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Sample records for human alpha-synuclein triggers

  1. Inducible alpha-synuclein expression affects human Neural Stem Cell behavior.

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    Zasso, Jacopo; Mastad, Ahmed; Cutarelli, Alessandro; Conti, Luciano

    2018-04-19

    Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinson's disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular systems is a crucial step. Here we present a novel human Tet-on hNSC cell line, in which aSyn timing and level of expression can be tightly experimentally tuned. Induction of aSyn in self-renewing hNSCs leads to progressive formation of aSyn aggregates and impairs their proliferation and cell survival. Furthermore, aSyn induction during the neuronal differentiation process results in reduced neuronal differentiation and increased number astrocytes and undifferentiated cells in culture. Finally, acute aSyn induction in hNSC-derived dopaminergic neuronal cultures results in cell toxicity. This novel conditional in vitro cell model system may be a valuable tool for dissecting of aSyn pathogenic effects in hNSCs and neurons and in developing new potential therapeutic strategies.

  2. Inducible alpha-synuclein overexpression affects human Neural Stem Cells behavior

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    Conti, Luciano; Zasso, Jacopo; Cutarelli, Alessandro; Ahmed, Mastad

    2018-01-01

    Converging evidence suggest that levels of alpha-Synuclein (aSyn) expression play a critical role in Parkinson's disease (PD). Several mutations of the SNCA gene, encoding for aSyn have been associated to either the familial or the sporadic forms of PD. Nonetheless, the mechanism underlying wild type aSyn-mediated neurotoxicity in neuronal cells as well as its specific driving role in PD pathogenesis has yet to be fully clarified. In this view, the development of proper in vitro cellular syst...

  3. Co-ordinate transcriptional regulation of dopamine synthesis genes by alpha-synuclein in human neuroblastoma cell lines.

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    Baptista, Melisa J; O'Farrell, Casey; Daya, Sneha; Ahmad, Rili; Miller, David W; Hardy, John; Farrer, Matthew J; Cookson, Mark R

    2003-05-01

    Abnormal accumulation of alpha-synuclein in Lewy bodies is a neuropathological hallmark of both sporadic and familial Parkinson's disease (PD). Although mutations in alpha-synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic cell death occurs remains unknown. We investigated transcriptional changes in neuroblastoma cell lines transfected with either normal or mutant (A30P or A53T) alpha-synuclein using microarrays, with confirmation of selected genes by quantitative RT-PCR. Gene products whose expression was found to be significantly altered included members of diverse functional groups such as stress response, transcription regulators, apoptosis-inducing molecules, transcription factors and membrane-bound proteins. We also found evidence of altered expression of dihydropteridine reductase, which indirectly regulates the synthesis of dopamine. Because of the importance of dopamine in PD, we investigated the expression of all the known genes in dopamine synthesis. We found co-ordinated downregulation of mRNA for GTP cyclohydrolase, sepiapterin reductase (SR), tyrosine hydroxylase (TH) and aromatic acid decarboxylase by wild-type but not mutant alpha-synuclein. These were confirmed at the protein level for SR and TH. Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor.

  4. The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice

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    Migdalska-Richards, Anna; Wegrzynowicz, Michal; Rusconi, Raffaella; Deangeli, Giulio; Di Monte, Donato A; Spillantini, Maria G; Schapira, Anthony H V

    2017-01-01

    Abstract Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson’s disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson’s disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression. PMID:28969384

  5. Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors.

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    Hall, Hélène; Jewett, Michael; Landeck, Natalie; Nilsson, Nathalie; Schagerlöf, Ulrika; Leanza, Giampiero; Kirik, Deniz

    2013-01-01

    Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.

  6. ALPHA-SYNUCLEIN STRUCTURE, AGGREGATION AND MODULATORS

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    Pinakin K. Makwana

    2016-06-01

    Full Text Available Alpha-synuclein is an intrinsically unstructured protein, involved in various neurodegenerative disorders. In vitro/in vivo experiments, as well as genetic mutation studies establish a direct link between alphasynuclein and synucleinopathies. Due to its natively unfolded state, alpha synuclein can adopt numerous conformations upon interaction with its partners and cellular factors, offering explanation for its diverse interactions. Aggregated form of alpha-synuclein has been observed in the brain of patients with synucleinopathies, a hallmark of neurodegeneration, and cell death has been attributed to aggregation induced toxicity. The process of aggregation involves nucleation, followed by intermediate oligomeric states, and finally the fibrillar amyloids. Of the various conformations/species that alpha-synuclein assumes before it transforms into mature amyloid fibrils, the oligomeric species is the most toxic. Thus, an effective way to limit disease progression is by modifying/slowing down protein aggregation/deposition in the brain. Various small natural products, synthetic chemicals, peptides and antibodies specific to alpha-synuclein have been designed/identified to reduce its rate of aggregation. Unfortunately, not even a handful of the molecules have cleared the clinical trials. Even today, medications available for Parkinson’s patients are mostly the drugs that adjust for loss of dopamine in the brain, and hence do not stop the progression of the disease or cure the symptoms. Thus, more molecular level studies are warranted to fully elucidate the process of alpha-synuclein aggregation, which in turn could help in identifying novel therapeutics and preventives. The present review summarizes the insights gained into the structure, in vitro aggregation and inhibitors/modulators of alpha-synuclein aggregation, that can be used to design better and effective inhibitors against the diseases.

  7. Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson's Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque.

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    James B Koprich

    Full Text Available Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml, this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.

  8. 17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy.

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    Riedel, Michael; Goldbaum, Olaf; Schwarz, Lisa; Schmitt, Sebastian; Richter-Landsberg, Christiane

    2010-01-18

    The accumulation and aggregation of alpha-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases termed synucleinopathies. alpha-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved. In the present study the possible aggregate clearing effects of the geldanamycin analogue 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) was investigated. Towards this, an oligodendroglial cell line (OLN-93 cells), stably expressing human alpha-synuclein (A53T mutation) was used. In these cells small punctate aggregates, not staining with thioflavine S, representing prefibrillary aggregates, occur characteristically. Our data demonstrate that 17-AAG attenuated the formation of alpha-synuclein aggregates by stimulating macroautophagy. By blocking the lysosomal compartment with NH(4)Cl the aggregate clearing effects of 17-AAG were abolished and alpha-synuclein deposits were enlarged. Analysis of LC3-II immunoreactivity, which is an indicator of autophagosome formation, further revealed that 17-AAG led to the recruitment of LC3-II and to the formation of LC3 positive puncta. This effect was also observed in cultured oligodendrocytes derived from the brains of newborn rats. Inhibition of macroautophagy by 3-methyladenine prevented 17-AAG induced occurrence of LC3 positive puncta as well as the removal of alpha-synuclein aggregates in OLN-A53T cells. Our data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which alpha-synuclein can be removed. Hence geldanamycin derivatives may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging.

