density approx. = 25 A/cm 2 , duration approx. = 1.5 μs was injected into the acceleration gap. The ions are successfully accelerated from the grounded anode to the drift tube by applying negative pulse of voltage 180 kV, duration 60 ns to the drift tube. Pulsed ion beam of current density approx. = 40 A/cm 2 , duration approx. 60 ns was obtained at 42 mm downstream from the anode surface. (author)

  14. Acceleration waves in non-ideal magnetogasdynamics

    Directory of Open Access Journals (Sweden)

    R. Singh

    2014-03-01

    Full Text Available The problem of propagation of acceleration waves in an unsteady inviscid non-ideal gas under the influence of magnetic field is investigated. The characteristic solution to the problem in the neighbourhood of leading characteristics has been determined. An evolution equation governing the behaviour of acceleration waves has been derived. It is shown that a linear solution in the characteristic plane exhibits non-linear behaviour in physical plane. The effect of magnetic field on the formation of shock in non-ideal gas flow with planar and cylindrical symmetry is analysed. It is noticed that all compressive waves terminate into a shock wave. Further, we also compare/contrast the nature of solution in ideal and non-ideal magnetogasdynamic regime.

  15. Medical applications of accelerators

    CERN Document Server

    Rossi, Sandro

    1998-01-01

    At Present, about five thousands accelerators are devoted to biomedical applications. They are mainly used in radiotherapy, research and medical radioisotopes production. In this framework oncological hadron-therapy deserves particular attention since it represents a field in rapid evolution thanks to the joint efforts of laboratories with long experiences in particle physics. It is the case of CERN where the design of an optimised synchrotron for medical applications has been pursued. These lectures present these activities with particular attention to the new developments which are scientifically interesting and/or economically promising.

  16. Accelerated whole-brain multi-parameter mapping using blind compressed sensing.

    Science.gov (United States)

    Bhave, Sampada; Lingala, Sajan Goud; Johnson, Casey P; Magnotta, Vincent A; Jacob, Mathews

    2016-03-01

    To introduce a blind compressed sensing (BCS) framework to accelerate multi-parameter MR mapping, and demonstrate its feasibility in high-resolution, whole-brain T1ρ and T2 mapping. BCS models the evolution of magnetization at every pixel as a sparse linear combination of bases in a dictionary. Unlike compressed sensing, the dictionary and the sparse coefficients are jointly estimated from undersampled data. Large number of non-orthogonal bases in BCS accounts for more complex signals than low rank representations. The low degree of freedom of BCS, attributed to sparse coefficients, translates to fewer artifacts at high acceleration factors (R). From 2D retrospective undersampling experiments, the mean square errors in T1ρ and T2 maps were observed to be within 0.1% up to R = 10. BCS was observed to be more robust to patient-specific motion as compared to other compressed sensing schemes and resulted in minimal degradation of parameter maps in the presence of motion. Our results suggested that BCS can provide an acceleration factor of 8 in prospective 3D imaging with reasonable reconstructions. BCS considerably reduces scan time for multiparameter mapping of the whole brain with minimal artifacts, and is more robust to motion-induced signal changes compared to current compressed sensing and principal component analysis-based techniques. © 2015 Wiley Periodicals, Inc.

  17. Kaempferol Promotes Transplant Tolerance by Sustaining CD4+FoxP3+ Regulatory T Cells in the Presence of Calcineurin Inhibitor.

    Science.gov (United States)

    Zeng, Y Q; Liu, X S; Wu, S; Zou, C; Xie, Q; Xu, S M; Jin, X W; Li, W; Zhou, A; Dai, Z

    2015-07-01

    Calcineurin inhibitor cyclosporine is widely used as an immunosuppressant in clinic. However, mounting evidence has shown that cyclosporine hinders tolerance induction by dampening Tregs. Therefore, it is of paramount importance to overcome this pitfall. Kaempferol was reported to inhibit DC function. Here, we found that kaempferol delayed islet allograft rejection. Combination of kaempferol and low-dose, but not high-dose, of cyclosporine induced allograft tolerance in majority of recipient mice. Although kaempferol plus either dose of cyclosporine largely abrogated proliferation of graft-infiltrating T cells and their CTL activity, both proliferation and CTL activity in mice treated with kaempferol plus low-dose, but not high-dose, cyclosporine reemerged rapidly upon treatment withdrawal. Kaempferol increased CD4+FoxP3+ Tregs both in transplanted mice and in vitro, likely by suppressing DC maturation and their IL-6 expression. Reduction in Tregs by low dose of cyclosporine was reversed by kaempferol. Kaempferol-induced Tregs exhibited both allospecific and non-allospecific suppression. Administering IL-6 abrogated allograft tolerance induced by kaempferol and cyclosporine via diminishing CD4+FoxP3+ Tregs. Thus, for the first time, we demonstrated that kaempferol promotes transplant tolerance in the presence of low dose of cyclosporine, which allows for sufficient Treg generation while minimizing side effects, resulting in much-needed synergy between kaempferol and cyclosporine. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

  18. Accelerators and alternative nuclear fuel management options

    International Nuclear Information System (INIS)

    Harms, A.A.

    1983-01-01

    The development of special accelerators suggests the po tential for new directions in nuclear energy systems evolution. Such directions point towards a more acceptable form of nuclear energy by reason of the consequent accessibility of enhanced fuel management choices. Essential and specifically directed research and development activity needs to be under taken in order to clarify and resolve a number of technical issues

  19. SWS2 visual pigment evolution as a test of historically contingent patterns of plumage color evolution in warblers.

    Science.gov (United States)

    Bloch, Natasha I; Morrow, James M; Chang, Belinda S W; Price, Trevor D

    2015-02-01

    Distantly related clades that occupy similar environments may differ due to the lasting imprint of their ancestors-historical contingency. The New World warblers (Parulidae) and Old World warblers (Phylloscopidae) are ecologically similar clades that differ strikingly in plumage coloration. We studied genetic and functional evolution of the short-wavelength-sensitive visual pigments (SWS2 and SWS1) to ask if altered color perception could contribute to the plumage color differences between clades. We show SWS2 is short-wavelength shifted in birds that occupy open environments, such as finches, compared to those in closed environments, including warblers. Phylogenetic reconstructions indicate New World warblers were derived from a finch-like form that colonized from the Old World 15-20 Ma. During this process, the SWS2 gene accumulated six substitutions in branches leading to New World warblers, inviting the hypothesis that passage through a finch-like ancestor resulted in SWS2 evolution. In fact, we show spectral tuning remained similar across warblers as well as the finch ancestor. Results reject the hypothesis of historical contingency based on opsin spectral tuning, but point to evolution of other aspects of visual pigment function. Using the approach outlined here, historical contingency becomes a generally testable theory in systems where genotype and phenotype can be connected. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  20. Calculation of accelerating electric fields in the CO2 injector

    International Nuclear Information System (INIS)

    Baron, E.

    1999-01-01

    The accelerating structure in the injecting cyclotron for O.A.E. can be divided, if one takes the inflector exit as departure point, into the following two regions: 1. the relatively complex central zone comprising three accelerating gaps which is flanked by vertical pillars destined to increase the transit time factor and, at the same time, to reduce the influence of electric field vertical components; 2. the so-called 'large radius' subsequent zone where the gaps are no longer radially delimited. To study the behavior of the individual trajectories in these fields, the equations of motion must be integrated step by step (for instance by Runge-Kutta method) what implies the knowledge of field (or at least of potential) in every point. This is the method for the calculation of potential contour maps which is presented here; the potentials are static, and a sinusoidal time variation is subsequently applied to perform dynamical calculations. The paper has the following sections: 1. Introduction; 2. Potential and large radius field components; 2.1. Calculation of median plane potential; 2.2. Calculation of the off-median-plane potential and field; 3. Potential in the central region; 4. Further Developments

  1. IL-12 and IL-23 modulate plasticity of FoxP3+ regulatory T cells in human Leprosy.

    Science.gov (United States)

    Tarique, Mohd; Saini, Chaman; Naqvi, Raza Ali; Khanna, Neena; Sharma, Alpana; Rao, D N

    2017-03-01

    Leprosy is a bacterial disease caused by M. leprae. Its clinical spectrum reflects the host's immune response to the M. leprae and provide an ideal model to investigate the host pathogen interaction and immunological dysregulation. Tregs are high in leprosy patients and responsible for immune suppression of the host by producing IL-10 and TGF-β cytokines. In leprosy, plasticity of Tregs remain unstudied. This is the first study describing the conversion of Tregs into Th1-like and Th17-like cells using in vitro cytokine therapy in leprosy patients. Peripheral blood mononuclear cells from leprosy patients were isolated and stimulated with M. leprae antigen (MLCwA), rIL-12 and rIL-23 for 48h. Expression of FoxP3 in CD4 + CD25 + Tregs, intracellular cytokines IFN-γ, TGF-β, IL-10 and IL-17 in Tregs cells were evaluated by flow cytometry (FACS) after stimulation. rIL-12 treatment increases the levels of pStat4 in Tregs and IFN-γ production. In the presence of rIL-23, pStat3 + and IL-17A + cells increase. rIL-12 and r-IL-23 treatment downregulated the FoxP3 expression, IL-10 and TGF-β production by Tregs and enhances the expression of co-stimulatory molecules (CD80, CD86). In conclusion rIL-12 converts Tregs into IFN-γ producing cells through STAT-4 signaling while rIL-23 converts Tregs into IL-17 producing cells through STAT-3 signaling in leprosy patients. This study may helpful to provide a new avenue to overcome the immunosuprression in leprosy patients using in vitro cytokine. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Stochastic particle acceleration by plasma waves in AGN jets

    International Nuclear Information System (INIS)

    Li, Hui; Colgate, S.A.; Miller, J.A.

    1997-01-01

    The free energy stored in the stressed magnetic fields in AGN jets could be dissipated via generating turbulent plasma waves. The authors review several key wave-particle resonant interactions and point out the importance of a broad wave spectrum. Under several idealized assumptions, they show that the transit-time damping process can accelerate electrons to TeV energies in an AGN jet environment, and present a preliminary calculation on the evolution of plasma wave, electron, and photon distributions. The authors especially emphasize several open questions on particle acceleration by waves, and argue that a plausible scenario is to energize electrons out of the thermal background via transit-time damping and further accelerate them by the parallel propagating right-handed waves

  3. A fast-starting mechanical fish that accelerates at 40 m s-2

    International Nuclear Information System (INIS)

    Conte, J; Modarres-Sadeghi, Y; Watts, M N; Hover, F S; Triantafyllou, M S

    2010-01-01

    We have built a simple mechanical system to emulate the fast-start performance of fish. The system consists of a thin metal beam covered by a urethane rubber, the fish body and an appropriately shaped tail. The body form of the mechanical fish was modeled after a pike species and selected because it is a widely-studied fast-start specialist. The mechanical fish was held in curvature and hung in water by two restraining lines, which were simultaneously released by a pneumatic cutting mechanism. The potential energy in the beam was transferred into the fluid, thereby accelerating the fish. We measured the resulting acceleration, and calculated the efficiency of propulsion for the mechanical fish model, defined as the ratio of the final kinetic energy of the fish and the initially stored potential energy in the body beam. We also ran a series of flow visualization tests to observe the resulting flow patterns. The maximum start-up acceleration was measured to be around 40 m s -2 , with the maximum final velocity around 1.2 m s -1 . The form of the measured acceleration signal as function of time is quite similar to that of type I fast-start motions studied by Harper and Blake (1991 J. Exp. Biol. 155 175-92). The hydrodynamic efficiency of the fish was found to be around 10%. Flow visualization of the mechanical fast-start wake was also analyzed, showing that the acceleration peaks are associated with the shedding of two vortex rings in near-lateral directions.

  4. Dosimetry measurements during the commissioning of the GJ-2 electron accelerator

    DEFF Research Database (Denmark)

    Chosdu, R.; Hilmy, N.; Tobing, R.

    1995-01-01

    The GJ-2 electron accelerator (made in China, Sanghai) was put into operation at the Centre for Application of Isotopes and Radiation in Jakarta, Indonesia. In the course of the commissioning of the machine its main technical parameters were measured under different operating conditions. The elec......The GJ-2 electron accelerator (made in China, Sanghai) was put into operation at the Centre for Application of Isotopes and Radiation in Jakarta, Indonesia. In the course of the commissioning of the machine its main technical parameters were measured under different operating conditions......, ethanol-chlorobenzene dosimeter solution and FWT-60 film dosimeters. The applicability of polystyrene calorimeters designed for low electron energies at Ris phi National Laboratory was also tested for nominal dose determination....

  5. Co-evolution of electric and telecommunications networks

    Energy Technology Data Exchange (ETDEWEB)

    Rivkin, S.R.

    1998-05-01

    There are potentially significant societal benefits in co-evolution between electricity and telecommunications in the areas of common infrastructure, accelerated deployment of distributed energy, tighter integration of information flow for energy management and distribution, and improved customer care. With due regard for natural processes that are more potent than any regulation and more real than any ideology, the gains from co-evolution would far outweigh the attenuated and speculative savings from restructuring of electricity that is too simplistic.

  6. Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Sarah L May

    Full Text Available Nfatc2 and Tob1 are intrinsic negative regulators of T cell activation. Nfatc2-deficient and Tob1-deficient T cells show reduced thresholds of activation; however, whether these factors have independent or overlapping roles in negative regulation of T cell responses has not been previously examined. Here, we show that Nfatc2 knockout (KO but not Tob1 KO mice have age-associated accumulation of persistently activated T cells in vivo and expansion of the CD44+ memory cell compartment and age-associated lymphocytic infiltrates in visceral organs, without significant changes in numbers of CD4+CD25+Foxp3+ regulatory T cells (Treg. In vitro, CD4+CD25- "conventional" T cells (Tconvs from both KO strains showed greater proliferation than wild type (WT Tconvs. However, while Tregs from Nfatc2 KO mice retained normal suppressive function, Tregs from Tob1 KOs had enhanced suppressive activity. Nfatc2 KO Tconvs expanded somewhat more rapidly than WT Tconvs under conditions of homeostatic proliferation, but their accelerated growth capacity was negated, at least acutely, in a lymphoreplete environment. Finally, Nfatc2 KO mice developed a previously uncharacterized increase in B-cell malignancies, which was not accelerated by the absence of Tob1. The data thus support the prevailing hypothesis that Nfatc2 and Tob1 are non-redundant regulators of lymphocyte homeostasis.

  7. Modelling the reflective thermal contribution to the acceleration of the Pioneer spacecraft

    International Nuclear Information System (INIS)

    Francisco, F.; Bertolami, O.; Gil, P.J.S.; Páramos, J.

    2012-01-01

    We present an improved method to compute the radiative momentum transfer in the Pioneer 10 and 11 spacecraft that takes into account both diffusive and specular reflection. The method allows for more reliable results regarding the thermal acceleration of the deep-space probes, confirming previous findings. A parametric analysis is performed in order to set upper and lower bounds for the thermal acceleration and its evolution with time.