  9. Curcumin inhibits aggregation of alpha-synuclein.

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    Pandey, Neeraj; Strider, Jeffrey; Nolan, William C; Yan, Sherry X; Galvin, James E

    2008-04-01

    Aggregation of amyloid-beta protein (Abeta) is a key pathogenic event in Alzheimer's disease (AD). Curcumin, a constituent of the Indian spice Turmeric is structurally similar to Congo Red and has been demonstrated to bind Abeta amyloid and prevent further oligomerization of Abeta monomers onto growing amyloid beta-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation are similar in Parkinson's disease (PD) and AD, we investigated the effect of curcumin on alpha-synuclein (AS) protein aggregation. In vitro model of AS aggregation was developed by treatment of purified AS protein (wild-type) with 1 mM Fe3+ (Fenton reaction). It was observed that the addition of curcumin inhibited aggregation in a dose-dependent manner and increased AS solubility. The aggregation-inhibiting effect of curcumin was next investigated in cell culture utilizing catecholaminergic SH-SY5Y cell line. A model system was developed in which the red fluorescent protein (DsRed2) was fused with A53T mutant of AS and its aggregation examined under different concentrations of curcumin. To estimate aggregation in an unbiased manner, a protocol was developed in which the images were captured automatically through a high-throughput cell-based screening microscope. The obtained images were processed automatically for aggregates within a defined dimension of 1-6 microm. Greater than 32% decrease in mutant alpha-synuclein aggregation was observed within 48 h subsequent to curcumin addition. Our data suggest that curcumin inhibits AS oligomerization into higher molecular weight aggregates and therefore should be further explored as a potential therapeutic compound for PD and related disorders.

  10. The temporal expression pattern of alpha-synuclein modulates olfactory neurogenesis in transgenic mice.

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    Sebastian R Schreglmann

    Full Text Available Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS under the murine Thy1 (mThy1 promoter, a model known to have a particularly high tg expression associated with impaired olfaction.Survival of newly generated neurons (NeuN-positive in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex.The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.

  11. Impaired baroreflex function in mice overexpressing alpha-synuclein

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    Sheila eFleming

    2013-07-01

    Full Text Available Cardiovascular autonomic dysfunction, such as orthostatic hypotension consequent to baroreflex failure and cardiac sympathetic denervation, is frequently observed in the synucleinopathy Parkinson’s disease (PD. In the present study, the baroreceptor reflex was assessed in mice overexpressing human wildtype alpha-synuclein (Thy1-aSyn, a genetic mouse model of synucleinopathy. The beat-to-beat change in heart rate, computed from R-R interval, in relation to blood pressure was measured in anesthetized and conscious mice equipped with arterial blood pressure telemetry transducers during transient bouts of hypertension and hypotension. Compared to wildtype, tachycardia following nitroprusside-induced hypotension was significantly reduced in Thy1-aSyn mice. Thy1-aSyn mice also showed an abnormal cardiovascular response (i.e., diminished tachycardia to muscarinic blockade with atropine. We conclude that Thy1-aSyn mice have impaired basal and dynamic range of sympathetic and parasympathetic-mediated changes in heart rate and will be a useful model for long-term study of cardiovascular autonomic dysfunction associated with PD.

  12. Alpha-synuclein in cutaneous small nerve fibers

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    Siepmann T

    2016-10-01

    Full Text Available Timo Siepmann,1 Ben Min-Woo Illigens,2 Kristian Barlinn1 1Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; 2Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Abstract: Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson’s disease (PD and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice. Keywords: Parkinson’s disease, diagnosis, skin

  13. Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra.

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    Alison L McCormack

    Full Text Available The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left vs. untreated (right hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i the number and phenotype of nigral dopaminergic neurons, and (ii the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.

  14. Mice with deleted multimerin 1 and alpha-synuclein genes have impaired platelet adhesion and impaired thrombus formation that is corrected by multimerin 1.

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    Reheman, Adili; Tasneem, Subia; Ni, Heyu; Hayward, Catherine P M

    2010-05-01

    Multimerin 1 is a stored platelet and endothelial cell adhesive protein that shows significant conservation. In vitro, multimerin 1 supports platelet adhesion and it also binds to collagen and enhances von Willebrand factor-dependent platelet adhesion to collagen. As selective, multimerin 1 deficient mice have not been generated, we investigated multimerin 1 effects on platelet adhesion using a subpopulation of C57BL/6J mice with tandem deletion of the genes for multimerin 1 and alpha-synuclein, a protein that inhibits alpha-granule release in vitro. We postulated that multimerin 1/alpha-synuclein deficient mice might show impaired platelet adhesive function from multimerin 1 deficiency and increased alpha-granule release from alpha-synuclein deficiency. Platelet function was assessed by intravital microscopy, after ferric chloride injury, using untreated and human multimerin 1-transfused multimerin 1/alpha-synuclein deficient mice, and by in vitro assays of adhesion, aggregation and thrombin-induced P-selectin release. Multimerin 1/alpha-synuclein deficient mice showed impaired platelet adhesion and their defective thrombus formation at sites of vessel injury improved with multimerin 1 transfusion. Although multimerin 1/alpha-synuclein deficient platelets showed increased P-selectin release at low thrombin concentrations, they also showed impaired adhesion to collagen, and attenuated aggregation with thrombin, that improved with added multimerin 1. Our data suggest that multimerin 1 supports platelet adhesive functions and thrombus formation, which will be important to verify by generating and testing selective multimerin 1 deficient mice. Copyright (c) 2010. Published by Elsevier Ltd.

  15. Alpha-synuclein levels in blood plasma decline with healthy aging.

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    Koehler, Niklas K U; Stransky, Elke; Meyer, Mirjam; Gaertner, Susanne; Shing, Mona; Schnaidt, Martina; Celej, Maria S; Jovin, Thomas M; Leyhe, Thomas; Laske, Christoph; Batra, Anil; Buchkremer, Gerhard; Fallgatter, Andreas J; Wernet, Dorothee; Richartz-Salzburger, Elke

    2015-01-01

    There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (phealthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

  16. Bimolecular Fluorescence Complementation of Alpha-synuclein Demonstrates its Oligomerization with Dopaminergic Phenotype in Mice

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    Waijiao Cai

    2018-03-01

    Full Text Available Alpha-synuclein (αSyn is encoded by the first causal gene identified in Parkinson's disease (PD and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species. We report here neurochemical, neuropathological and behavioral characterization of BiFC of αSyn in mice. Overexpression and oligomerization of αSyn through BiFC is detected by conjugated fluorescence. Reduced striatal dopamine and loss of nigral dopaminergic neurons are accompanied neuroinflammation and abnormal motor activities. Our mouse model may provide a valuable tool to study the role of αSyn in PD and to explore therapeutic approaches. Keywords: Parkinson's disease, Alpha-synuclein, Mouse model, Oligomers, Neuroinflammation

  17. Alpha-synuclein levels in blood plasma decline with healthy aging.

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    Niklas K U Koehler

    Full Text Available There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years compared to younger (avg. 27.6 years individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001, possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

  18. Alpha-Synuclein: From Early Synaptic Dysfunction to Neurodegeneration

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    Veronica Ghiglieri

    2018-05-01

    Full Text Available Over the last two decades, many experimental and clinical studies have provided solid evidence that alpha-synuclein (α-syn, a small, natively unfolded protein, is closely related to Parkinson’s disease (PD pathology. To provide an overview on the different roles of this protein, here we propose a synopsis of seminal and recent studies that explored the many aspects of α-syn. Ranging from the physiological functions to its neurodegenerative potential, the relationship with the possible pathogenesis of PD will be discussed. Close attention will be paid on early cellular and molecular alterations associated with the presence of α-syn aggregates.

  19. Alpha-Synuclein Toxicity in the Early Secretory Pathway: How it Drives Neurodegeneration in Parkinsons Disease

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    Ting eWang

    2015-11-01

    Full Text Available Alpha-synuclein is a predominant player in the pathogenesis of Parkinson’s Disease. However, despite extensive study for two decades, its physiological and pathological mechanisms remain poorly understood. Alpha-synuclein forms a perplexing web of interactions with lipids, trafficking machinery, and other regulatory factors. One emerging consensus is that synaptic vesicles are likely the functional site for alpha-synuclein, where it appears to facilitate vesicle docking and fusion. On the other hand, the disfunctions of alpha-synuclein are more dispersed and numerous; when mutated or over-expressed, alpha-synuclein affects several membrane trafficking and stress pathways, including exocytosis, ER-to-Golgi transport, ER stress, Golgi homeostasis, endocytosis, autophagy, oxidative stress and others. Here we examine recent developments in alpha-synuclein’s toxicity in the early secretory pathway placed in the context of emerging themes from other affected pathways to help illuminate its underlying pathogenic mechanisms in neurodegeneration.

  20. Interaction between viologen-phosphorus dendrimers and {alpha}-synuclein

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    Milowska, Katarzyna, E-mail: milowska@biol.uni.lodz.pl [Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz (Poland); Grochowina, Justyna [Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz (Poland); Katir, Nadia [Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne, 31077 Toulouse (France); El Kadib, Abdelkrim [Institute of Nanomaterials and Nanotechnology (INANOTECH)-MAScIR (Moroccan Foundation for Advanced Science, Innovation and Research), ENSET, Avenue de I' Armee Royale, Madinat El Irfane, 10100 Rabat (Morocco); Majoral, Jean-Pierre [Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne, 31077 Toulouse (France); Bryszewska, Maria; Gabryelak, Teresa [Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz (Poland)

    2013-02-15

    In this study the interaction between viologen-phosphorus dendrimers and {alpha}-synuclein (ASN) was examined. Polycationic viologen-phosphorus dendrimers (two positive charges per viologen unit) are novel compounds with relatively unknown properties. The influence of these viologen dendrimers on ASN was tested using fluorimetric and circular dichroism methods. ASN contains four tyrosine residues; therefore, the influence of dendrimers on protein molecular conformation by measuring the changes in the ASN fluorescence in the presence of dendrimers was evaluated. The interaction of dendrimers with free L-tyrosine was also monitored. Results show that viologen-phosphorus dendrimers interact with ASN; they quenched the fluorescence of ASN as well as free tyrosine by dynamic and static ways. However, the quenching was not accompanied by modifications in the ASN secondary structure. - Highlights: Black-Right-Pointing-Pointer Interaction between viologen-phosphorus dendrimers and {alpha}-synuclein (ASN) was investigated. Black-Right-Pointing-Pointer Viologen-phosphorus dendrimers can quench the fluorescence of tyrosine in ASN. Black-Right-Pointing-Pointer Dendrimers caused red-shift in maximum of fluorescence. Black-Right-Pointing-Pointer Viologen-phosphorus dendrimers did not change the secondary structure of ASN.

  1. Modification of C Terminus Provides New Insights into the Mechanism of alpha-Synuclein Aggregation

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    Afitska, Kseniia; Fučíková, A.; Shvadchak, Volodymyr V.; Yushchenko, Dmytro A.

    2017-01-01

    Roč. 113, č. 10 (2017), s. 2182-2191 ISSN 0006-3495 Institutional support: RVO:61388963 Keywords : alpha-synuclein * aggregation * kinetics Subject RIV: BO - Biophysics OBOR OECD: Biophysics Impact factor: 3.656, year: 2016

  2. C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging.

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    Tjakko J van Ham

    2008-03-01

    Full Text Available Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha- synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders.

  3. Alpha-synuclein gene deletion decreases brain palmitate uptake and alters the palmitate metabolism in the absence of alpha-synuclein palmitate binding

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    Golovko, Mikhail Y; Færgeman, Nils J.; Cole, Nelson B

    2005-01-01

    Alpha-synuclein is an abundant protein in the central nervous system that is associated with a number of neurodegenerative disorders, including Parkinson's disease. Its physiological function is poorly understood, although recently it was proposed to function as a fatty acid binding protein. To b......, alpha-synuclein has effects on 16:0 uptake and metabolism similar to those of an FABP, but unlike FABP, it does not directly bind 16:0; hence, the mechanism underlying these effects is different from that of a classical FABP....

  4. Analysis of alpha-synuclein in malignant melanoma - development of a SRM quantification assay.

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    Charlotte Welinder

    Full Text Available Globally, malignant melanoma shows a steady increase in the incidence among cancer diseases. Malignant melanoma represents a cancer type where currently no biomarker or diagnostics is available to identify disease stage, progression of disease or personalized medicine treatment. The aim of this study was to assess the tissue expression of alpha-synuclein, a protein implicated in several disease processes, in metastatic tissues from malignant melanoma patients. A targeted Selected Reaction Monitoring (SRM assay was developed and utilized together with stable isotope labeling for the relative quantification of two target peptides of alpha-synuclein. Analysis of alpha-synuclein protein was then performed in ten metastatic tissue samples from the Lund Melanoma Biobank. The calibration curve using peak area ratio (heavy/light versus concentration ratios showed linear regression over three orders of magnitude, for both of the selected target peptide sequences. In support of the measurements of specific protein expression levels, we also observed significant correlation between the protein and mRNA levels of alpha-synuclein in these tissues. Investigating levels of tissue alpha-synuclein may add novel aspect to biomarker development in melanoma, help to understand disease mechanisms and ultimately contribute to discriminate melanoma patients with different prognosis.