  8. Modelling the reflective thermal contribution to the acceleration of the Pioneer spacecraft

    Energy Technology Data Exchange (ETDEWEB)

    Francisco, F., E-mail: frederico.francisco@ist.utl.pt [Instituto de Plasmas e Fusao Nuclear, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa (Portugal); Bertolami, O., E-mail: orfeu.bertolami@fc.up.pt [Departamento de Fisica e Astronomia, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto (Portugal); Instituto de Plasmas e Fusao Nuclear, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa (Portugal); Gil, P.J.S., E-mail: p.gil@dem.ist.utl.pt [Departamento de Engenharia Mecanica and IDMEC - Instituto de Engenharia Mecanica, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa (Portugal); Paramos, J., E-mail: paramos@ist.edu [Instituto de Plasmas e Fusao Nuclear, Instituto Superior Tecnico, Universidade Tecnica de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa (Portugal)

    2012-05-23

    We present an improved method to compute the radiative momentum transfer in the Pioneer 10 and 11 spacecraft that takes into account both diffusive and specular reflection. The method allows for more reliable results regarding the thermal acceleration of the deep-space probes, confirming previous findings. A parametric analysis is performed in order to set upper and lower bounds for the thermal acceleration and its evolution with time.

  9. Application of the UKP-2-1 accelerator of heavy ions in the field of nuclear and radiation physics. Chapter 2

    International Nuclear Information System (INIS)

    2003-01-01

    The UKP-2-1 accelerator is intended for research works conducting in the field of solid state physics, low energy nuclear physics, nuclear microanalysis, materials modification and others. The accelerator includes two autonomous beam transporting channels jointed by one accelerating potential. One of the channel is intended for hydrogen and inert gases' ions acceleration, obtained from duoplasmatron. The second one includes the source with cesium dispersion and it is intended for heavy ions acceleration. On the base of the accelerator the set of the analytical methods such as PIXE, RBS, NRA were developed allowing to study of samples element content, distribution of elements by depth, analysis of thin films thickness. The accelerator intensively using in the filed of inertial nuclear fusion and studies on Coulomb energy losses of plasma target fast protons. The experience of the accelerator in different environmental researches is gained as well. In particular of deuterium determination in the water samples by the nuclear reaction method and study of plutonium and uranium distribution in 'hot' particles by the proton-induced X-ray method are developed. Beginning of 1999 on the accelerator a new research activity trend related with nuclear physical analysis methods adaptation on charged particles beams for study of a biological objects has been developed. At present the accelerator hardware does not concedes to hardware of the best world laboratories

  10. Community petascale project for accelerator science and simulation: Advancing computational science for future accelerators and accelerator technologies

    International Nuclear Information System (INIS)

    Spentzouris, P.; Cary, J.; McInnes, L.C.; Mori, W.; Ng, C.; Ng, E.; Ryne, R.

    2008-01-01

    The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessary accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R and D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.

  11. Recent Progress in Power Refrigeration below 2 K for Superconducting Accelerators

    CERN Document Server

    Claudet, Serge

    2005-01-01

    As a result of technico-economical optimization and quest for increased performance, 2 K cryogenics is now present in large accelerator projects using superconducting magnets or acceleration cavities. Consequently, large cryogenic systems producing refrigeration capacity below 2 K in the kW range and with high efficiency over a large dynamic range are needed. After CEBAF and SNS, this is the case for the Large Hadron Collider (LHC) project at CERN for which eight 2.4 kW @ 1.8 K refrigeration units are needed to cool each a 3.3 km long sector of high-field magnets. Combining cold hydrodynamic compressors in series with warm volumetric compressors, complete pre-series units as well as sets of series cold compressors have been intensively tested and validated from two different industrial suppliers. After recalling the possible 2 K refrigeration cycles and their comparative merits, this paper describes the specific features of the LHC system and presents the achieved performance with emphasis on the progress in...

  12. Accurate modeling of the hose instability in plasma wakefield accelerators

    Science.gov (United States)

    Mehrling, T. J.; Benedetti, C.; Schroeder, C. B.; Martinez de la Ossa, A.; Osterhoff, J.; Esarey, E.; Leemans, W. P.

    2018-05-01

    Hosing is a major challenge for the applicability of plasma wakefield accelerators and its modeling is therefore of fundamental importance to facilitate future stable and compact plasma-based particle accelerators. In this contribution, we present a new model for the evolution of the plasma centroid, which enables the accurate investigation of the hose instability in the nonlinear blowout regime. It paves the road for more precise and comprehensive studies of hosing, e.g., with drive and witness beams, which were not possible with previous models.

  13. Focusing of geodesic congruences in an accelerated expanding Universe

    International Nuclear Information System (INIS)

    Albareti, F.D.; Cembranos, J.A.R.; Cruz-Dombriz, A. de la

    2012-01-01

    We study the accelerated expansion of the Universe through its consequences on a congruence of geodesics. We make use of the Raychaudhuri equation which describes the evolution of the expansion rate for a congruence of timelike or null geodesics. In particular, we focus on the space-time geometry contribution to this equation. By straightforward calculation from the metric of a Robertson-Walker cosmological model, it follows that in an accelerated expanding Universe the space-time contribution to the Raychaudhuri equation is positive for the fundamental congruence, favoring a non-focusing of the congruence of geodesics. However, the accelerated expansion of the present Universe does not imply a tendency of the fundamental congruence to diverge. It is shown that this is in fact the case for certain congruences of timelike geodesics without vorticity. Therefore, the focusing of geodesics remains feasible in an accelerated expanding Universe. Furthermore, a negative contribution to the Raychaudhuri equation from space-time geometry which is usually interpreted as the manifestation of the attractive character of gravity is restored in an accelerated expanding Robertson-Walker space-time at high speeds

  14. Focusing of geodesic congruences in an accelerated expanding Universe

    Energy Technology Data Exchange (ETDEWEB)

    Albareti, F.D.; Cembranos, J.A.R. [Departamento de Física Teórica I, Universidad Complutense de Madrid, Ciudad Universitaria, E-28040 Madrid (Spain); Cruz-Dombriz, A. de la, E-mail: fdalbareti@estumail.ucm.es, E-mail: cembra@fis.ucm.es, E-mail: alvaro.delacruz-dombriz@uct.ac.za [Astrophysics, Cosmology and Gravity Centre (ACGC), University of Cape Town, 7701 Rondebosch, Cape Town (South Africa)

    2012-12-01

    We study the accelerated expansion of the Universe through its consequences on a congruence of geodesics. We make use of the Raychaudhuri equation which describes the evolution of the expansion rate for a congruence of timelike or null geodesics. In particular, we focus on the space-time geometry contribution to this equation. By straightforward calculation from the metric of a Robertson-Walker cosmological model, it follows that in an accelerated expanding Universe the space-time contribution to the Raychaudhuri equation is positive for the fundamental congruence, favoring a non-focusing of the congruence of geodesics. However, the accelerated expansion of the present Universe does not imply a tendency of the fundamental congruence to diverge. It is shown that this is in fact the case for certain congruences of timelike geodesics without vorticity. Therefore, the focusing of geodesics remains feasible in an accelerated expanding Universe. Furthermore, a negative contribution to the Raychaudhuri equation from space-time geometry which is usually interpreted as the manifestation of the attractive character of gravity is restored in an accelerated expanding Robertson-Walker space-time at high speeds.

  15. Capped CuInS2 quantum dots for H2 evolution from water under visible light illumination

    International Nuclear Information System (INIS)

    Li, Tzung-Luen; Cai, Cheng-Da; Yeh, Te-Fu; Teng, Hsisheng

    2013-01-01

    Highlights: ► Dispersed CuInS 2 quantum dots showed remarkable photosynthetic activity using visible light. ► Photogenerated electrons in CuInS 2 were effective in H 2 production from aqueous solution. ► The bifunctional capping reagent effectively transported photogenerated electrons for reaction. ► Ru-loaded CuInS 2 quantum dots showed a quantum efficiency of 4.7% in H 2 evolution. ► Attaching CuInS 2 to TiO 2 with CdS passivation achieved a quantum efficiency of 41%. - Abstract: This study demonstrates H 2 evolution from water decomposition catalyzed by capped CuInS 2 quantum dots (QDs) that are highly dispersed in a polysulfide aqueous solution. The CuInS 2 QDs, which are obtained from solvothermal synthesis, have a size of 4.3 nm and a band gap of 1.97 eV. For photosynthetic H 2 evolution in the aqueous solution, the QDs are capped with a multidentate ligand (3-mercaptopropionic acid), which has a thiol end for attaching the QDs and a hydrophilic carboxylic end for dispersion in water. The capped QDs exhibit low activity in catalyzing H 2 evolution under visible illumination. After photodepositing 0.5 wt.% Ru, the capped QDs are active in producing H 2 with illumination. This demonstrates that the photogenerated electrons travel through the capping reagent to generate deposited Ru, which subsequently serves as an electron trap for H 2 evolution. A heterostructure formed by attaching the capped QDs on TiO 2 nanoparticles, followed by coating CdS with photodeposition, exhibits a high quantum efficiency of 41% for H 2 evolution from the polysulfide solution. These results demonstrate the potential for photosynthesis and phototherapy in biologic in vivo or microfluidic systems based on this capped QD material.

  16. Investigation of UO2 as an accelerator for quantitative extraction of F- and Cl- in ThO2 and sintered ThO2

    International Nuclear Information System (INIS)

    Pandey, Ashish; Fulzele, Ajit; Das, D.K.; Prakash, Amrit; Behere, P.G.; Afzal, Mohd

    2013-01-01

    This paper presents UO 2 as an effective accelerator for the quantitative extraction of F - and Cl - from ThO 2 and sintered ThO 2 . Thoria requires higher temperature to loose its structural integrity to release halides. Sample composed of UO 2 and ThO 2 or UO 2 and sintered ThO 2 gives quantitative yield of F - and Cl - even at lower temperature. Accelerator amount and pyrohydrolysis conditions were optimized. The pyrohydrolyzate was analyzed for F - and Cl - by ISE. The limit of detection was 1 μg/g in the samples with good recovery (95%) and relative standard deviation less than 5%. (author)

  17. Heavy ions acceleration in RF wells of 2-frequency electromagnetic field and in the inverted FEL

    International Nuclear Information System (INIS)

    Dzergach, A.I.; Kabanov, V.S.; Nikulin, M.G.; Vinogradov, S.V.

    1995-03-01

    Last results of the study of heavy ions acceleration by electrons trapped in moving 2-frequency 3-D RF wells are described. A linearized theoretical model of ions acceleration in a polarized spheroidal plasmoid is proposed. The equilibrium state of this plasmoid is described by the modified microcanonical distribution of the Courant-Snyder invariant (open-quotes quasienergyclose quotes of electrons). Some new results of computational simulation of the acceleration process are given. The method of computation takes into account the given cylindrical field E 011 (var-phi,r,z) and the self fields of electrons and ions. The results of the computation at relatively short time intervals confirm the idea and estimated parameters of acceleration. The heavy ion accelerator using this principle may be constructed with the use of compact cm band iris-loaded and biperiodical waveguides with double-sided 2-frequency RF feeding. It can accelerate heavy ions with a charge number Z i from small initial energies ∼ 50 keV/a.u. with the rate ∼ Z i · 10 MeV/m. Semirelativistic ions may be accelerated with similar rate also in the inverted FEL

  18. Dealing with post-accelerated electrons in the ITER SINGAP accelerator

    International Nuclear Information System (INIS)

    Esch, H. de; Hemsworth, R.S.

    2006-01-01

    Electrons formed by stripping of the negative deuterium beam can be accelerated up to 960 keV in the 1 MeV SINGAP 40 A negative ion accelerator proposed by Europe for the ITER neutral beam injectors. SINGAP accelerates 1280 pre-accelerated 40 keV deuterium beamlets to 1 MeV in a single 350 mm wide gap. At the expected gas pressure of 0.03 Pa inside the accelerator, 2.7 MW of electrons are calculated to leave the accelerator and strike various beamline components, especially the neutraliser. The accelerators of the ITER injectors are designed to produce 4 '' column '' beams which pass through the 4 vertical channels of the neutraliser. Unperturbed the accelerated electrons create small, high power density, 3.3 kW/cm 2 , spots on the leading edges of the neutraliser channels, which is far in excess of their power handling capability. The hot spots arise from the overlapping of beamlets due to the bending induced by the far field of the magnetic filter in the ion source. The proposed solution bends the electrons further downwards, redistributing the power over the neutraliser floor, a vertical electron dump perpendicular to the beam axis located below the neutraliser entrance, and the neutraliser entrance. The bending is to be effected by a magnetic field transverse to the beam direction at the exit of the post-acceleration grid. This field is created by vertical columns of permanent magnets either side of each column beam. After passing between the magnet columns, the electron beams reach the electron dump with a maximum power density of 2.1 kW/cm 2 . The peak power density on the neutraliser entrance is 1.35 kW/cm 2 and on the neutraliser floor 0.82 kW/cm 2 . Electron backscattering would reduce all the numbers by 20%. To further reduce the average power density seen by the beamline components it is proposed to sweep the electron beam in an oscillatory fashion. It is suggested that a failsafe, inexpensive, way is to use a power supply with a ripple of ± 10% to

  19. Illinois Accelerator Research Center

    Science.gov (United States)

    Kroc, Thomas K.; Cooper, Charlie A.

    The Illinois Accelerator Research Center (IARC) hosts a new accelerator development program at Fermi National Accelerator Laboratory. IARC provides access to Fermi's state-of-the-art facilities and technologies for research, development and industrialization of particle accelerator technology. In addition to facilitating access to available existing Fermi infrastructure, the IARC Campus has a dedicated 36,000 ft2 Heavy Assembly Building (HAB) with all the infrastructure needed to develop, commission and operate new accelerators. Connected to the HAB is a 47,000 ft2 Office, Technology and Engineering (OTE) building, paid for by the state, that has office, meeting, and light technical space. The OTE building, which contains the Accelerator Physics Center, and nearby Accelerator and Technical divisions provide IARC collaborators with unique access to world class expertise in a wide array of accelerator technologies. At IARC scientists and engineers from Fermilab and academia work side by side with industrial partners to develop breakthroughs in accelerator science and translate them into applications for the nation's health, wealth and security.

  20. An introduction to acceleration mechanisms

    International Nuclear Information System (INIS)

    Palmer, R.B.

    1987-05-01

    This paper discusses the acceleration of charged particles by electromagnetic fields, i.e., by fields that are produced by the motion of other charged particles driven by some power source. The mechanisms that are discussed include: Ponderamotive Forces, Acceleration, Plasma Beat Wave Acceleration, Inverse Free Electron Laser Acceleration, Inverse Cerenkov Acceleration, Gravity Acceleration, 2D Linac Acceleration and Conventional Iris Loaded Linac Structure Acceleration

  1. Heavy ion accelerators

    International Nuclear Information System (INIS)

    Schmelzer, C.

    1974-01-01

    This review of the present state of work on heavy-ion accelerators pays particular attention to the requirements for nuclear research. It is divided into the following sections: single-particle versus collective acceleration, heavy-ion accelerators, beam quality, and a status report on the UNILAC facility. Among the topics considered are the recycling cyclotron, linacs with superconducting resonators, and acceleration to the GeV/nucleon range. (8 figures, 2 tables) (U.S.)

  2. CD4+CD25hiFOXP3+ cells in cord blood of neonates born from filaria infected mother are negatively associated with CD4+Tbet+ and CD4+RORγt+ T cells.