  5. Exogenous Alpha-Synuclein Alters Pre- and Post-Synaptic Activity by Fragmenting Lipid Rafts

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    Marco Emanuele

    2016-05-01

    Full Text Available Alpha-synuclein (αSyn interferes with multiple steps of synaptic activity at pre-and post-synaptic terminals, however the mechanism/s by which αSyn alters neurotransmitter release and synaptic potentiation is unclear. By atomic force microscopy we show that human αSyn, when incubated with reconstituted membrane bilayer, induces lipid rafts' fragmentation. As a consequence, ion channels and receptors are displaced from lipid rafts with consequent changes in their activity. The enhanced calcium entry leads to acute mobilization of synaptic vesicles, and exhaustion of neurotransmission at later stages. At the post-synaptic terminal, an acute increase in glutamatergic transmission, with increased density of PSD-95 puncta, is followed by disruption of the interaction between N-methyl-d-aspartate receptor (NMDAR and PSD-95 with ensuing decrease of long term potentiation. While cholesterol loading prevents the acute effect of αSyn at the presynapse; inhibition of casein kinase 2, which appears activated by reduction of cholesterol, restores the correct localization and clustering of NMDARs.

  6. Alpha-synuclein mutations impair axonal regeneration in models of Parkinson´s disease

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    Lars eTönges

    2014-09-01

    Full Text Available The dopaminergic (DAergic nigrostriatal tract has an intrinsic regenerative capacity which can be impaired in Parkinson’s disease (PD. Alpha-synuclein (aSyn is a major pathogenic component in PD but its impact on DAergic axonal regeneration is largely unknown. In this study, we expressed pathogenic variants of human aSyn by means of recombinant adeno-associated viral vectors in experimental paradigms of DAergic regeneration. In a scratch lesion model in vitro, both aSyn(A30P and aSyn(A53T significantly reduced DAergic neurite regeneration and induced loss of TH-immunopositive cells while aSyn(WT showed only minor cellular neurotoxic effects. The striatal density of TH-immunopositive axons in the striatal 6-OHDA lesion mouse model was attenuated only by aSyn(A30P. However, striatal expression levels of the regeneration marker GAP-43 in TH-immunopositive fibers were reduced by both aSyn(A30P and aSyn(A53T, but not by aSyn(WT which was associated with an activation of the ROCK signaling pathway. Nigral DAergic cell loss was only mildly enhanced by additional overexpression of aSyn variants. Our findings indicate that mutations of aSyn have a strong impact on the regenerative capacity of DAergic neurons, which may contribute to their pathogenic effects.

  7. Propagated but Topologically Distributed Forebrain Neurons Expressing Alpha-Synuclein in Aged Macaques.

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    Katsuo Kimura

    Full Text Available In neurodegenerative disorders, such as Parkinson's disease (PD, alpha-synuclein (α-syn accumulates to induce cell death and/or form a cytoplasmic inclusion called Lewy body (LB. This α-syn-related pathology is termed synucleinopathy. It remains unclear how α-syn accumulation expands during the progress of synucleinopathy in the human brain. In our study, we investigated the patterns of distribution and propagation of forebrain neurons expressing α-syn in aged macaques. It was found that the occurrence of α-syn-positive neurons proceeded topologically based on the midbrain dopamine pathways arising from the substantia nigra and the ventral tegmental area where they were primarily observed. In the nigrostriatal or mesolimbic dopamine pathway, the age-dependent increase in α-syn-positive neurons was evident in the striatum or the nucleus accumbens, respectively. Concerning the nigrostriatal pathway, a mediolateral or rostrocaudal gradient was seen in the substantia nigra or the striatum, respectively, and a compensatory increase in dopamine transporter occurred in the striatum regardless of the decreased dopamine level. In the mesocortical dopamine pathway, α-syn-positive neurons appeared in the prefrontal and then motor areas of the frontal lobe. Given that neither LB formation nor clinical phenotype manifestation was detected in any of the monkeys examined in the present study, aged macaques may be useful as a potential presymptomatic model for PD and LB-related neuropsychiatric disorders.

  8. Changes in interfacial properties of alpha-synuclein preceding its aggregation

    Czech Academy of Sciences Publication Activity Database

    Paleček, Emil; Ostatná, Veronika; Masařík, Michal; Bertoncini, C.W.; Jovin, T.

    2008-01-01

    Roč. 133, - (2008), s. 76-84 ISSN 0003-2654 R&D Projects: GA AV ČR(CZ) KAN400310651; GA MŠk(CZ) LC06035 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : alpha-synuclein * Parkinson's disease Subject RIV: BO - Biophysics Impact factor: 3.761, year: 2008

  9. Sensitive electrochemical detection of native and aggregated alpha-synuclein protein involved in Parkinson's disease

    Czech Academy of Sciences Publication Activity Database

    Masařík, Michal; Stobiecka, A.; Kizek, René; Jelen, František; Pechan, Zdeněk; Hoyer, W.; Jovin, T.; Subramaniam, V.; Paleček, Emil

    2004-01-01

    Roč. 16, 13-14 (2004), s. 1172-1181 ISSN 1040-0397 R&D Projects: GA ČR GA204/03/0566 Institutional research plan: CEZ:AV0Z5004920 Keywords : electrochemistry of proteins * alpha-synuclein aggregation * adsorptive transfer stripping Subject RIV: BO - Biophysics Impact factor: 2.038, year: 2004

  10. Dermal phospho-alpha-synuclein deposits confirm REM sleep behaviour disorder as prodromal Parkinson's disease

    NARCIS (Netherlands)

    Doppler, Kathrin; Jentschke, Hanna-Maria; Schulmeyer, Lena; Vadasz, David; Janzen, Annette; Luster, Markus; Höffken, Helmut; Mayer, Geert; Brumberg, Joachim; Booij, Jan; Musacchio, Thomas; Klebe, Stephan; Sittig-Wiegand, Elisabeth; Volkmann, Jens; Sommer, Claudia; Oertel, Wolfgang H.