    Science.gov (United States)

    Ateba-Ngoa, Ulysse; Mombo-Ngoma, Ghyslain; Zettlmeissl, Eva; van der Vlugt, Luciën E P M; de Jong, Sanne E; de Jong, Sanne; Matsiegui, Pierre-Blaise; Ramharter, Michael; Kremsner, Peter G; Yazdanbakhsh, Maria; Adegnika, Ayola Akim

    2014-01-01

    Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses. Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3. No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively). Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.

  3. Auroral ion acceleration from lower hybrid solitary structures: A summary of sounding rocket observations

    Science.gov (United States)

    Lynch, K. A.; Arnoldy, R. L.; Kintner, P. M.; Schuck, P.; Bonnell, J. W.; Coffey, V.

    In this paper we present a review of sounding rocket observations of the ion acceleration seen in nightside auroral zone lower hybrid solitary structures. Observations from Topaz3, Amicist, and Phaze2 are presented on various spatial scales, including the two-point measurements of the Amicist mission. From this collection of observations we will demonstrate the following characteristics of transverse acceleration of ions (TAI) in lower hybrid solitary structures (LHSS). The ion acceleration process is narrowly confined to 90° pitch angle, in spatially confined regions of up to a few hundred meters across B. The acceleration process does not affect the thermal core of the ambient distribution and does not directly create a measurable effect on the ambient ion population outside the LHSS themselves. This precludes observation with these data of any nonlinear feedback between the ion acceleration and the existence or evolution of the density irregularities on which these LHSS events grow. Within the LHSS region the acceleration process creates a high-energy tail beginning at a few times the thermal ion speed. The ion acceleration events are closely associated with localized wave events. Accelerated ions bursts are also seen without a concurrent observation of a localized wave event, for two possible reasons. In some cases, the pitch angles of the accelerated tail ions are elevated above perpendicular; that is, the acceleration occurred below the observer and the mirror force has begun to act upon the distribution, moving it upward from the source. In other cases, the accelerated ion structure is spatially larger than the wave event structure, and the observation catches only the ion event. The occurrence rate of these ion acceleration events is related to the ambient environment in two ways: its altitude dependence can be modeled with the parameter B2/ne, and it is highest in regions of intense VLF activity. The cumulative ion outflow from these LHSS TAI is

  4. Channel-accelerating gap interaction and beam acceleration and transport experiments with the recirculating linear accelerator (RLA)

    International Nuclear Information System (INIS)

    Mazarakis, M.G.; Smith, D.L.; Poukey, J.W.; Wagner, J.S.; Bennett, L.F.; Olson, W.R.; Turman, B.N.; Prestwich, K.R.; Wells, J.; Struve, K.

    1992-01-01

    The lifetime of the Ion Focusing Regime (IFR) channel following the pulsing of the post-accelerating gaps is critical for open-ended low energy devices. It dictates the number of allowable beam recirculations through the gaps. In the case of a closed racetrack configuration, it is significant but not as critical, since the presence of the electron beam focuses the ions and lengthens the lifetime of the ion channel. The authors have experimentally established that pulsing an accelerating gap perturbs the IFR channel. However for the parameters studied, the lifetime is long enough to allow at least four beam recirculations in a spiral device. In addition transparent grids of cusp fields positioned upstream and downstream from the gaps prevent them from perturbing the IFR channel. Experiments were performed with and without injected electron beams. For the experiments investigating the IFR channel interaction with the accelerating gap, the injector was removed and the beam line was extended downstream and upstream from the accelerating cavity. Only the first straight section of the RLA with one accelerating cavity (ET-2) was utilized. The acceleration and transport experiments were performed utilizing two injectors: first the low energy 1.3-MV Isolated Blumlein (IB) injector and most recently the new 4-MV 20-kA injector. Beams of 6--20 kA current were produced and successfully transported and accelerated through the ET-2 post-accelerating gap. For both injectors an apertured non-immersed ion-focused foilless diode was selected among various options. It is the simplest and easiest to operate and can be adjusted to provide variable beam impedance loads to the injector. The transport efficiencies were 90% for the low energy injector and 100% for the new 4-MV injector. The beam Gaussian profile and radius (5 mm) remain the same through acceleration. Experimental results will be presented and compared with numerical simulations

  5. Accelerated Optimization in the PDE Framework: Formulations for the Manifold of Diffeomorphisms

    KAUST Repository

    Sundaramoorthi, Ganesh

    2018-04-04

    We consider the problem of optimization of cost functionals on the infinite-dimensional manifold of diffeomorphisms. We present a new class of optimization methods, valid for any optimization problem setup on the space of diffeomorphisms by generalizing Nesterov accelerated optimization to the manifold of diffeomorphisms. While our framework is general for infinite dimensional manifolds, we specifically treat the case of diffeomorphisms, motivated by optical flow problems in computer vision. This is accomplished by building on a recent variational approach to a general class of accelerated optimization methods by Wibisono, Wilson and Jordan, which applies in finite dimensions. We generalize that approach to infinite dimensional manifolds. We derive the surprisingly simple continuum evolution equations, which are partial differential equations, for accelerated gradient descent, and relate it to simple mechanical principles from fluid mechanics. Our approach has natural connections to the optimal mass transport problem. This is because one can think of our approach as an evolution of an infinite number of particles endowed with mass (represented with a mass density) that moves in an energy landscape. The mass evolves with the optimization variable, and endows the particles with dynamics. This is different than the finite dimensional case where only a single particle moves and hence the dynamics does not depend on the mass. We derive the theory, compute the PDEs for accelerated optimization, and illustrate the behavior of these new accelerated optimization schemes.

  6. Accelerated Optimization in the PDE Framework: Formulations for the Manifold of Diffeomorphisms

    KAUST Repository

    Sundaramoorthi, Ganesh; Yezzi, Anthony

    2018-01-01

    We consider the problem of optimization of cost functionals on the infinite-dimensional manifold of diffeomorphisms. We present a new class of optimization methods, valid for any optimization problem setup on the space of diffeomorphisms by generalizing Nesterov accelerated optimization to the manifold of diffeomorphisms. While our framework is general for infinite dimensional manifolds, we specifically treat the case of diffeomorphisms, motivated by optical flow problems in computer vision. This is accomplished by building on a recent variational approach to a general class of accelerated optimization methods by Wibisono, Wilson and Jordan, which applies in finite dimensions. We generalize that approach to infinite dimensional manifolds. We derive the surprisingly simple continuum evolution equations, which are partial differential equations, for accelerated gradient descent, and relate it to simple mechanical principles from fluid mechanics. Our approach has natural connections to the optimal mass transport problem. This is because one can think of our approach as an evolution of an infinite number of particles endowed with mass (represented with a mass density) that moves in an energy landscape. The mass evolves with the optimization variable, and endows the particles with dynamics. This is different than the finite dimensional case where only a single particle moves and hence the dynamics does not depend on the mass. We derive the theory, compute the PDEs for accelerated optimization, and illustrate the behavior of these new accelerated optimization schemes.

  7. Strong ion accelerating by collisionless magnetosonic shock wave propagating perpendicular to a magnetic field

    International Nuclear Information System (INIS)

    Ohsawa, Yukiharu.

    1984-12-01

    A 2-1/2 dimensional fully relativistic, fully electromagnetic particle code is used to study a time evolution of nonlinear magnetosonic pulse propagating in the direction perpendicular to a magnetic field. The pulse is excited by an instantaneous piston acceleration, and evolves totally self-consistently. Large amplitude pulse traps some ions and accelerates them parallel to the wave front. They are detrapped when their velocities become of the order of the sum of the ExB drift velocity and the wave phase velocity, where E is the electric field in the direction of wave propagation. The pulse develops into a quasi-shock wave in a collisionless plasma by a dissipation due to the resonant ion acceleration. Simple nonlinear wave theory for a cold plasma well describes the shock properties observed in the simulation except for the effects of resonant ions. In particular, magnitude of an electric potential across the shock region is derived analytically and is found to be in good agreement with our simulations. The potential jump is proportional to B 2 , and hence the ExB drift velocity of the trapped ions is proportional to B. (author)

  8. 3D electromagnetic simulation of spatial autoresonance acceleration of electron beams

    International Nuclear Information System (INIS)

    Dugar-Zhabon, V D; Orozco, E A; González, J D

    2016-01-01

    The results of full electromagnetic simulations of the electron beam acceleration by a TE 112 linear polarized electromagnetic field through Space Autoresonance Acceleration mechanism are presented. In the simulations, both the self-sustaned electric field and selfsustained magnetic field produced by the beam electrons are included into the elaborated 3D Particle in Cell code. In this system, the space profile of the magnetostatic field maintains the electron beams in the acceleration regime along their trajectories. The beam current density evolution is calculated applying the charge conservation method. The full magnetic field in the superparticle positions is found by employing the trilinear interpolation of the mesh node data. The relativistic Newton-Lorentz equation presented in the centered finite difference form is solved using the Boris algorithm that provides visualization of the beam electrons pathway and energy evolution. A comparison between the data obtained from the full electromagnetic simulations and the results derived from the motion equation depicted in an electrostatic approximation is carried out. It is found that the self-sustained magnetic field is a factor which improves the resonance phase conditions and reduces the beam energy spread. (paper)

  9. Deletion of Fanca or Fancd2 dysregulates Treg in mice

    Science.gov (United States)

    Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

    2014-01-01

    Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

  10. Deletion of Fanca or Fancd2 dysregulates Treg in mice.

    Science.gov (United States)

    Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C; Steinbrecher, Kris A; Davies, Stella M; Pang, Qishen

    2014-03-20

    Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.

  11. Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells

    International Nuclear Information System (INIS)

    Wirsdörfer, Florian; Cappuccini, Federica; Niazman, Muska; Leve, Simone de; Westendorf, Astrid M; Lüdemann, Lutz; Stuschke, Martin; Jendrossek, Verena

    2014-01-01

    Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease

  12. Accelerators and Dinosaurs

    CERN Multimedia

    Turner, Michael Stanley

    2003-01-01

    Using naturally occuring particles on which to research might have made accelerators become extinct. But in fact, results from astrophysics have made accelerator physics even more important. Not only are accelerators used in hospitals but they are also being used to understand nature's inner workings by searching for Higgs bosons, CP violation, neutrino mass and dark matter (2 pages)

  13. TRF2 and the evolution of the bilateria.

    Science.gov (United States)

    Duttke, Sascha H C; Doolittle, Russell F; Wang, Yuan-Liang; Kadonaga, James T

    2014-10-01

    The development of a complex body plan requires a diversity of regulatory networks. Here we consider the concept of TATA-box-binding protein (TBP) family proteins as "system factors" that each supports a distinct set of transcriptional programs. For instance, TBP activates TATA-box-dependent core promoters, whereas TBP-related factor 2 (TRF2) activates TATA-less core promoters that are dependent on a TCT or downstream core promoter element (DPE) motif. These findings led us to investigate the evolution of TRF2. TBP occurs in Archaea and eukaryotes, but TRF2 evolved prior to the emergence of the bilateria and subsequent to the evolutionary split between bilaterians and nonbilaterian animals. Unlike TBP, TRF2 does not bind to the TATA box and could thus function as a new system factor that is largely independent of TBP. We postulate that this TRF2-based system served as the foundation for new transcriptional programs, such as those involved in triploblasty and body plan development, that facilitated the evolution of bilateria. © 2014 Duttke et al.; Published by Cold Spring Harbor Laboratory Press.

  14. Evolution of the solar wind acceleration region during 1990-1994

    International Nuclear Information System (INIS)

    Tokumaru, Munetoshi; Kondo, Tetsuro; Takaba, Hiroshi; Mori, Hirotaka; Tanaka, Takashi

    1996-01-01

    The single-station measurements of interplanetary scintillation (IPS) at 2GHz and 8GHz using the Kashima radio telescope are used to study the distribution of the solar wind velocity and density fluctuations near the sun. Wind velocities derived from our IPS data with the IPS co-spectrum method show a radial increase in the distance range between 10 and 30 Rs (solar radii). From the scintillation index analysis, it is found that the radial fall of density fluctuations in the solar wind is described by the power-law function. A series of Kashima IPS observations reveals that a pronounced change in velocity and turbulence level occurs at the polar region of the sun during 1990-1994. That is, the high-speed wind and the reduced-turbulence region develop there as the solar activity declines. This fact is consistent with the long-term evolution of the coronal magnetic structure inferred from He1083nm observations

  15. Small-sized accelerating tube for electron acceleration to 500 keV at pulse duration of 2 ns

    International Nuclear Information System (INIS)

    Pavlovskaya, N.G.; Ehl'yash, S.L.; Dron', N.A.; Sloeva, G.N.

    1978-01-01

    The design and characteristics (current, voltage, current density, electron beam structure, energy spectrum, and dose rate) of a soldered small-size two-electrode 600 kV accelerating tube are considered. A six-stage Arkadiev-Marx generator is the pulse high-voltage supply of nanosecond duration. When using a cathode (diameter of 8 mm) made of tantalum foil 0.02 mm thick and with interelectrode gap of 10 mm, the amplitude of the electron beam current beyond the beryllium anode equals to 1040 A under maximum voltage of 490 kV, current pulse duration of 2 ns, number of electrons is 10 13 . The increased electron density on the anode in a spot of 4 mm in diameter is observed; the current density in the spot reaches 1 kA/cm 2 . The electron energy in the beam beyond the anode is as much as 0.6-0.8 J per pulse, and the dose rate near the outer surface of the outlet window is 10 14 -10 15 rad/s. The use of an intensifying oil spark gap is shown to increase radiation hardness. The accelerating tube provides more than 10 5 shots in a single-switching mode

  16. Activation of aryl hydrocarbon receptor (AhR leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis.

    Directory of Open Access Journals (Sweden)

    Narendra P Singh

    Full Text Available Aryl hydrocarbon receptor (AhR, a transcription factor of the bHLH/PAS family, is well characterized to regulate the biochemical and toxic effects of environmental chemicals. More recently, AhR activation has been shown to regulate the differentiation of Foxp3(+ Tregs as well as Th17 cells. However, the precise mechanisms are unclear. In the current study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AhR ligand, on epigenetic regulation leading to altered Treg/Th17 differentiation, and consequent suppression of colitis.Dextran sodium sulphate (DSS administration induced acute colitis in C57BL/6 mice, as shown by significant weight loss, shortening of colon, mucosal ulceration, and increased presence of CXCR3(+ T cells as well as inflammatory cytokines. Interestingly, a single dose of TCDD (25 µg/kg body weight was able to attenuate all of the clinical and inflammatory markers of colitis. Analysis of T cells in the lamina propria (LP and mesenteric lymph nodes (MLN, during colitis, revealed decreased presence of Tregs and increased induction of Th17 cells, which was reversed following TCDD treatment. Activation of T cells from AhR(+/+ but not AhR (-/- mice, in the presence of TCDD, promoted increased differentiation of Tregs while inhibiting Th17 cells. Analysis of MLN or LP cells during colitis revealed increased methylation of CpG islands of Foxp3 and demethylation of IL-17 promoters, which was reversed following TCDD treatment.These studies demonstrate for the first time that AhR activation promotes epigenetic regulation thereby influencing reciprocal differentiation of Tregs and Th17 cells, and amelioration of inflammation.