    2017-01-01

    Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in

  11. Explorations of the application of cyanine dyes for quantitative alpha-synuclein detection

    NARCIS (Netherlands)

    Volkova, Kateryna D; Kovalska, V B; Segers-Nolten, G M J; Veldhuis, G.; Subramaniam, V; Yarmoluk, S M

    We examined the practical aspects of using fluorescent mono (T-284) and trimethinecyanine (SH-516) dyes for detecting and quantifying fibrillar alpha-synuclein (ASN). We studied the interaction of cyanine dyes with fibrillar proteins using fluorescence spectroscopy and atomic force microscopy. The

  12. Dynamic Changes in Striatal mGluR1 But Not mGluR5 during Pathological Progression of Parkinson's Disease in Human Alpha-Synuclein A53T Transgenic Rats: A Multi-PET Imaging Study.

    Science.gov (United States)

    Yamasaki, Tomoteru; Fujinaga, Masayuki; Kawamura, Kazunori; Furutsuka, Kenji; Nengaki, Nobuki; Shimoda, Yoko; Shiomi, Satoshi; Takei, Makoto; Hashimoto, Hiroki; Yui, Joji; Wakizaka, Hidekatsu; Hatori, Akiko; Xie, Lin; Kumata, Katsushi; Zhang, Ming-Rong

    2016-01-13

    Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by resting tremor and movement deficits. Group I metabotropic glutamate receptor subtypes 1 and 5 (mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human α-synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET ligand for mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E)-[(11)C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[(11)C]methyloxime], a specific PET ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[(18)F]fluoroethoxy-3β-(4-methylphenyl) nortropane], a specific PET ligand for the dopamine transporter, a biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model. Synaptic signaling by glutamate, the principal excitatory neurotransmitter in the brain, is modulated by group I metabotropic glutamate

  13. Microglia acquire distinct activation profiles depending on the degree of alpha-synuclein neuropathology in a rAAV based model of Parkinson's disease.

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    Vanesa Sanchez-Guajardo

    Full Text Available Post-mortem analysis of brains from Parkinson's disease (PD patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by alpha-synuclein (alpha-syn, which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human alpha-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68 and MCH II. In our study, when alpha-syn induced neuronal pathology but not cell death, a fast transient increase in microglia cell numbers resulted in the long-term induction of MHC II+ microglia, denoting antigen-presenting ability. On the other hand, when alpha-syn induced both neuronal pathology and cell death, there was a delayed increase in microglia cell numbers, which correlated with long-lasting CD68 expression and a morphology reminiscent of peripheral macrophages. In addition T-lymphocyte infiltration, as judged by the presence of CD4+ and CD8+ cells, showed distinct kinetics depending on the degree of neurodegeneration, and was significantly higher when cell death occurred. We have thus for the first time shown that the microglial response differs depending on whether alpha-syn expression results on cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial response is modulated by early events related to alpha-syn expression in substantia nigra and persists at the long term.

  14. Polychlorinated biphenyls alter expression of alpha-synuclein, synaptophysin and parkin in the rat brain

    DEFF Research Database (Denmark)

    Malkiewicz, Katarzyna; Mohammed, Roma; Folkesson, Ronnie

    2006-01-01

    Polychlorinated Biphenyls (PCBs)-induced changes in synaptic transmission are one of the effects of their neurotoxicity but the mechanism remains unknown. We assessed the in vivo effects of the PCBs mixture, Aroclor 1254 on the expression of neuronal proteins that are involved in the synaptic...... function and/or are associated with neurodegeneration. Wistar rats were treated orally with repeated doses of Aroclor 1254 and the levels of soluble alpha-synuclein, parkin, synaptophysin and amyloid precursor protein (APP) in the brain were determined by Western blotting. The results showed that Aroclor...... did not cause changes in the expression and processing of APP but at a dose 100 microg/g/day repeated for 6 days caused a decrease in the expression of alpha-synuclein in the cerebellum, cortex, hippocampus and hypothalamus of the animals sacrificed 2 days after treatment. The decrease in alpha...

  15. An alpha-synuclein MRM assay with diagnostic potential for Parkinson's disease and monitoring disease progression

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Li [Department of Pathology, University of Washington, Seattle WA USA; Stewart, Tessandra [Department of Pathology, University of Washington, Seattle WA USA; Shi, Min [Department of Pathology, University of Washington, Seattle WA USA; Pottiez, Gwenael [Department of Pathology, University of Washington, Seattle WA USA; Dator, Romel [Department of Pathology, University of Washington, Seattle WA USA; Wu, Rui [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, No. 3 Hospital of Beijing University, Beijing China; Aro, Patrick [Department of Pathology, University of Washington, Seattle WA USA; Schuster, Robert J. [Department of Pathology, University of Washington, Seattle WA USA; Ginghina, Carmen [Department of Pathology, University of Washington, Seattle WA USA; Pan, Catherine [Department of Pathology, University of Washington, Seattle WA USA; Gao, Yuqian [Pacific Northwest National Laboratory, Richland WA USA; Qian, Weijun [Pacific Northwest National Laboratory, Richland WA USA; Zabetian, Cyrus P. [Parkinson' s Disease Research and Geriatric Research, Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle WA USA; Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Hu, Shu-Ching [Department of Neurology, University of Washington School of Medicine, Seattle WA USA; Quinn, Joseph F. [Department of Neurology, Oregon Health and Science University, Portland OR USA; Zhang, Jing [Department of Pathology, University of Washington, Seattle WA USA; Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing 100083 China

    2017-04-19

    Aim: The alpha-synuclein (α-syn) level in human cerebrospinal fluid (CSF), as measured by immunoassays, is promising as a Parkinson’s disease (PD) biomarker. However, the levels of total α-syn are inconsistent among studies with large cohorts and different measurement platforms. Total α-syn level also does not correlate with disease severity or progression. Here, we developed a highly sensitive Multiple Reaction Monitoring (MRM) method to measure absolute CSF α-syn peptide concentrations without prior enrichment or fractionation, aiming to discover new candidate biomarkers. Results: Six peptides covering 73% of protein sequence were reliably identified, and two were consistently quantified in cross-sectional and longitudinal cohorts. Absolute concentration of α-syn in human CSF was determined to be 2.1ng/mL. A unique α-syn peptide, TVEGAGSIAAATGFVK (81-96), displayed excellent correlation with previous immunoassay results in two independent PD cohorts (p < 0.001), correlated with disease severity, and its changes significantly tracked the disease progression longitudinally. Conclusions: An MRM assay to quantify human CSF α-syn was developed and optimized. Sixty clinical samples from cross-sectional and longitudinal PD cohorts were analyzed with this approach. Although further larger-scale validation is needed, the results suggest that α-syn peptide could serve as a promising biomarker in PD diagnosis and progression.