  17. Results from recent hydrogen pellet acceleration studies with a 2-m railgun

    International Nuclear Information System (INIS)

    Kim, K.; Zhang, D.J.; King, T.; Haywood, R.; Manns, W.; Venneri, F.

    1989-12-01

    A new 3.2-mm-diameter, two-stage, fuseless, plasma-arc-driven electromagnetic railgun has been designed, constructed, and successfully operated to achieve a record velocity of 2.67 km/s( b ) for 3.2 mmD x 4 mmL solid hydrogen pellet. The first stage of this hydrogen pellet injector is a combination of a hydrogen pellet generator and a gas fun. The second stage is a 2-m-long railgun which serves as a booster accelerator. The gas fun accelerates a frozen hydrogen pellet to a medium velocity and injects it into the railgun through a perforated coupling piece, which also serves a pressure-relieving mechanism. An electrical breakdown of the propellant gas, which has followed the pellet from the gas fun into the railgun, forms a conducting plasma-arc armature immediately behind the pellet allowing for fuseless operation of the railgun. Study of the pressure profile and the behavior of the plasma-arc armature inside the railgun bore led to elimination of spurious arcing, which prevents operation of the railgun at high voltages (and, therefore, at high currents). A timing circuit that can automatically measure the pellet input velocity and allows for accurate control of arc initiation behind the pellet helps prevent pellet disintegration and mistriggering of the arc initiation circuit. Results from the recent cryogenic operation of the two-stage pellet acceleration system are reported. 11 refs., 2 figs., 1 tab

  18. Design and simulation of a 1.2MeV electron accelerator used for desulfuration and denitrogenation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, J.; Zhu, D.J.; Liu, S.G.; Wang, H.B.; Xu, Z.; Liu, X.S. [University of Electrical Science & Technology of China, Chengdu (China)

    2005-07-01

    This paper presents the structural design and functional analysis of a new kind of 1.2MeV industrial electron accelerator. PIC (Particle-In-Cell) method is used to simulate this accelerator and to optimize the design. The results show that the optics property of this accelerator has been improved. This electron accelerator is used for desulfurisation and denitrification in environmental industry. This application purifies flue gases of the thermal power stations from sulphur oxide and nitrogen oxides in order to reduce air pollution.

  19. miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

    Directory of Open Access Journals (Sweden)

    William Becker

    2018-04-01

    Full Text Available The promise of inducing immunological tolerance through regulatory T cell (Treg control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4+ T cells in the draining lymph node (dLN of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC after allogeneic transplantation, in CD4+ T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p, targeting transforming growth factor beta 2 (TGF-β2, as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4+ T cells led to a decreased inducible FoxP3+ Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.

  20. GARP (LRRC32) is essential for the surface expression of latent TGF-β on platelets and activated FOXP3+ regulatory T cells

    OpenAIRE

    Tran, Dat Q.; Andersson, John; Wang, Rui; Ramsey, Heather; Unutmaz, Derya; Shevach, Ethan M.

    2009-01-01

    TGF-β family members are highly pleiotropic cytokines with diverse regulatory functions. TGF-β is normally found in the latent form associated with latency-associated peptide (LAP). This latent complex can associate with latent TGFβ-binding protein (LTBP) to produce a large latent form. Latent TGF-β is also found on the surface of activated FOXP3+ regulatory T cells (Tregs), but it is unclear how it is anchored to the cell membrane. We show that GARP or LRRC32, a leucine-rich repeat molecule ...

  1. The parental antagonism theory of language evolution: preliminary evidence for the proposal.

    Science.gov (United States)

    Brown, William M

    2011-04-01

    Language--as with most communication systems--likely evolved by means of natural selection. Accounts for the genetical selection of language can usually be divided into two scenarios, either of which used in isolation of the other appear insufficient to explain the phenomena: (1) there are group benefits from communicating, and (2) there are individual benefits from being a better communicator. In contrast, it is hypothesized that language phenotypes emerged during a coevolutionary struggle between parental genomes via genomic imprinting, which is differential gene expression depending on parental origin of the genetic element. It is hypothesized that relatedness asymmetries differentially selected for patrigene-caused language phenotypes to extract resources from mother (early in development) and matrigene-caused language phenotypes to influence degree of cooperativeness among asymmetric kin (later in development). This paper reports that imprinted genes have a high frequency of involvement in language phenotypes (~36%), considering their presumed rarity in the human genome (~2%). For example, two well-studied genes associated with language impairments (FOXP2 and UBE3A) exhibit parent-of- origin effects. Specifically, FOXP2 is putatively paternally expressed, whereas UBE3A is a maternally expressed imprinted gene. It is also hypothesized that the more unique and cooperative aspects of human language emerged to the benefit of matrilineal inclusive fitness. Consistent with this perspective, it is reported here that the X-chromosome has higher involvement in loci that have associations with language than would be expected by chance. It is also reported, for the first time, that human and chimpanzee maternally expressed overlapping imprinted genes exhibit greater evolutionary divergence (in terms of the degree of overlapping transcripts) than paternally expressed overlapping imprinted genes. Finally, an analysis of global language patterns reveals that paternally but

  2. Design of MgB2 superconducting dipole magnet for particle beam transport in accelerators

    DEFF Research Database (Denmark)

    Abrahamsen, A.B.; Zangenberg, N.; Baurichter, A.

    2006-01-01

    for the collaborating company Danfysik A/S, which has a strongtradition in building resistive magnets for particle accelerators[4]. A technology transfer project was formulated at the end of 2005 with the purpose to collect the knowledge about the MgB2 superconductor gained in the STVF program and in the European...... in a dipole magnet for guiding particle beams in a small scale accelerator is examined with the purpose to build lighter and smaller than the present resistive magnets. Here the criticalcurrent density of primarily MgB2 will be compared with current density determined by specifications similar to the Tevatron...... accelerator, B = 4:4 Tesla and coil aperture D = 76 mm [6], which has been identified by Danfysik A/S as interesting. It isconcluded that MgB2 is useful for the dipole application and construction of a small test coil of one half of the magnet is planned in 2007....

  3. TiO2 promoted by two different non-noble metal cocatalysts for enhanced photocatalytic H2 evolution

    International Nuclear Information System (INIS)

    Lin, Jing-Dong; Yan, Shi; Huang, Qin-Dong; Fan, Mei-Ting; Yuan, You-Zhu; Tan, Timothy Thatt-Yang; Liao, Dai-Wei

    2014-01-01

    TiO 2 photocatalysts modified by cobalt and nickel cocatalysts were prepared via polymerized complex method (PCM) and evaluated by photocatalytic hydrogen evolution. Hydrogen generation in 6 h for the TiO 2 promoted by cobalt and nickel (0.1%Co + 0.2%Ni/TiO 2 ) is about two times (2456 μmol H 2 ) compared to that of TiO 2 promoted only by cobalt (1180 μmol H 2 for 0.1%Co/TiO 2 ) or nickel (1127 μmol H 2 for 0.2%Ni/TiO 2 ), and mechanically mixed TiO 2 promoted by cobalt and TiO 2 promoted by nickel (0.1%Co/TiO 2 :0.2%Ni/TiO 2 = 1:1 (m/m), 1282 μmol H 2 ). The high photocatalytic H 2 evolution activity over TiO 2 promoted by cobalt and nickel is ascribed to enhanced photo response due to the presence of cobalt and nickel impurity level, and effective separation of photogenerated electrons and holes due to the synergistic effect of cobalt and nickel, which serve as active sites for H 2 evolution reaction (HER) and oxidation reaction (OR) respectively. This study demonstrates a viable strategy to design more active photocatalysts for photocatalytic H 2 evolution by substituting noble metals with more abundant elements using as HER and OR cocatalysts, respectively.

  4. Design and simulation of a 1.2 MeV electron accelerator used for desulfuration and denitrogenation

    International Nuclear Information System (INIS)

    Zhou Jun; Zhu Dajun; Liu Shenggang

    2005-01-01

    This paper presents the structural design and functional analysis of a new kind of 1.2 MeV industrial electron accelerator. PIC (Particle-In-Cell) method is used to simulate this accelerator and to optimize the design, the results show that the optics property of this accelerator has been improved. This electron accelerator is used for desulfuration and denitrogenation in environmental industry. This application purifies flue gases of the thermal power station from Sulphurous oxide and Nitrogen oxide in order to reduce the pollution in the air. (author)

  5. Insights into hominid evolution from the gorilla genome sequence

    Science.gov (United States)

    Scally, Aylwyn; Dutheil, Julien Y.; Hillier, LaDeana W.; Jordan, Greg E.; Goodhead, Ian; Herrero, Javier; Hobolth, Asger; Lappalainen, Tuuli; Mailund, Thomas; Marques-Bonet, Tomas; McCarthy, Shane; Montgomery, Stephen H.; Schwalie, Petra C.; Tang, Y. Amy; Ward, Michelle C.; Xue, Yali; Yngvadottir, Bryndis; Alkan, Can; Andersen, Lars N.; Ayub, Qasim; Ball, Edward V.; Beal, Kathryn; Bradley, Brenda J.; Chen, Yuan; Clee, Chris M.; Fitzgerald, Stephen; Graves, Tina A.; Gu, Yong; Heath, Paul; Heger, Andreas; Karakoc, Emre; Kolb-Kokocinski, Anja; Laird, Gavin K.; Lunter, Gerton; Meader, Stephen; Mort, Matthew; Mullikin, James C.; Munch, Kasper; O’Connor, Timothy D.; Phillips, Andrew D.; Prado-Martinez, Javier; Rogers, Anthony S.; Sajjadian, Saba; Schmidt, Dominic; Shaw, Katy; Simpson, Jared T.; Stenson, Peter D.; Turner, Daniel J.; Vigilant, Linda; Vilella, Albert J.; Whitener, Weldon; Zhu, Baoli; Cooper, David N.; de Jong, Pieter; Dermitzakis, Emmanouil T.; Eichler, Evan E.; Flicek, Paul; Goldman, Nick; Mundy, Nicholas I.; Ning, Zemin; Odom, Duncan T.; Ponting, Chris P.; Quail, Michael A.; Ryder, Oliver A.; Searle, Stephen M.; Warren, Wesley C.; Wilson, Richard K.; Schierup, Mikkel H.; Rogers, Jane; Tyler-Smith, Chris; Durbin, Richard

    2012-01-01

    Summary Gorillas are humans’ closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago (Mya). In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. PMID:22398555

  6. First International Conference on the Evolution and Development of the Universe

    CERN Document Server

    EDU2008

    2009-01-01

    This document is the Special Issue of the First International Conference on the Evolution and Development (EDU 2008). Please refer to the preface and introduction for more details on the contributions. Keywords: acceleration, artificial cosmogenesis, artificial life, Big Bang, Big History, biological evolution, biological universe, biology, causality, classical vacuum energy, complex systems, complexity, computational universe, conscious evolution, cosmological artificial selection, cosmological natural selection, cosmology, critique, cultural evolution, dark energy, dark matter, development of the universe, development, emergence, evolution of the universe evolution, exobiology, extinction, fine-tuning, fractal space-time, fractal, information, initial conditions, intentional evolution, linear expansion of the universe, log-periodic laws, macroevolution, materialism, meduso-anthropic principle, multiple worlds, natural sciences, Nature, ontology, order, origin of the universe, particle hierarchy, philosophy,...

  7. Low- to medium-β cavities for heavy ion acceleration

    Science.gov (United States)

    Facco, Alberto

    2017-02-01

    Acceleration of low- and medium-β heavy ions by means of superconducting (SC) linear accelerators (linacs) was made possible by the development, during four decades, of a particular class of cavities characterized by low operation frequency, several different shapes and different electromagnetic modes of operation. Their performance, initially rather poor in operating accelerators, have steadily increased along with the technological progress and nowadays the gap with the high-β, elliptical cavities is close to be filled. Initially confined to a very small number of applications, this family of cavities evolved in many directions becoming one of the most widespread in linacs. Nowadays it is present in the majority of superconducting radio-frequency ion linac projects worldwide. An overview of low- and medium-β SC cavities for heavy ions, focused on their recent evolution and achievements, will be given.

  8. Variations in tumour oxygen tension (pO2) during accelerated radiotherapy of head and neck carcinoma

    International Nuclear Information System (INIS)

    Guichard, M.; Eschwege, F.; Luboinski, B.; Wibault, P.; Weeger, P.; Lusinchi, A.; Lartigau, E.

    1998-01-01

    The study was performed to assess the effect of accelerated radiotherapy on oxygenation of primary tumours and metastatic nodes in patients with advanced head and neck tumours. In 14 patients with head and neck tumour, oxygen tension (pO 2 ) was evaluated in normal tissues and tumours (primary tumour or metastatic neck node) before (0 Gy) and after 2 weeks (32 Gy) of accelerated radiotherapy (70 Gy in 3.5 weeks, with three daily fractions). Radiotherapy was combined with carbogen breathing in 5 patients. pO 2 was measured using a polarographic technique. For pooled normal tissues, median pO 2 was 38 mmHg before treatment and 46 mmHg after 2 weeks. For tumours, very low values ( 2 12 mmHg before treatment versus 26 mmHg after 2 weeks, P 2 was 44 mmHg at 2 weeks, compared with 13.5 mmHg before treatment (P=0.05). Very low pO 2 values, corresponding to tumour hypoxia, were found in the tumours (primary and metastatic neck nodes) prior to accelerated treatment. During the first 2 weeks of accelerated treatment, an increase in median pO 2 was found in nine of the 14 tumours, together with a decrease in the frequency of very low values. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

  9. Recombinant ESAT-6-CFP10 Fusion Protein Induction of Th1/Th2 Cytokines and FoxP3 Expressing Treg Cells in Pulmonary TB.

    Directory of Open Access Journals (Sweden)

    Dolly Jackson-Sillah

    Full Text Available Early secretory antigenic target 6 (ESAT-6 and culture filtrate protein 10 (CFP-10 are Mycobacterium tuberculosis (Mtb-specific antigens that are secreted by actively metabolising bacteria and contribute to the virulence of the bacteria. Their ability to induce Treg and Th2 responses, particularly during the first two weeks of treatment, has not been comprehensively examined to date. The purpose of this work was to characterise Th1, Th2 and Treg responses to rESAT-6-CFP10 fusion protein in TB patients before and during the intensive phase of treatment and in healthy M.bovis BCG vaccinated donors.Forty-six newly diagnosed, HIV-negative, smear-positive pulmonary TB patients and 20 healthy donors were recruited in the UK and Ghana. Their peripheral blood mononuclear cells (PBMC were used in ex vivo ELISPOT and in vitro cultures to identify immunological parameters of interest.The study confirmed that protective immune responses to rESAT-6-CFP10 are impaired in active TB but improved during treatment: circulating antigen-specific IL-4-producing T-cells were increased in untreated TB but declined by two weeks of treatment while the circulating antigen-specific IFN-γ producing T cells which showed a transient rise at one week of treatment, persisted at baseline levels at two months of treatment. In vitro T cell proliferation and IFN-γ production were reduced, while IL-4 and CD4(+FoxP3(+CD25(hi cell expression were increased in response to rESAT-6-CFP10 fusion protein in untreated TB. These responses were reversed during early treatment of TB.These observations support further investigations into the possible utility of these parameters as markers of active disease and favourable treatment outcomes.

  10. Recombinant ESAT-6-CFP10 Fusion Protein Induction of Th1/Th2 Cytokines and FoxP3 Expressing Treg Cells in Pulmonary TB.

    Science.gov (United States)

    Jackson-Sillah, Dolly; Cliff, Jacqueline M; Mensah, Gloria Ivy; Dickson, Emmanuel; Sowah, Sandra; Tetteh, John K A; Addo, Kwasi K; Ottenhoff, Tom H M; Bothamley, Graham; Dockrell, Hazel M

    2013-01-01

    Early secretory antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10) are Mycobacterium tuberculosis (Mtb)-specific antigens that are secreted by actively metabolising bacteria and contribute to the virulence of the bacteria. Their ability to induce Treg and Th2 responses, particularly during the first two weeks of treatment, has not been comprehensively examined to date. The purpose of this work was to characterise Th1, Th2 and Treg responses to rESAT-6-CFP10 fusion protein in TB patients before and during the intensive phase of treatment and in healthy M.bovis BCG vaccinated donors. Forty-six newly diagnosed, HIV-negative, smear-positive pulmonary TB patients and 20 healthy donors were recruited in the UK and Ghana. Their peripheral blood mononuclear cells (PBMC) were used in ex vivo ELISPOT and in vitro cultures to identify immunological parameters of interest. The study confirmed that protective immune responses to rESAT-6-CFP10 are impaired in active TB but improved during treatment: circulating antigen-specific IL-4-producing T-cells were increased in untreated TB but declined by two weeks of treatment while the circulating antigen-specific IFN-γ producing T cells which showed a transient rise at one week of treatment, persisted at baseline levels at two months of treatment. In vitro T cell proliferation and IFN-γ production were reduced, while IL-4 and CD4(+)FoxP3(+)CD25(hi) cell expression were increased in response to rESAT-6-CFP10 fusion protein in untreated TB. These responses were reversed during early treatment of TB. These observations support further investigations into the possible utility of these parameters as markers of active disease and favourable treatment outcomes.

  11. Electron accelerator

    International Nuclear Information System (INIS)

    Abramyan.

    1981-01-01

    The USSR produces an electron accelerator family of a simple design powered straight from the mains. The specifications are given of accelerators ELITA-400, ELITA-3, ELT-2, TEUS-3 and RIUS-5 with maximum electron energies of 0.3 to 5 MeV, a mean power of 10 to 70 kW operating in both the pulsed and the continuous (TEUS-3) modes. Pulsed accelerators ELITA-400 and ELITA-3 and RIUS-5 in which TESLA resonance transformers are used are characterized by their compact size. (Ha)

  12. Essay: Robert H. Siemann As Leader of the Advanced Accelerator Research Department

    Energy Technology Data Exchange (ETDEWEB)

    Colby, Eric R.; Hogan, Mark J.; /SLAC

    2011-11-14

    Robert H. Siemann originally conceived of the Advanced Accelerator Research Department (AARD) as an academic, experimental group dedicated to probing the technical limitations of accelerators while providing excellent educational opportunities for young scientists. The early years of the Accelerator Research Department B, as it was then known, were dedicated to a wealth of mostly student-led experiments to examine the promise of advanced accelerator techniques. High-gradient techniques including millimeter-wave rf acceleration, beam-driven plasma acceleration, and direct laser acceleration were pursued, including tests of materials under rf pulsed heating and short-pulse laser radiation, to establish the ultimate limitations on gradient. As the department and program grew, so did the motivation to found an accelerator research center that brought experimentalists together in a test facility environment to conduct a broad range of experiments. The Final Focus Test Beam and later the Next Linear Collider Test Accelerator provided unique experimental facilities for AARD staff and collaborators to carry out advanced accelerator experiments. Throughout the evolution of this dynamic program, Bob maintained a department atmosphere and culture more reminiscent of a university research group than a national laboratory department. His exceptional ability to balance multiple roles as scientist, professor, and administrator enabled the creation and preservation of an environment that fostered technical innovation and scholarship.

  13. Essay: Robert H. Siemann As Leader of the Advanced Accelerator Research Department

    International Nuclear Information System (INIS)

    Colby, Eric R.; Hogan, Mark J.

    2008-01-01

    Robert H. Siemann originally conceived of the Advanced Accelerator Research Department (AARD) as an academic, experimental group dedicated to probing the technical limitations of accelerators while providing excellent educational opportunities for young scientists. The early years of the Accelerator Research Department B, as it was then known, were dedicated to a wealth of mostly student-led experiments to examine the promise of advanced accelerator techniques. High-gradient techniques including millimeter-wave rf acceleration, beam-driven plasma acceleration, and direct laser acceleration were pursued, including tests of materials under rf pulsed heating and short-pulse laser radiation, to establish the ultimate limitations on gradient. As the department and program grew, so did the motivation to found an accelerator research center that brought experimentalists together in a test facility environment to conduct a broad range of experiments. The Final Focus Test Beam and later the Next Linear Collider Test Accelerator provided unique experimental facilities for AARD staff and collaborators to carry out advanced accelerator experiments. Throughout the evolution of this dynamic program, Bob maintained a department atmosphere and culture more reminiscent of a university research group than a national laboratory department. His exceptional ability to balance multiple roles as scientist, professor, and administrator enabled the creation and preservation of an environment that fostered technical innovation and scholarship.

  14. The miniature accelerator

    CERN Multimedia

    Antonella Del Rosso

    2015-01-01

    The image that most people have of CERN is of its enormous accelerators and their capacity to accelerate particles to extremely high energies. But thanks to some cutting-edge studies on beam dynamics and radiofrequency technology, along with innovative construction techniques, teams at CERN have now created the first module of a brand-new accelerator, which will be just 2 metres long. The potential uses of this miniature accelerator will include deployment in hospitals for the production of medical isotopes and the treatment of cancer. It’s a real David-and-Goliath story.   Serge Mathot, in charge of the construction of the "mini-RFQ", pictured with the first of the four modules that will make up the miniature accelerator. The miniature accelerator consists of a radiofrequency quadrupole (RFQ), a component found at the start of all proton accelerator chains around the world, from the smallest to the largest. The LHC is designed to produce very high-intensity beams ...

  15. Exfoliated MoS2 nanosheets as efficient catalysts for electrochemical hydrogen evolution

    International Nuclear Information System (INIS)

    Ji, Shanshan; Yang, Zhe; Zhang, Chao; Liu, Zhenyan; Tjiu, Weng Weei; Phang, In Yee; Zhang, Zheng; Pan, Jisheng; Liu, Tianxi

    2013-01-01

    Graphical abstract: An efficient electrocatalyst for hydrogen evolution has been developed based on exfoliation of bulk MoS 2 crystals via a direct dispersion and ultrasonication method. Drop-casting method is used to fabricate the exfoliated MoS 2 nanosheets modified glass carbon electrode (E-MoS 2 /GCE) with various loadings. The E-MoS 2 /GCE with electrode loading of 48 μg cm −1 exhibits high catalytic activity for hydrogen evolution with a low overpotential (−0.12 V) and a high current density (1.26 mA cm −2 , at η = 150 mV). -- Highlights: • Two-dimensional MoS 2 nanosheets have been obtained by exfoliation of bulk MoS 2 crystals. • Exfoliated MoS 2 nanosheets show high electrocatalytic activity for H 2 production. • This study provides a new approach for renewable and economic H 2 production. -- Abstract: An efficient electrocatalyst for hydrogen evolution has been developed based on liquid exfoliation of bulk MoS 2 via a direct dispersion and ultrasonication method. Transmission electron microscopy and atomic force microscopy measurements show that the exfoliated MoS 2 consists of two-dimensional nanosheets. The exfoliated MoS 2 nanosheets modified glass carbon electrode (E-MoS 2 /GCE) with various loadings is fabricated via a drop-casting method. The electrocatalytic activity of E-MoS 2 /GCE toward hydrogen evolution reaction is examined using linear sweep voltammetry. It is shown that the E-MoS 2 /GCE with an electrode loading of 48 μg cm −2 exhibits a high catalytic activity for hydrogen evolution with a low overpotential (−0.12 V) and a high current density (1.26 mA cm −2 , at η = 150 mV)

  16. Transverse emittance growth in staged laser-wakefield acceleration

    Directory of Open Access Journals (Sweden)

    T. Mehrling

    2012-11-01

    Full Text Available We present a study on the emittance evolution of electron bunches, externally injected into laser-driven plasma waves using the three-dimensional particle-in-cell (PIC code OSIRIS. Results show order-of-magnitude transverse emittance growth during the injection process, if the electron bunch is not matched to its intrinsic betatron motion inside the wakefield. This behavior is supported by analytic theory reproducing the simulation data to a percent level. The length over which the full emittance growth develops is found to be less than or comparable to the typical dimension of a single plasma module in current multistage designs. In addition, the analytic theory enables the quantitative prediction of emittance degradation in two consecutive accelerators coupled by free-drift sections, excluding this as a scheme for effective emittance-growth suppression, and thus suggests the necessity of beam-matching sections between acceleration stages with fundamental implications on the overall design of staged laser-wakefield accelerators.

  17. Injection and acceleration of H+ and He2+ at Earth's bow shock

    Directory of Open Access Journals (Sweden)

    M. Scholer

    1999-05-01

    Full Text Available We have performed a number of one-dimensional hybrid simulations (particle ions, massless electron fluid of quasi-parallel collisionless shocks in order to investigate the injection and subsequent acceleration of part of the solar wind ions at the Earth's bow shock. The shocks propagate into a medium containing magnetic fluctuations, which are initially superimposed on the background field, as well as generated or enhanced by the electromagnetic ion/ion beam instability between the solar wind and backstreaming ions. In order to study the mass (M and charge (Q dependence of the acceleration process He2+ is included self-consistently. The upstream differential intensity spectra of H+ and He2+ can be well represented by exponentials in energy. The e-folding energy Ec is a function of time: Ec increases with time. Furthermore the e-folding energy (normalized to the shock ramming energy Ep increases with increasing Alfvén Mach number of the shock and with increasing fluctuation level of the initially superimposed turbulence. When backstreaming ions leave the shock after their first encounter they exhibit already a spectrum which extends to more than ten times the shock ramming energy and which is ordered in energy per charge. From the injection spectrum it is concluded that leakage of heated downstream particles does not contribute to ion injection. Acceleration models that permit thermal particles to scatter like the non-thermal population do not describe the correct physics.Key words. Interplanetary physics (planetary bow shocks · Space plasma physics (charged particle motion and acceleration; numerical simulation studies

  18. Injection and acceleration of H+ and He2+ at Earth's bow shock

    Directory of Open Access Journals (Sweden)

    K.-H. Trattner

    Full Text Available We have performed a number of one-dimensional hybrid simulations (particle ions, massless electron fluid of quasi-parallel collisionless shocks in order to investigate the injection and subsequent acceleration of part of the solar wind ions at the Earth's bow shock. The shocks propagate into a medium containing magnetic fluctuations, which are initially superimposed on the background field, as well as generated or enhanced by the electromagnetic ion/ion beam instability between the solar wind and backstreaming ions. In order to study the mass (M and charge (Q dependence of the acceleration process He2+ is included self-consistently. The upstream differential intensity spectra of H+ and He2+ can be well represented by exponentials in energy. The e-folding energy Ec is a function of time: Ec increases with time. Furthermore the e-folding energy (normalized to the shock ramming energy Ep increases with increasing Alfvén Mach number of the shock and with increasing fluctuation level of the initially superimposed turbulence. When backstreaming ions leave the shock after their first encounter they exhibit already a spectrum which extends to more than ten times the shock ramming energy and which is ordered in energy per charge. From the injection spectrum it is concluded that leakage of heated downstream particles does not contribute to ion injection. Acceleration models that permit thermal particles to scatter like the non-thermal population do not describe the correct physics.Key words. Interplanetary physics (planetary bow shocks · Space plasma physics (charged particle motion and acceleration; numerical simulation studies

  19. Physical condition for the slowing down of cosmic acceleration

    Science.gov (United States)

    Zhang, Ming-Jian; Xia, Jun-Qing

    2018-04-01

    The possible slowing down of cosmic acceleration was widely studied. However, judgment on this effect in different dark energy parameterizations was very ambiguous. Moreover, the reason of generating these uncertainties was still unknown. In the present paper, we analyze the derivative of deceleration parameter q‧ (z) using the Gaussian processes. This model-independent reconstruction suggests that no slowing down of acceleration is presented within 95% C.L. from the Union2.1 and JLA supernova data. However, q‧ (z) from the observational H (z) data is a little smaller than zero at 95% C.L., which indicates that future H (z) data may have a potential to test this effect. From the evolution of q‧ (z), we present an interesting constraint on the dark energy and observational data. The physical constraint clearly solves the problem of why some dark energy models cannot produce this effect in previous work. Comparison between the constraint and observational data also shows that most of current data are not in the allowed regions. This implies a reason of why current data cannot convincingly measure this effect.

  20. [Evolution of human brain and intelligence].

    Science.gov (United States)

    Lakatos, László; Janka, Zoltán

    2008-07-30

    The biological evolution, including human evolution is mainly driven by environmental changes. Accidental genetic modifications and their innovative results make the successful adaptation possible. As we know the human evolution started 7-8 million years ago in the African savannah, where upright position and bipedalism were significantly advantageous. The main drive of improving manual actions and tool making could be to obtain more food. Our ancestor got more meat due to more successful hunting, resulting in more caloric intake, more protein and essential fatty acid in the meal. The nervous system uses disproportionally high level of energy, so better quality of food was a basic condition for the evolution of huge human brain. The size of human brain was tripled during 3.5 million years, it increased from the average of 450 cm3 of Australopithecinae to the average of 1350 cm3 of Homo sapiens. A genetic change in the system controlling gene expression could happen about 200 000 years ago, which influenced the development of nervous system, the sensorimotor function and learning ability for motor processes. The appearance and stabilisation of FOXP2 gene structure as feature of modern man coincided with the first presence and quick spread of Homo sapiens on the whole Earth. This genetic modification made opportunity for human language, as the basis of abrupt evolution of human intelligence. The brain region being responsible for human language is the left planum temporale, which is much larger in left hemisphere. This shows the most typical human brain asymmetry. In this case the anatomical asymmetry means a clearly defined functional asymmetry as well, where the brain hemispheres act differently. The preference in using hands, the lateralised using of tools resulted in the brain asymmetry, which is the precondition of human language and intelligence. However, it cannot be held anymore, that only humans make tools, because our closest relatives, the chimpanzees are

  1. Accelerated degradation of the D2 protein of photosystem II under ultraviolet radiation

    International Nuclear Information System (INIS)

    Jansen, M.A.K.; Edelman, M.; Greenberg, B.M.; Gaba, V.