  16. Genetic variants of the alpha-synuclein gene SNCA are associated with multiple system atrophy.

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    Ammar Al-Chalabi

    Full Text Available BACKGROUND: Multiple system atrophy (MSA is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of alpha-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the alpha-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson's disease has identified association of a SNP in SNCA with MSA. METHODOLOGY/FINDINGS: We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044, and rs3775444 (P = 0.012, although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3-3.6; rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6-11.7. A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7 x 10(-4. The association with rs3822086 was replicated in the independent samples (P = 0.035. CONCLUSIONS/SIGNIFICANCE: We report a genetic association between MSA and alpha-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00211224.

  17. Neuropathology in mice expressing mouse alpha-synuclein.

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    Claus Rieker

    Full Text Available α-Synuclein (αSN in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN, which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occurred in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are

  18. Differential expression of alpha-synuclein in hippocampal neurons.

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    Katsutoshi Taguchi

    Full Text Available α-Synuclein is the major pathological component of synucleinopathies including Parkinson's disease and dementia with Lewy bodies. Recent studies have demonstrated that α-synuclein also plays important roles in the release of synaptic vesicles and synaptic membrane recycling in healthy neurons. However, the precise relationship between the pathogenicity and physiological functions of α-synuclein remains to be elucidated. To address this issue, we investigated the subcellular localization of α-synuclein in normal and pathological conditions using primary mouse hippocampal neuronal cultures. While some neurons expressed high levels of α-synuclein in presynaptic boutons and cell bodies, other neurons either did not or only very weakly expressed the protein. These α-synuclein-negative cells were identified as inhibitory neurons by immunostaining with specific antibodies against glutamic acid decarboxylase (GAD, parvalbumin, and somatostatin. In contrast, α-synuclein-positive synapses were colocalized with the excitatory synapse marker vesicular glutamate transporter-1. This expression profile of α-synuclein was conserved in the hippocampus in vivo. In addition, we found that while presynaptic α-synuclein colocalizes with synapsin, a marker of presynaptic vesicles, it is not essential for activity-dependent membrane recycling induced by high potassium treatment. Exogenous supply of preformed fibrils generated by recombinant α-synuclein was shown to promote the formation of Lewy body (LB -like intracellular aggregates involving endogenous α-synuclein. GAD-positive neurons did not form LB-like aggregates following treatment with preformed fibrils, however, exogenous expression of human α-synuclein allowed intracellular aggregate formation in these cells. These results suggest the presence of a different mechanism for regulation of the expression of α-synuclein between excitatory and inhibitory neurons. Furthermore, α-synuclein expression

  19. Brain region-dependent differential expression of alpha-synuclein.

    Science.gov (United States)

    Taguchi, Katsutoshi; Watanabe, Yoshihisa; Tsujimura, Atsushi; Tanaka, Masaki

    2016-04-15

    α-Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α-synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α-synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α-synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α-synuclein was highly expressed in the neuronal cell bodies of some early PD-affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α-synuclein was mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory presynaptic marker. In contrast, expression of α-synuclein in the GABAergic inhibitory synapses was different among brain regions. α-Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD-affected human brain regions express high levels of perikaryal α-synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α-synuclein are different in various brain regions. © 2015 Wiley Periodicals, Inc.

  20. Accumulation of phosphorylated alpha-synuclein (p129S) and retinal pathology in a mouse model of Parkinson's disease

    Science.gov (United States)

    Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded alpha-synuclein within the CNS. Although non-motor clinical phenotypes of PD such as visual dysfunction have become increasingly apparent, retinal pathology associated with PD is not well under...

  1. Alpha-synuclein gene ablation increases docosahexaenoic acid incorporation and turnover in brain phospholipids

    DEFF Research Database (Denmark)

    Golovko, Mikhail Y; Rosenberger, Thad A; Feddersen, Søren

    2007-01-01

    Previously, we demonstrated that ablation of alpha-synuclein (Snca) reduces arachidonate (20:4n-6) turnover in brain phospholipids through modulation of an endoplasmic reticulum-localized acyl-CoA synthetase (Acsl). The effect of Snca ablation on docosahexaenoic acid (22:6n-3) metabolism is unknown...... and turnover in ethanolamine glycerophospholipid, phosphatidylserine, and phosphatidylinositol pools. Increased 22:6n-3-CoA mass was not the result of altered Acsl activity, which was unaffected by the absence of Snca. While Snca bound 22:6n-3, Kd = 1.0 +/- 0.5 micromol/L, it did not bind 22:6n-3-Co...

  2. A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

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    Alexander Kurz

    2010-07-01

    Full Text Available Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice.Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

  3. Clearing Extracellular Alpha-Synuclein from Cerebrospinal Fluid: A New Therapeutic Strategy in Parkinson’s Disease

    Science.gov (United States)

    Padilla-Zambrano, Huber S.; Tomás-Zapico, Cristina; García, Benjamin Fernández

    2018-01-01

    This concept article aims to show the rationale of targeting extracellular α-Synuclein (α-Syn) from cerebrospinal fluid (CSF) as a new strategy to remove this protein from the brain in Parkinson’s disease (PD). Misfolding and intracellular aggregation of α-synuclein into Lewy bodies are thought to be crucial in the pathogenesis of PD. Recent research has shown that small amounts of monomeric and oligomeric α-synuclein are released from neuronal cells by exocytosis and that this extracellular alpha-synuclein contributes to neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In PD, extracellular oligomeric-α-synuclein moves in constant equilibrium between the interstitial fluid (ISF) and the CSF. Thus, we expect that continuous depletion of oligomeric-α-synuclein in the CSF will produce a steady clearance of the protein in the ISF, preventing transmission and deposition in the brain. PMID:29570693

  4. Features of alpha-synuclein that could explain the progression and irreversibility of Parkinson's disease

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    Scarlet eGallegos

    2015-03-01

    Full Text Available Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson’s disease (PD which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of α-synuclein allows it to adopt different conformations, i.e. bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of α-synuclein, transmission and toxicity that could help to understand the pathological characteristics of PD. One important feature of α-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of α-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation, and lead to apoptosis pathway activation and consequent cell death. The complexity of α-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease.

  5. Mitochondrial Dysfunction: The Road to Alpha-Synuclein Oligomerization in PD

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    A. R. Esteves

    2011-01-01

    Full Text Available While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers, of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.

  6. A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies.

    Science.gov (United States)

    Ryskalin, Larisa; Busceti, Carla L; Limanaqi, Fiona; Biagioni, Francesca; Gambardella, Stefano; Fornai, Francesco

    2018-01-01

    Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the α-syn gene (SNCA) and in a variety of experimental models, where overexpression of α-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured α-syn produces a damage, which is even worse compared with that produced by α-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of α-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions α-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous α-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing α-syn. In line with this, an increased expression of α-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of α-syn is combined with a depletion of β- and γ- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous α-syn. The specific role of α-syn as a chaperone protein is discussed to explain such a dual effect. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons.