    1996-01-01

    The D2 protein of photosystem II is relatively stable in vivo under photosynthetic active radiation, but its degradation accelerates under UVB radiation. Little is known about accelerated D2 protein degradation. We characterized wavelength dependence and sensitivity toward photosystem II inhibitors. The in vivo D2 degradation spectrum resembles the pattern for the rapidly turning over D1 protein of photosystem II, with rates being maximal in the UVB region. We propose that D2 degradation, like D1 degradation, is activated by distinct photosensitizers in the UVB and visible regions of the spectrum. In both wavelength regions, photosystem II inhibitors that are known to be targeted to the D1 protein affect D2 degradation. This suggests that degradation of the two proteins is coupled, D2 degradation being influenced by events occurring at the Q B niche on the D1 protein. (Author)

  2. Evaluation of accelerated aging procedures of painted galvanised steels by EIS

    Energy Technology Data Exchange (ETDEWEB)

    Fedrizzi, L. [Department of Chemical Science and Technology, University of Udine, Via Cotonificio 108, 33100 Udine (Italy)]. E-mail: lorenzo.fedrizzi@uniud.it; Bergo, A. [Department of ICMMPM, University of Rome ' La Sapienza' , Via Eudossiana 18, 00184 Rome (Italy); Fanicchia, M. [Department of ICMMPM, University of Rome ' La Sapienza' , Via Eudossiana 18, 00184 Rome (Italy)

    2006-01-20

    Coil-coated sheets are usually cut and shaped or deep drawn to obtain the final profile of the manufacture. Mechanical deformation can affect the barrier properties of an organic coating and the adhesion to the substrate, thus accelerating degradation by natural weathering. UV radiations too can deeply affect the barrier properties of organic coatings and contribute along with rain, snow, thermal and hygrometric cycles and other factors to a fast decaying of the anticorrosive properties of painted systems. In this work some coil coating products for outdoor exposure, were subjected to the combined action of UV irradiation and mechanical deformation in order to simulate some of the stress occurring in their actual use. After mechanical deformation and UV irradiation, samples were exposed to a proper thermal cycle in order to accelerate water uptake and to discriminate in very short time among different formulations. Electrochemical impedance spectroscopy (EIS) was used to monitor the evolution of the systems during the accelerated aging. Qc and Rp (i.e. the constant phase element describing the dielectric properties and the ionic resistance of the coating) were selected to describe the protective system evolution. Adhesive and barrier properties were monitored and discussed during the combined thermal-mechanical and photo-oxidative aging.

  3. Evaluation of accelerated aging procedures of painted galvanised steels by EIS

    International Nuclear Information System (INIS)

    Fedrizzi, L.; Bergo, A.; Fanicchia, M.

    2006-01-01

    Coil-coated sheets are usually cut and shaped or deep drawn to obtain the final profile of the manufacture. Mechanical deformation can affect the barrier properties of an organic coating and the adhesion to the substrate, thus accelerating degradation by natural weathering. UV radiations too can deeply affect the barrier properties of organic coatings and contribute along with rain, snow, thermal and hygrometric cycles and other factors to a fast decaying of the anticorrosive properties of painted systems. In this work some coil coating products for outdoor exposure, were subjected to the combined action of UV irradiation and mechanical deformation in order to simulate some of the stress occurring in their actual use. After mechanical deformation and UV irradiation, samples were exposed to a proper thermal cycle in order to accelerate water uptake and to discriminate in very short time among different formulations. Electrochemical impedance spectroscopy (EIS) was used to monitor the evolution of the systems during the accelerated aging. Qc and Rp (i.e. the constant phase element describing the dielectric properties and the ionic resistance of the coating) were selected to describe the protective system evolution. Adhesive and barrier properties were monitored and discussed during the combined thermal-mechanical and photo-oxidative aging

  4. Frequency-Domain Tomography for Single-shot, Ultrafast Imaging of Evolving Laser-Plasma Accelerators

    Science.gov (United States)

    Li, Zhengyan; Zgadzaj, Rafal; Wang, Xiaoming; Downer, Michael

    2011-10-01

    Intense laser pulses propagating through plasma create plasma wakefields that often evolve significantly, e.g. by expanding and contracting. However, such dynamics are known in detail only through intensive simulations. Laboratory visualization of evolving plasma wakes in the ``bubble'' regime is important for optimizing and scaling laser-plasma accelerators. Recently snap-shots of quasi-static wakes were recorded using frequency-domain holography (FDH). To visualize the wake's evolution, we have generalized FDH to frequency-domain tomography (FDT), which uses multiple probes propagating at different angles with respect to the pump pulse. Each probe records a phase streak, imprinting a partial record of the evolution of pump-created structures. We then topographically reconstruct the full evolution from all phase streaks. To prove the concept, a prototype experiment visualizing nonlinear index evolution in glass is demonstrated. Four probes propagating at 0, 0.6, 2, 14 degrees to the index ``bubble'' are angularly and temporally multiplexed to a single spectrometer to achieve cost-effective FDT. From these four phase streaks, an FDT algorithm analogous to conventional CT yields a single-shot movie of the pump's self-focusing dynamics.

  5. Development of a numerical 2-dimensional beach evolution model

    DEFF Research Database (Denmark)

    Baykal, Cüneyt

    2014-01-01

    This paper presents the description of a 2-dimensional numerical model constructed for the simulation of beach evolution under the action of wind waves only over the arbitrary land and sea topographies around existing coastal structures and formations. The developed beach evolution numerical model...... is composed of 4 submodels: a nearshore spectral wave transformation model based on an energy balance equation including random wave breaking and diffraction terms to compute the nearshore wave characteristics, a nearshore wave-induced circulation model based on the nonlinear shallow water equations...... to compute the nearshore depth-averaged wave-induced current velocities and mean water level changes, a sediment transport model to compute the local total sediment transport rates occurring under the action of wind waves, and a bottom evolution model to compute the bed level changes in time based...

  6. FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease

    DEFF Research Database (Denmark)

    Rømer, Johanne Lade

    2005-01-01

    Summary CD4(+)CD25(+) regulatory T cells (T(regs)) are involved in the maintenance of peripheral tolerance and ensure a balanced immune response competent of fighting pathogens and at the same time recognizing commensals as harmless. This feature is lost in Crohn's disease (CD). The forkhead/wing......(+) T cells. Thus, we demonstrate that FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be propagated in vitro from inflamed mucosa of CD patients, which may be of interest in adoptive immunotherapy....

  7. Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation

    Directory of Open Access Journals (Sweden)

    Rohimah Mohamud

    2017-12-01

    Full Text Available Synthetic glycine coated 50 nm polystyrene nanoparticles (NP (PS50G, unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2 expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

  8. Preliminary accelerator plans for maximizing the integrated LHC luminosity

    CERN Document Server

    Benedikt, Michael; Ruggiero, F; Ostojic, R; Scandale, Walter; Shaposhnikova, Elena; Wenninger, J

    2006-01-01

    A working group on "Proton Accelerators for the Future" (PAF) has been created in May 2005 by the CERN direction to elaborate a baseline scenario of the possible development and upgrade of the present Proton Accelerator Complex. This report is the result of the investigation conducted until the end of 2005, in close connection with the working group on "Physics Opportunities with Future Proton Accelerators" (POFPA) and is consistent with their recommendations. Focused on the goal of maximizing the integrated luminosity for the LHC experiments, a scenario of evolution is proposed, subject to further refinement using the future experience of commissioning and running-in the collider and its injector complex. The actions to be taken in terms of consolidation, R & D and improvement are outlined. The benefits for other types of physics are mentioned and will be investigated in more detail in the future.

  9. Physics with a 15-30 GeV electron accelerator (ELFE)

    International Nuclear Information System (INIS)

    Frois, B.; Pire, B.

    1993-01-01

    Proposals for ELFE (Electron Laboratory For Europe), a 15-30 GeV high luminosity, continuous beam electron accelerator are discussed. These proposals form an extensive research program on exclusive reactions to probe the evolution of correlated quarks systems. Using the nucleus itself as a microscopic detector is one of the important ideas of this program. The same reaction is measured using nuclei of different sizes and thus the differences are observed in the evolution from quarks and gluons to hadrons in the nuclear medium. A brief overview of the physics with ELFE is presented. (R.P.) 1 tab

  10. Human papilloma virus load and PD-1/PD-L1, CD8+ and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy

    Science.gov (United States)

    Balermpas, Panagiotis; Martin, Daniel; Wieland, Ulrike; Rave-Fränk, Margret; Strebhardt, Klaus; Rödel, Claus; Fokas, Emmanouil; Rödel, Franz

    2017-01-01

    ABSTRACT We examined the prognostic role of immune markers programmed cell death protein-1 (PD-1) and its ligand (PD-L1), CD8+ tumor-infiltrating lymphocytes (TILs), FOXP3+ Tregs and phosphorylated Caspase-8 (T273) in patients with anal squamous cell cancer (ASCC) treated with standard chemoradiotherapy (CRT). The baseline immunohistochemical expression of immune markers was correlated with clinicopathologic characteristics, and cumulative incidence of local failure, disease-free survival (DFS) and overall survival (OS) in 150 patients, also in the context of human papilloma virus 16 (HPV16) DNA load and p16INK4a expression. After a median follow-up of 40 mo (1–205 mo), the 5-y cumulative incidence of local failure and DFS was 19.4% and 67.2%, respectively. Strong immune marker expression was significantly more common in tumors with high HPV16 viral load. In multivariant analysis, high CD8+ and PD-1+ TILs expression predicted for improved local control (p = 0.023 and p = 0.007, respectively) and DFS (p = 0.020 and p = 0.014, respectively). Also, high p16INK4a (p = 0.011) and PD-L1 (p = 0.033) expression predicted for better local control, whereas high FOXP3+ Tregs (p = 0.050) and phosphorylated Caspase-8 (p = 0.031) expression correlated with superior DFS. Female sex and high HPV16 viral load correlated with favorable outcome for all three clinical endpoints. The present data provide, for the first time, robust explanation for the favorable clinical outcome of HPV16-positive ASCC patients harboring strong immune cell infiltration. Our findings are relevant for treatment stratification with immune PD-1/PD-L1 checkpoint inhibitors to complement CRT and should be explored in a clinical trial. PMID:28405521

  11. Possibility of analysis using RBS, PIXE and nuclear reaction on the electrostatic Pelletron accelerator 5SDH-2

    International Nuclear Information System (INIS)

    Nguyen The Nghia; Bui Van Loat; Le Hong Khiem

    2011-01-01

    The electrostatic Pelletron accelerator 5SDH-2 is installing at Hanoi University of Sciences. This accelerator will be the first tandem electrostatic accelerator installed in Vietnam. The schematic structure, principle of operation of the machine and its application for analysis using Rutherford Back Scattering (RBS), Particle-Induced X-ray Emission (PIXE) and Nuclear Reaction Analysis (NRA) will be presented. (author)

  12. Phylogeny, rate variation, and genome size evolution of Pelargonium (Geraniaceae).

    Science.gov (United States)

    Weng, Mao-Lun; Ruhlman, Tracey A; Gibby, Mary; Jansen, Robert K

    2012-09-01

    The phylogeny of 58 Pelargonium species was estimated using five plastid markers (rbcL, matK, ndhF, rpoC1, trnL-F) and one mitochondrial gene (nad5). The results confirmed the monophyly of three major clades and four subclades within Pelargonium but also indicate the need to revise some sectional classifications. This phylogeny was used to examine karyotype evolution in the genus: plotting chromosome sizes, numbers and 2C-values indicates that genome size is significantly correlated with chromosome size but not number. Accelerated rates of nucleotide substitution have been previously detected in both plastid and mitochondrial genes in Pelargonium, but sparse taxon sampling did not enable identification of the phylogenetic distribution of these elevated rates. Using the multigene phylogeny as a constraint, we investigated lineage- and locus-specific heterogeneity of substitution rates in Pelargonium for an expanded number of taxa and demonstrated that both plastid and mitochondrial genes have had accelerated substitution rates but with markedly disparate patterns. In the plastid, the exons of rpoC1 have significantly accelerated substitution rates compared to its intron and the acceleration was mainly due to nonsynonymous substitutions. In contrast, the mitochondrial gene, nad5, experienced substantial acceleration of synonymous substitution rates in three internal branches of Pelargonium, but this acceleration ceased in all terminal branches. Several lineages also have dN/dS ratios significantly greater than one for rpoC1, indicating that positive selection is acting on this gene, whereas the accelerated synonymous substitutions in the mitochondrial gene are the result of elevated mutation rates. Published by Elsevier Inc.

  13. Large electrostatic accelerators

    Energy Technology Data Exchange (ETDEWEB)

    Jones, C.M.

    1984-01-01

    The increasing importance of energetic heavy ion beams in the study of atomic physics, nuclear physics, and materials science has partially or wholly motivated the construction of a new generation of large electrostatic accelerators designed to operate at terminal potentials of 20 MV or above. In this paper, the author briefly discusses the status of these new accelerators and also discusses several recent technological advances which may be expected to further improve their performance. The paper is divided into four parts: (1) a discussion of the motivation for the construction of large electrostatic accelerators, (2) a description and discussion of several large electrostatic accelerators which have been recently completed or are under construction, (3) a description of several recent innovations which may be expected to improve the performance of large electrostatic accelerators in the future, and (4) a description of an innovative new large electrostatic accelerator whose construction is scheduled to begin next year. Due to time and space constraints, discussion is restricted to consideration of only tandem accelerators.

  14. Large electrostatic accelerators

    International Nuclear Information System (INIS)

    Jones, C.M.

    1984-01-01

    The increasing importance of energetic heavy ion beams in the study of atomic physics, nuclear physics, and materials science has partially or wholly motivated the construction of a new generation of large electrostatic accelerators designed to operate at terminal potentials of 20 MV or above. In this paper, the author briefly discusses the status of these new accelerators and also discusses several recent technological advances which may be expected to further improve their performance. The paper is divided into four parts: (1) a discussion of the motivation for the construction of large electrostatic accelerators, (2) a description and discussion of several large electrostatic accelerators which have been recently completed or are under construction, (3) a description of several recent innovations which may be expected to improve the performance of large electrostatic accelerators in the future, and (4) a description of an innovative new large electrostatic accelerator whose construction is scheduled to begin next year. Due to time and space constraints, discussion is restricted to consideration of only tandem accelerators

  15. Development of bipolar-pulse accelerator for intense pulsed ion beam acceleration

    Energy Technology Data Exchange (ETDEWEB)

    Masugata, Katsumi [Department of Electrical and Electronic System Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555 (Japan)]. E-mail: masugata@eng.toyama-u.ac.jp; Shimizu, Yuichro [Department of Electrical and Electronic System Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555 (Japan); Fujioka, Yuhki [Department of Electrical and Electronic System Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555 (Japan); Kitamura, Iwao [Department of Electrical and Electronic System Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555 (Japan); Tanoue, Hisao [National Institute of Advanced Industry Science and Technology, 1-1-1, Umezono, Tsukuba-shi, Ibaraki 305-8568 (Japan); Arai, Kazuo [National Institute of Advanced Industry Science and Technology, 1-1-1, Umezono, Tsukuba-shi, Ibaraki 305-8568 (Japan)

    2004-12-21

    To improve the purity of intense pulsed ion beams, a new type of pulsed ion beam accelerator named 'bipolar pulse accelerator' was proposed. To confirm the principle of the accelerator a prototype of the experimental system was developed. The system utilizes By type magnetically insulated acceleration gap and operated with single polar negative pulse. A coaxial gas puff plasma gun was used as an ion source, which was placed inside the grounded anode. Source plasma (nitrogen) of current density {approx}25A/cm2, duration {approx}1.5{mu}s was injected into the acceleration gap by the plasma gun. The ions were successfully accelerated from the grounded anode to the drift tube by applying negative pulse of voltage 240kV, duration 100ns to the drift tube. Pulsed ion beam of current density {approx}40A/cm2, duration {approx}50ns was obtained at 41mm downstream from the anode surface. To evaluate the irradiation effect of the ion beam to solid material, an amorphous silicon thin film of thickness {approx}500nm was used as the target, which was deposited on the glass substrate. The film was found to be poly-crystallized after 4-shots of the pulsed nitrogen ion beam irradiation.

  16. The electron accelerator Ridgetron

    International Nuclear Information System (INIS)

    Hayashizaki, N.; Hattori, T.; Odera, M.; Fujisawa, T.

    1999-01-01

    Many electron accelerators of DC or RF type have been widely used for electron beam irradiation (curing, crosslinking of polymers, sterilization of medical disposables, preservation of food, etc.). Regardless of the acceleration energy, the accelerators to be installed in industrial facilities, have to satisfy the requires of compact size, low power consumption and stable operation. The DC accelerator is realized very compact in the energy under 300 keV, however, it is large to prevent the discharge of an acceleration column in the energy over 300 keV. The RF electron accelerator Ridgetron has been developed to accelerate the continuous beam of the 0.5-10 MeV range in compact space. It is the first example as an electron accelerator incorporated a ridged RF cavity. A prototype system of final energy of 2.5 MeV has been studied to confirm the feasibility at present

  17. DUST PRODUCTION AND PARTICLE ACCELERATION IN SUPERNOVA 1987A REVEALED WITH ALMA

    Energy Technology Data Exchange (ETDEWEB)

    Indebetouw, R.; Chevalier, R. [Department of Astronomy, University of Virginia, PO Box 400325, Charlottesville, VA 22904 (United States); Matsuura, M.; Barlow, M. J. [Department of Physics and Astronomy, University College London, Gower Street, London WC1E 6BT (United Kingdom); Dwek, E. [NASA Goddard Space Flight Center, 8800 Greenbelt Road, Greenbelt, MD 20771 (United States); Zanardo, G. [International Centre for Radio Astronomy Research (ICRAR), University of Western Australia, Crawley, WA 6009 (Australia); Baes, M. [Sterrenkundig Observatorium, Universiteit Gent, Krijgslaan 281 S9, B-9000 Gent (Belgium); Bouchet, P. [CEA-Saclay, F-91191 Gif-sur-Yvette (France); Burrows, D. N. [Department of Astronomy and Astrophysics, The Pennsylvania State University, University Park, PA 16802 (United States); Clayton, G. C. [Department of Physics and Astronomy, Louisiana State University, Baton Rouge, LA 70803 (United States); Fransson, C.; Lundqvist, P. [Department of Astronomy and the Oskar Klein Centre, Stockholm University, AlbaNova, SE-106 91 Stockholm (Sweden); Gaensler, B. [Australian Research Council Centre of Excellence for All-sky Astrophysics (CAASTRO) (Australia); Kirshner, R. [Harvard-Smithsonian Center for Astrophysics, 60 Garden St., Cambridge, MA 02138 (United States); Lakićević, M. [Lennard-Jones Laboratories, Keele University, ST5 5BG (United Kingdom); Long, K. S.; Meixner, M. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Martí-Vidal, I. [Department of Earth and Space Sciences, Chalmers University of Technology, Onsala Space Observatory, SE-43992 Onsala (Sweden); Marcaide, J. [Universidad de Valencia, C/Dr. Moliner 50, E-46100 Burjassot (Spain); McCray, R., E-mail: remy@virginia.edu [Department of Astrophysical and Planetary Sciences, University of Colorado at Boulder, UCB 391, Boulder, CO 80309 (United States); and others

    2014-02-10

    Supernova (SN) explosions are crucial engines driving the evolution of galaxies by shock heating gas, increasing the metallicity, creating dust, and accelerating energetic particles. In 2012 we used the Atacama Large Millimeter/Submillimeter Array to observe SN 1987A, one of the best-observed supernovae since the invention of the telescope. We present spatially resolved images at 450 μm, 870 μm, 1.4 mm, and 2.8 mm, an important transition wavelength range. Longer wavelength emission is dominated by synchrotron radiation from shock-accelerated particles, shorter wavelengths by emission from the largest mass of dust measured in a supernova remnant (>0.2 M {sub ☉}). For the first time we show unambiguously that this dust has formed in the inner ejecta (the cold remnants of the exploded star's core). The dust emission is concentrated at the center of the remnant, so the dust has not yet been affected by the shocks. If a significant fraction survives, and if SN 1987A is typical, supernovae are important cosmological dust producers.

  18. Derp1-modified dendritic cells attenuate allergic inflammation by regulating the development of T helper type1(Th1)/Th2 cells and regulatory T cells in a murine model of allergic rhinitis.

    Science.gov (United States)

    Yu, Shaoqing; Han, Bing; Liu, Shuangxi; Wang, Hong; Zhuang, Wenjie; Huang, Yu; Zhang, Ruxin

    2017-10-01

    The CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) are known to regulate Th2-induced allergic rhinitis (AR). In this study, we evaluated the efficacy of Derp1-modified dendritic cells (DCs) in AR immunotherapy. Derp1 was synthesized and transfected into DCs to generate Derp1-modified DCs. Phenotypes of Derp1-modified DCs were analyzed with flow cytometry using antibodies against DC markers CD11c, CD11b, CD59, CD103 and Toll-like receptor 1(TLR1). Four groups of subject mice were formed; the controls were treated with immature DCs, while the AR mice models were sensitized with Derp1(AR) and treated with DCs(DC-AR) or Derp1-modified DCs (Derp1DC-AR). The frequency of sneezing and scratching, eosinophil cell count, and Th1/Th2 ratio in the spleen were measured for all groups. The percentage of CD4 + CD25 + Foxp3 + Tregs in peripheral blood mononuclear cells was measured using flow cytometry; serum IgE, IgG1, and histamine were measured using enzyme-linked immunosorbent assay; expression levels of transcription factors T-bet, GATA3, Foxp3+ and IL-10 were analyzed using reverse transcription-polymerase chain reaction, and Western blot used in analyzed expression of Foxp3+ and IL-10 in nasal mucosa. Treatment with Derp1-modified DCs ameliorated the allergic response. The Derp1DC-AR group had significantly lower eosinophil cell count and the IgE, IgG1, and histamine levels than the AR and DC-AR groups, and higher mRNA levels of Th1 transcription factors T-bet, IL-10 and Foxp3 in nasal mucosa than DC-AR mice, but Th2 transcription factors GATA3 mRNA expression level has the opposite results. Furthermore, the Th1/Th2 ratio and percentage of CD4 + CD25 + Foxp3 + Tregs was significantly lower in the AR group (pTh1/Th2, showing an immunotherapeutic effect against AR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Evidence of accelerated evolution and ectodermal-specific expression of presumptive BDS toxin cDNAs from Anemonia viridis.

    Science.gov (United States)

    Nicosia, Aldo; Maggio, Teresa; Mazzola, Salvatore; Cuttitta, Angela

    2013-10-30

    Anemonia viridis is a widespread and extensively studied Mediterranean species of sea anemone from which a large number of polypeptide toxins, such as blood depressing substances (BDS) peptides, have been isolated. The first members of this class, BDS-1 and BDS-2, are polypeptides belonging to the β-defensin fold family and were initially described for their antihypertensive and antiviral activities. BDS-1 and BDS-2 are 43 amino acid peptides characterised by three disulfide bonds that act as neurotoxins affecting Kv3.1, Kv3.2 and Kv3.4 channel gating kinetics. In addition, BDS-1 inactivates the Nav1.7 and Nav1.3 channels. The development of a large dataset of A. viridis expressed sequence tags (ESTs) and the identification of 13 putative BDS-like cDNA sequences has attracted interest, especially as scientific and diagnostic tools. A comparison of BDS cDNA sequences showed that the untranslated regions are more conserved than the protein-coding regions. Moreover, the KA/KS ratios calculated for all pairwise comparisons showed values greater than 1, suggesting mechanisms of accelerated evolution. The structures of the BDS homologs were predicted by molecular modelling. All toxins possess similar 3D structures that consist of a triple-stranded antiparallel β-sheet and an additional small antiparallel β-sheet located downstream of the cleavage/maturation site; however, the orientation of the triple-stranded β-sheet appears to differ among the toxins. To characterise the spatial expression profile of the putative BDS cDNA sequences, tissue-specific cDNA libraries, enriched for BDS transcripts, were constructed. In addition, the proper amplification of ectodermal or endodermal markers ensured the tissue specificity of each library. Sequencing randomly selected clones from each library revealed ectodermal-specific expression of ten BDS transcripts, while transcripts of BDS-8, BDS-13, BDS-14 and BDS-15 failed to be retrieved, likely due to under-representation in our

  20. Evidence of Accelerated Evolution and Ectodermal-Specific Expression of Presumptive BDS Toxin cDNAs from Anemonia viridis

    Directory of Open Access Journals (Sweden)

    Aldo Nicosia

    2013-10-01

    Full Text Available Anemonia viridis is a widespread and extensively studied Mediterranean species of sea anemone from which a large number of polypeptide toxins, such as blood depressing substances (BDS peptides, have been isolated. The first members of this class, BDS-1 and BDS-2, are polypeptides belonging to the β-defensin fold family and were initially described for their antihypertensive and antiviral activities. BDS-1 and BDS-2 are 43 amino acid peptides characterised by three disulfide bonds that act as neurotoxins affecting Kv3.1, Kv3.2 and Kv3.4 channel gating kinetics. In addition, BDS-1 inactivates the Nav1.7 and Nav1.3 channels. The development of a large dataset of A. viridis expressed sequence tags (ESTs and the identification of 13 putative BDS-like cDNA sequences has attracted interest, especially as scientific and diagnostic tools. A comparison of BDS cDNA sequences showed that the untranslated regions are more conserved than the protein-coding regions. Moreover, the KA/KS ratios calculated for all pairwise comparisons showed values greater than 1, suggesting mechanisms of accelerated evolution. The structures of the BDS homologs were predicted by molecular modelling. All toxins possess similar 3D structures that consist of a triple-stranded antiparallel β-sheet and an additional small antiparallel β-sheet located downstream of the cleavage/maturation site; however, the orientation of the triple-stranded β-sheet appears to differ among the toxins. To characterise the spatial expression profile of the putative BDS cDNA sequences, tissue-specific cDNA libraries, enriched for BDS transcripts, were constructed. In addition, the proper amplification of ectodermal or endodermal markers ensured the tissue specificity of each library. Sequencing randomly selected clones from each library revealed ectodermal-specific expression of ten BDS transcripts, while transcripts of BDS-8, BDS-13, BDS-14 and BDS-15 failed to be retrieved, likely due to under

  1. Acceleration of black hole universe

    Science.gov (United States)

    Zhang, T. X.; Frederick, C.

    2014-01-01

    Recently, Zhang slightly modified the standard big bang theory and developed a new cosmological model called black hole universe, which is consistent with Mach's principle, governed by Einstein's general theory of relativity, and able to explain all observations of the universe. Previous studies accounted for the origin, structure, evolution, expansion, and cosmic microwave background radiation of the black hole universe, which grew from a star-like black hole with several solar masses through a supermassive black hole with billions of solar masses to the present state with hundred billion-trillions of solar masses by accreting ambient matter and merging with other black holes. This paper investigates acceleration of the black hole universe and provides an alternative explanation for the redshift and luminosity distance measurements of type Ia supernovae. The results indicate that the black hole universe accelerates its expansion when it accretes the ambient matter in an increasing rate. In other words, i.e., when the second-order derivative of the mass of the black hole universe with respect to the time is positive . For a constant deceleration parameter , we can perfectly explain the type Ia supernova measurements with the reduced chi-square to be very close to unity, χ red˜1.0012. The expansion and acceleration of black hole universe are driven by external energy.

  2. Semiconductor acceleration sensor

    Science.gov (United States)

    Ueyanagi, Katsumichi; Kobayashi, Mitsuo; Goto, Tomoaki

    1996-09-01

    This paper reports a practical semiconductor acceleration sensor especially suited for automotive air bag systems. The acceleration sensor includes four beams arranged in a swastika structure. Two piezoresistors are formed on each beam. These eight piezoresistors constitute a Wheatstone bridge. The swastika structure of the sensing elements, an upper glass plate and a lower glass plate exhibit the squeeze film effect which enhances air dumping, by which the constituent silicon is prevented from breakdown. The present acceleration sensor has the following features. The acceleration force component perpendicular to the sensing direction can be cancelled. The cross-axis sensitivity is less than 3 percent. And, the erroneous offset caused by the differences between the thermal expansion coefficients of the constituent materials can be canceled. The high aspect ratio configuration realized by plasma etching facilitates reducing the dimensions and improving the sensitivity of the acceleration sensor. The present acceleration sensor is 3.9 mm by 3.9 mm in area and 1.2 mm in thickness. The present acceleration sensor can measure from -50 to +50 G with sensitivity of 0.275 mV/G and with non-linearity of less than 1 percent. The acceleration sensor withstands shock of 3000 G.

  3. Bi{sub 2}O{sub 3} cocatalyst improving photocatalytic hydrogen evolution performance of TiO{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Difa; Hai, Yang; Zhang, Xiangchao; Zhang, Shiying; He, Rongan, E-mail: hslra@tom.com

    2017-04-01

    Highlights: • Bi-Bi{sub 2}O{sub 3}-anatase-rutile TiO{sub 2} multijunction photocatalyst was prepared. • Bi{sub 2}O{sub 3} quantum dots with size of 2–3 nm were uniformly distributed. • Improved H{sub 2} evolution was noticed in glycerol-water mixture. • Optimal amount of Bi{sub 2}O{sub 3} was found to be 0.89 mol%. - Abstract: Photocatalytic hydrogen production using water splitting is of potential importance from the viewpoint of renewable energy development. Herein, Bi{sub 2}O{sub 3}-TiO{sub 2} composite photocatalysts presented as Bi-Bi{sub 2}O{sub 3}-anatase-rutile TiO{sub 2} multijunction were first fabricated by a simple impregnation-calcination method using Bi{sub 2}O{sub 3} as H{sub 2}-production cocatalysts. The obtained multijunction samples exhibit an obvious enhancement in photocatalytic H{sub 2} evolution activity in the presence of glycerol. The effect of Bi{sub 2}O{sub 3} amount on H{sub 2}-evolution activity of TiO{sub 2} was investigated and the optimal Bi{sub 2}O{sub 3} content was found to be 0.89 mol%, achieving a H{sub 2}-production rate of 920 μmol h{sup −1}, exceeding that of pure TiO{sub 2} by more than 73 times. The enhanced mechanism of photocatalytic H{sub 2}-evolution activity is proposed. This study will provide new insight into the design and fabrication of TiO{sub 2}-based hydrogen-production photocatalysts using low-cost Bi{sub 2}O{sub 3} as cocatalyst.