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    Eric J Benner

    2008-01-01

    Full Text Available The neuropathology of Parkinson's disease (PD includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.Nitrotyrosine (NT-modified alpha-Syn was detected readily in cervical lymph nodes (CLN from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss.These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease.

  8. LARGE ANIMAL PARKINSONS DISEASE MODELS USING VIRAL VECTORS AND INOCULATION OF PREFORMED FIBRILS TO MEDIATE ALPHA-SYNUCLEIN OVEREXPRESSION AND MISFOLDING IN THE GOTTINGEN MINIPIG CNS

    DEFF Research Database (Denmark)

    Glud, Andreas Nørgaard; Landau, A.M.; Johnsen, Erik Lisbjerg

    2015-01-01

    Animal models towards understanding and treating Parkinson’s disease (PD) are important translational steps toward clinical applications. The Göttingen minipig(GM), fits progressional neurological models due to an relative low adult weight between 20-40 kg, and has a large gyrencephalic brain (6x...... such as antiaggreganttreatment, induced pluripotent stem cells or immunotherapy and development of novel radioligands for early diagnosis and assess disease progression....... x 4 cm) that can be examined at sufficient resolution using both conventional clinical scanning modalities and preclinical testing of deep brain stimulation, stem cell grafting and other neuromodulatory devices. Aim: Using inoculating of human or pig alpha-synuclein(aSYN) fibrils or overexpressing a......SYN using Lenti virus(LV) and Adeno Assosiated Virus(AAV) vectors in the nigrostriatal system, we hope to create a new porcine model for PD. Methods: Using conventional human-intended stereotaxic neurosurgery methods, we apply aSYN in the catecholamine nigrostriatal system of 13 GM. The changes...

  9. The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression

    Directory of Open Access Journals (Sweden)

    Sohan Mikkilineni

    2012-01-01

    Full Text Available There is compelling support for limiting expression of alpha-synuclein (α-syn in the brains of Parkinson’s disease (PD patients. An increase of SNCA gene copy number can genetically cause familial PD where increased dose of this pathogenic protein correlates with severity of symptoms (triplication of the SNCA gene causes dementia in PD patients. Gene promoter polymorphisms were shown to increase α-synuclein expression as a risk for PD. Cholinesterase inhibitors can clinically slow cognitive decline in the later stages of PD etiology similar to their widespread use in Alzheimer’s disease (AD. Pertinent to this, we identified that the well-tolerated anticholinesterase, phenserine, blocked neural SNCA mRNA translation and tested for targeting via its 5′untranslated region (5′UTR in a manner similar to its action to limit the expression of the AD-specific amyloid precursor protein (APP. Posiphen, its better-tolerated (+ enantiomer (devoid of anticholinesterase action, repressed neural α-synuclein translation. Primary metabolic analogs of posiphen were, likewise, characterized using primary fetal neurons grown ex vivo from the brains of Parkinson’s transgenic mice expressing the human SNCA gene.

  10. A Swedish family with de novo alpha-synuclein A53T mutation: evidence for early cortical dysfunction

    DEFF Research Database (Denmark)

    Puschmann, Andreas; Ross, Owen A; Vilariño-Güell, Carles

    2009-01-01

    A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cog......A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria......) and the Greek-American Family H kindreds. One unaffected family member carried the mutation haplotype without the c.209A mutation, strongly suggesting its de novo occurrence within this family. Furthermore, a novel mutation c.488G > A (p.Arg163His; R163H) in the presenilin-2 (PSEN2) gene was detected...

  11. The role of alpha-synuclein in melanin synthesis in melanoma and dopaminergic neuronal cells.

    Directory of Open Access Journals (Sweden)

    Tianhong Pan

    Full Text Available The relatively high co-occurrence of Parkinson's disease (PD and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM, the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR and inhibit tyrosine hydroxylase (TH, both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA, led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in

  12. Alpha-synuclein, epigenetics, mitochondria, metabolism, calcium traffic, & circadian dysfunction in Parkinson's disease. An integrated strategy for management.

    Science.gov (United States)

    Phillipson, Oliver T

    2017-11-01

    The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features. The main nutrient targets include impaired mitochondria and the associated oxidative/nitrosative stress, calcium stress and impaired gene transcription induced by pathogenic forms of alpha- synuclein. Benefits may be achieved via nutrient influence on epigenetic signaling pathways governing transcription factors for mitochondrial biogenesis, antioxidant defences and the autophagy-lysosomal pathway, via regulation of the metabolic energy sensor AMP activated protein kinase (AMPK) and the mammalian target of rapamycin mTOR. Nutrients also benefit expression of the transcription factor for neuronal survival (NR4A2), trophic factors GDNF and BDNF, and age-related calcium signals. In addition a number of non-motor related dysfunctions in circadian control, clock genes and associated metabolic, endocrine and sleep-wake activity are briefly addressed, as are late-stage complications in respect of cognitive decline and osteoporosis. Analysis of the network of nutrient effects reveals how beneficial synergies may counter the accumulation and promote clearance of pathogenic alpha-synuclein. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  13. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    Science.gov (United States)

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-01

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  14. Dose-dependent striatal changes in dopaminergic terminals and alpha-synuclein reactivity in a porcine model of progressive Parkinson’s disease

    DEFF Research Database (Denmark)

    Nielsen, Mette Slot; Glud, Andreas Nørgaard; Møller, Arne

    2011-01-01

    to discover effective compounds halting PD progression have so far failed in clinical trials, perhaps because current animal models do not imitate the neuropathological progression of PD well enough. We recently established a progressive large animal PD model in Göttingen minipigs based on chronic infusion......Parkinson disease (PD) is a common neurodegenerative disorder, resulting from a progressive dopaminergic neuron loss in the substantia nigra (SN). Alpha-synuclein positive neuronal inclusion bodies and progressive loss of dopaminergic striatal terminals is also well described in PD. Attempts...... the SN were paraffin embedded and immunohistochemically stained for tyrosine hydroxylase (TH) and alpha-synuclein. Stereological examination of the SN showed progressive nigral neuron loss with increased MPTP dosages. Occasional neuronal staining confined to the cytoplasm and cell membrane was observed...