  4. Stochastic Acceleration in Turbulent Electric Fields Generated by 3D Reconnection

    International Nuclear Information System (INIS)

    Onofri, Marco; Isliker, Heinz; Vlahos, Loukas

    2006-01-01

    Electron and proton acceleration in three-dimensional electric and magnetic fields is studied through test particle simulations. The fields are obtained by a three-dimensional magnetohydrodynamic simulation of magnetic reconnection in slab geometry. The nonlinear evolution of the system is characterized by the growth of many unstable modes and the initial current sheet is fragmented with formation of small scale structures. We inject at random points inside the evolving current sheet a Maxwellian distribution of particles. In a relatively short time (less than a millisecond) the particles develop a power-law tail. The acceleration is extremely efficient and the electrons absorb a large percentage of the available energy in a small fraction of the characteristic time of the MHD simulation, suggesting that resistive MHD codes are unable to represent the full extent of particle acceleration

  5. Intermittent Lagrangian velocities and accelerations in three-dimensional porous medium flow.

    Science.gov (United States)

    Holzner, M; Morales, V L; Willmann, M; Dentz, M

    2015-07-01

    Intermittency of Lagrangian velocity and acceleration is a key to understanding transport in complex systems ranging from fluid turbulence to flow in porous media. High-resolution optical particle tracking in a three-dimensional (3D) porous medium provides detailed 3D information on Lagrangian velocities and accelerations. We find sharp transitions close to pore throats, and low flow variability in the pore bodies, which gives rise to stretched exponential Lagrangian velocity and acceleration distributions characterized by a sharp peak at low velocity, superlinear evolution of particle dispersion, and double-peak behavior in the propagators. The velocity distribution is quantified in terms of pore geometry and flow connectivity, which forms the basis for a continuous-time random-walk model that sheds light on the observed Lagrangian flow and transport behaviors.

  6. Laserwire at the Accelerator Test Facility 2 with submicrometer resolution

    Directory of Open Access Journals (Sweden)

    L. J. Nevay

    2014-07-01

    Full Text Available A laserwire transverse electron beam size measurement system has been developed and operated at the Accelerator Test Facility 2 at the High Energy Accelerator Research Organization, Japan (KEK. Special electron beam optics were developed to create an approximately 1×100  μm (vertical×horizontal electron beam at the laserwire location, which was profiled using 150 mJ, 71 ps laser pulses with a wavelength of 532 nm. The precise characterization of the laser propagation allows the non-Gaussian laserwire scan profiles caused by the laser divergence to be deconvolved. A minimum vertical electron beam size of 1.07±0.06(stat±0.05(sys  μm was measured. A vertically focusing quadrupole just before the laserwire was varied while making laserwire measurements and the projected vertical emittance was measured to be 82.56±3.04  pm rad.

  7. Translational Research 2.0: a framework for accelerating collaborative discovery.

    Science.gov (United States)

    Asakiewicz, Chris

    2014-05-01

    The world wide web has revolutionized the conduct of global, cross-disciplinary research. In the life sciences, interdisciplinary approaches to problem solving and collaboration are becoming increasingly important in facilitating knowledge discovery and integration. Web 2.0 technologies promise to have a profound impact - enabling reproducibility, aiding in discovery, and accelerating and transforming medical and healthcare research across the healthcare ecosystem. However, knowledge integration and discovery require a consistent foundation upon which to operate. A foundation should be capable of addressing some of the critical issues associated with how research is conducted within the ecosystem today and how it should be conducted for the future. This article will discuss a framework for enhancing collaborative knowledge discovery across the medical and healthcare research ecosystem. A framework that could serve as a foundation upon which ecosystem stakeholders can enhance the way data, information and knowledge is created, shared and used to accelerate the translation of knowledge from one area of the ecosystem to another.

  8. Studies of accelerated compact toruses

    International Nuclear Information System (INIS)

    Hartman, C.W.; Eddleman, J.; Hammer, J.H.

    1983-01-01

    In an earlier publication we considered acceleration of plasma rings (Compact Torus). Several possible accelerator configurations were suggested and the possibility of focusing the accelerated rings was discussed. In this paper we consider one scheme, acceleration of a ring between coaxial electrodes by a B/sub theta/ field as in a coaxial rail-gun. If the electrodes are conical, a ring accelerated towards the apex of the cone undergoes self-similar compression (focusing) during acceleration. Because the allowable acceleration force, F/sub a/ = kappaU/sub m//R where (kappa - 2 , the accelerating distance for conical electrodes is considerably shortened over that required for coaxial electrodes. In either case, however, since the accelerating flux can expand as the ring moves, most of the accelerating field energy can be converted into kinetic energy of the ring leading to high efficiency

  9. Dynamic Evolution Model Based on Social Network Services

    Science.gov (United States)

    Xiong, Xi; Gou, Zhi-Jian; Zhang, Shi-Bin; Zhao, Wen

    2013-11-01

    Based on the analysis of evolutionary characteristics of public opinion in social networking services (SNS), in the paper we propose a dynamic evolution model, in which opinions are coupled with topology. This model shows the clustering phenomenon of opinions in dynamic network evolution. The simulation results show that the model can fit the data from a social network site. The dynamic evolution of networks accelerates the opinion, separation and aggregation. The scale and the number of clusters are influenced by confidence limit and rewiring probability. Dynamic changes of the topology reduce the number of isolated nodes, while the increased confidence limit allows nodes to communicate more sufficiently. The two effects make the distribution of opinion more neutral. The dynamic evolution of networks generates central clusters with high connectivity and high betweenness, which make it difficult to control public opinions in SNS.

  10. Acceleration of magnetized plasma rings

    International Nuclear Information System (INIS)

    Hartman, D.; Eddleman, J.; Hammer, J.H.

    1982-01-01

    One scheme is considered, acceleration of a ring between coaxial electrodes by a B/sub theta/ field as in a coaxial rail-gun. If the electrodes are conical, a ring accelerated towards the apex of the cone undergoes self-similar compression (focussing) during acceleration. Because the allowable acceleration force F/sub a/ = kappa U/sub m//R (kappa - 2 , the accelerating distance for conical electrodes is considerably shortened over that required for coaxial electrodes. In either case however, since the accelerating flux can expand as the ring moves, most of the accelerating field energy can be converted into kinetic energy of the ring leading to high efficiency

  11. GPU accelerated manifold correction method for spinning compact binaries

    Science.gov (United States)

    Ran, Chong-xi; Liu, Song; Zhong, Shuang-ying

    2018-04-01

    The graphics processing unit (GPU) acceleration of the manifold correction algorithm based on the compute unified device architecture (CUDA) technology is designed to simulate the dynamic evolution of the Post-Newtonian (PN) Hamiltonian formulation of spinning compact binaries. The feasibility and the efficiency of parallel computation on GPU have been confirmed by various numerical experiments. The numerical comparisons show that the accuracy on GPU execution of manifold corrections method has a good agreement with the execution of codes on merely central processing unit (CPU-based) method. The acceleration ability when the codes are implemented on GPU can increase enormously through the use of shared memory and register optimization techniques without additional hardware costs, implying that the speedup is nearly 13 times as compared with the codes executed on CPU for phase space scan (including 314 × 314 orbits). In addition, GPU-accelerated manifold correction method is used to numerically study how dynamics are affected by the spin-induced quadrupole-monopole interaction for black hole binary system.

  12. Radiocarbon dating with the Chalk River MP Tandem accelerator

    International Nuclear Information System (INIS)

    Ball, G.C.; Andrews, H.R.; Brown, R.M.; Burn, N.; Davies, W.G.; Imahori, Y.; Milton, J.C.D.

    1981-01-01

    During the past three years an automated radiocarbon dating system based on the MP Tandem accelerator has been developed for the analysis of 14 C in groundwater samples from the nuclear waste disposal research program and other small samples of scientific interest. At the present time 14 C/ 12 C ratio measurements can be determined with an accuracy of about 5% and the system background levels (approx. 35000 to 45000 years) are totally determined by sample and/or ion source contamination. Our goal has been to develop a dedicated reliable system for routine analysis that will produce accurate results with a minimum expenditure of human resources and accelerator beam time. Improvements required to operate the tandem accelerator as a quantitative tool have also benefited the rest of the experimental nuclear physics program. The early evolution of the dating facility was described previously. This paper is a brief report of the current status at Chalk River

  13. Are powerful females powerful enough? Acceleration in gravid green iguanas (Iguana iguana).

    Science.gov (United States)

    Scales, Jeffrey; Butler, Marguerite

    2007-08-01

    One demand placed exclusively on the musculoskeletal system of females is maintaining locomotor performance with an increasing load over the reproductive cycle. Here, we examine whether gravid (i.e., "pregnant") iguanas can increase their force and power production to support, stabilize, and accelerate the additional mass of a clutch of eggs. At any acceleration, gravid iguanas produced very high mechanical power (average total power = 673 w/kg; total peak power = 1175 w/kg). While the increase in total power was partly a result of greater propulsive power (average propulsive power = 25% higher, peak propulsive power = 38% higher), increased vertical power (roughly 200% increase) was the main contributor. Gravid iguanas were also able to increase peak forces (propulsive = 23%, mediolateral = 44%, vertical = 42%), and step duration (44%) resulting in greater impulses (i.e., the sum of force produced during a step) to accelerate, balance, and support their increased mass. The increase in step duration and smaller increase in peak propulsive force suggests that gravid iguanas may be force-limited in the direction of motion. We discuss how biomechanical constraints due to females' reproductive role may influence the evolution of the female musculoskeletal systems and contribute to the evolution and maintenance of ecological dimorphism in lizards.

  14. Giessen polarization facility. II. 1. 2 MeV tandem accelerator

    Energy Technology Data Exchange (ETDEWEB)

    Arnold, W; Ulbricht, J; Berg, H; Keiner, P; Krause, H H; Schmidt, R; Clausnitzer, G [Giessen Univ. (Germany, F.R.). Strahlenzentrum

    1977-06-15

    A small pressure insulated tandem accelerator with 600 kV terminal voltage was constructed for the application of a polarized ion source of the Lambshift type: thin carbon foils or gas stripping is used for the charge exchange in the high voltage terminal. The calculated ion optical properties were realized in the construction; transmission and energy resolution are sufficient to obtain high intensity polarized beams on target (maximum 0.6..mu..A protons with P=0.75 ) for precision polarization experiments in the 0.2-1.2 MeV energy region.

  15. Innovative applications of genetic algorithms to problems in accelerator physics

    Directory of Open Access Journals (Sweden)

    Alicia Hofler

    2013-01-01

    Full Text Available The genetic algorithm (GA is a powerful technique that implements the principles nature uses in biological evolution to optimize a multidimensional nonlinear problem. The GA works especially well for problems with a large number of local extrema, where traditional methods (such as conjugate gradient, steepest descent, and others fail or, at best, underperform. The field of accelerator physics, among others, abounds with problems which lend themselves to optimization via GAs. In this paper, we report on the successful application of GAs in several problems related to the existing Continuous Electron Beam Accelerator Facility nuclear physics machine, the proposed Medium-energy Electron-Ion Collider at Jefferson Lab, and a radio frequency gun-based injector. These encouraging results are a step forward in optimizing accelerator design and provide an impetus for application of GAs to other problems in the field. To that end, we discuss the details of the GAs used, include a newly devised enhancement which leads to improved convergence to the optimum, and make recommendations for future GA developments and accelerator applications.

  16. Radio frequency for particle accelerators: evolution and anatomy of a technology

    CERN Document Server

    Vretenar, M

    2011-01-01

    This introductory lecture outlines the impressive progress of radio frequency technology, from the first table-top equipment to the present gigantic installations. The outcome of 83 years of evolution is subsequently submitted to an anatomical analysis, which allows identifying the main components of a modern RF system and their interrelations.

  17. Modeling of a new 2D Acceleration Sensor Array using SystemC-AMS

    International Nuclear Information System (INIS)

    Markert, Erik; Dienel, Marco; Herrmann, Goeran; Mueller, Dietmar; Heinkel, Ulrich

    2006-01-01

    This paper presents an approach for modeling and simulation of a new 2D acceleration sensor array using SystemC-AMS. The sensor array consists of six single acceleration sensors with different detection axes. These single sensors comprise of four capacitive segments and one mass segment, aligned in a semicircle. The redundant sensor information is used for offset correction. Modeling of the single sensors is achieved using sensor structure simplification into 11 points and analytic equations for capacity changes, currents and torques. This model was expanded by a PWM feedback circuit to keep the sensor displacement in a linear region. In this paper the single sensor model is duplicated considering different positions of the seismic mass resulting in different detection axes for the single sensors. The measured accelerations of the sensors are merged with different weights depending on the orientation. This also reduces calculation effort

  18. Results from the RACE [Ring ACceleration Experiment] Compact Torus Acceleration Experiment

    International Nuclear Information System (INIS)

    Hammer, J.H.; Hartman, C.W.; Eddleman, J.L.; Kusse, B.

    1987-06-01

    RACE (Ring ACceleration Experiment) is a proof-of-principle experiment aimed at demonstrating acceleration of magnetically confined compact torus plasma rings to directed kinetic energies well in excess of their magnetic and thermal energies. In the course of the first year of operation the following have been observed: successful formation of rings in the RACE geometry; acceleration of rings with large forces, F/sub accelerate/ ∼F/sub equilibrium/ without apparent degradation of the ring structure; peak velocities of ≅2.5 x 10 8 cm/sec; acceleration efficiency of >30% at speeds of 1.5 x 10 8 cm/sec inferred from trajectory and capacitor bank data; kinetic to magnetic energy ratios ∼10 were observed. Experiments in the near future will be aimed at confirmation of the mass/energy measurements by calorimetry and direct density measurements

  19. Soil CO2 evolution: Response from arginine additions

    Science.gov (United States)

    Short-term response of soil C mineralization following drying/rewetting has been proposed as an indicator of soil microbial activity. Houston Black clay was amended with four rates of arginine to vary microbial response and keep other soil properties constant. The evolution of CO2 during one and thr...

  20. Orchestrated structure evolution: accelerating direct-write nanomanufacturing by combining top-down patterning with bottom-up growth

    Energy Technology Data Exchange (ETDEWEB)

    Kitayaporn, Sathana; Baneyx, Francois; Schwartz, Daniel T [Department of Chemical Engineering, University of Washington, Seattle, WA 98195-1750 (United States); Hoo, Ji Hao; Boehringer, Karl F, E-mail: dts@uw.edu [Department of Electrical Engineering, University of Washington, Seattle, WA 98195-1750 (United States)

    2010-05-14

    Direct-write nanomanufacturing with scanning beams and probes is flexible and can produce high quality products, but it is normally slow and expensive to raster point-by-point over a pattern. We demonstrate the use of an accelerated direct-write nanomanufacturing method called 'orchestrated structure evolution' (OSE), where a direct-write tool patterns a small number of growth 'seeds' that subsequently grow into the final thin film pattern. Through control of seed size and spacing, it is possible to vary the ratio of 'top-down' to 'bottom-up' character of the patterning processes, ranging from conventional top-down raster patterning to nearly pure bottom-up space-filling via seed growth. Electron beam lithography (EBL) and copper electrodeposition were used to demonstrate trade-offs between process time and product quality over nano- to microlength scales. OSE can reduce process times for high-cost EBL patterning by orders of magnitude, at the expense of longer (but inexpensive) copper electrodeposition processing times. We quantify the degradation of pattern quality that accompanies fast OSE patterning by measuring deviations from the desired patterned area and perimeter. We also show that the density of OSE-induced grain boundaries depends upon the seed separation and size. As the seed size is reduced, the uniformity of an OSE film becomes more dependent on details of seed nucleation processes than normally seen for conventionally patterned films.