  15. Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

    Directory of Open Access Journals (Sweden)

    Gabriela S. Longo

    2015-06-01

    Full Text Available Introduction The pathogenesis of Parkinson’s disease (PD involves both genetic susceptibility and environmental factors, with focus on the mutation in the alpha-synuclein gene (SNCA.Objective To analyse the polymorphism SNCA-A53T in patients with familial PD (FPD and sporadic PD (SPD.Method A total of 294 individuals were studied, regardless of sex and with mixed ethnicity. The study group with 154 patients with PD, and the control group included 140 individuals without PD. The genotyping of SNCA-A53T was performed by PCR/RFLP. Significance level was p < 0.05.Results Among all patients, 37 (24% had FPD and 117 (75.9% had SPD. The absence of SNCA-A53T mutation was observed in all individuals.Conclusion SPD is notably observed in patients. However, the SNCA-A53T mutation was absent in all individuals, which does not differ controls from patients. This fact should be confirmed in a Brazilian study case with a more numerous and older population.

  16. Alpha-synuclein is present in dental calculus but not altered in Parkinson's disease patients in comparison to controls.

    Science.gov (United States)

    Schmid, Sabrina; Goldberg-Bockhorn, Eva; Schwarz, Silke; Rotter, Nicole; Kassubek, Jan; Del Tredici, Kelly; Pinkhardt, Elmar; Otto, Markus; Ludolph, Albert C; Oeckl, Patrick

    2018-06-01

    In autopsy cases staged for sporadic Parkinson's disease (PD), the neuropathology is characterized by a preclinical phase that targets the enteric nervous system of the gastrointestinal tract (GIT). Therefore, the ENS might be a source of potential (presymptomatic) PD biomarkers. In this clinically based study, we examined the alpha-synuclein (αSyn) concentration in an easily accessible protein storage medium of the GIT, dental calculus, in 21/50 patients with PD and 28/50 age- and gender-matched controls using ELISA. αSyn was detectable in dental calculus and the median concentration in the control patients was 8.6 pg/mg calculus (interquartile range 2.6-13.1 pg/mg). αSyn concentrations were significantly influenced by blood contamination and samples with a hemoglobin concentration of > 4000 ng/mL were excluded. There was no significant difference of αSyn concentrations in the dental calculus of PD patients (5.76 pg/mg, interquartile range 2.91-9.74 pg/mg) compared to those in controls (p = 0.40). The total αSyn concentration in dental calculus is not a suitable biomarker for sporadic PD. Disease-related variants such as oligomeric or phosphorylated αSyn in calculus might prove to be more specific.

  17. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease.

    Science.gov (United States)

    Masliah, Eliezer; Rockenstein, Edward; Mante, Michael; Crews, Leslie; Spencer, Brian; Adame, Anthony; Patrick, Christina; Trejo, Margarita; Ubhi, Kiren; Rohn, Troy T; Mueller-Steiner, Sarah; Seubert, Peter; Barbour, Robin; McConlogue, Lisa; Buttini, Manuel; Games, Dora; Schenk, Dale

    2011-04-29

    Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.

  18. Significant Changes in Plasma Alpha-Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder

    Directory of Open Access Journals (Sweden)

    Wilaiwan Sriwimol

    2018-01-01

    Full Text Available Alpha-synuclein (α-synuclein and beta-synuclein (β-synuclein are presynaptic proteins playing important roles in neuronal plasticity and synaptic vesicle regulation. To evaluate the association of these two proteins and autism spectrum disorder (ASD, we investigated the plasma α-synuclein and β-synuclein levels in 39 male children with ASD (2 subgroups: 25 autism and 14 pervasive developmental disorder-not otherwise specified (PDD-NOS comparing with 29 sex- and age-matched controls by using enzyme-linked immunosorbent assay (ELISA. We first determined the levels of these two proteins in the ASD subgroups and found that there were no significant differences in both plasma α-synuclein and β-synuclein levels in the autism and PDD-NOS groups. Thus, we could combine the 2 subgroups into one ASD group. Interestingly, the mean plasma α-synuclein level was significantly lower (P<0.001 in the ASD children (10.82±6.46 ng/mL than in the controls (29.47±18.62 ng/mL, while the mean plasma β-synuclein level in the ASD children (1344.19±160.26 ng/mL was significantly higher (P<0.05 than in the controls (1219.16±177.10 ng/mL. This is the first study examining the associations between α-synuclein and β-synuclein and male ASD patients. We found that alterations in the plasma α-synuclein and β-synuclein levels might be implicated in the association between synaptic abnormalities and ASD pathogenesis.

  19. The regulation of catalase activity by PPAR gamma is affected by alpha-synuclein

    NARCIS (Netherlands)

    Yakunin, Eugenia; Kisos, Haya; Kulik, Willem; Grigoletto, Jessica; Wanders, Ronald J. A.; Sharon, Ronit

    2014-01-01

    Objective: While evidence for oxidative injury is frequently detected in brains of humans affected by Parkinson's disease (PD) and in relevant animal models, there is uncertainty regarding its cause. We tested the potential role of catalase in the oxidative injury that characterizes PD. Methods:

  20. In vivo silencing of alpha-synuclein using naked siRNA

    OpenAIRE

    Charisse Klaus; Toudjarska Ivanka; Kent Caroline; Hinkle Kelly; Ogholikhan Sina; He Zhen; Braithwaite Adam; Lincoln Sarah; Zehr Cynthia; Hope Andrew; Bumcrot David; Melrose Heather; Lewis Jada; Braich Ravi; Pandey Rajendra K

    2008-01-01

    Abstract Background Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a...

  1. Role of Different Alpha-Synuclein Strains in Synucleinopathies, Similarities with other Neurodegenerative Diseases

    OpenAIRE

    Melki, Ronald

    2015-01-01

    Abstract Misfolded protein aggregates are the hallmark of several neurodegenerative diseases in humans. The main protein constituent of these aggregates and the regions within the brain that are affected differ from one neurodegenerative disorder to another. A plethora of reports suggest that distinct diseases have in common the ability of protein aggregates to spread and amplify within the central nervous system. This review summarizes briefly what is known about the nature of the protein ag...

  2. Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Géraldine H Petit

    Full Text Available Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

  3. In vivo silencing of alpha-synuclein using naked siRNA

    Directory of Open Access Journals (Sweden)

    Charisse Klaus

    2008-11-01

    Full Text Available Abstract Background Overexpression of α-synuclein (SNCA in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD, possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked, murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. Conclusion We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression.

  4. In vivo silencing of alpha-synuclein using naked siRNA

    Science.gov (United States)

    Lewis, Jada; Melrose, Heather; Bumcrot, David; Hope, Andrew; Zehr, Cynthia; Lincoln, Sarah; Braithwaite, Adam; He, Zhen; Ogholikhan, Sina; Hinkle, Kelly; Kent, Caroline; Toudjarska, Ivanka; Charisse, Klaus; Braich, Ravi; Pandey, Rajendra K; Heckman, Michael; Maraganore, Demetrius M; Crook, Julia; Farrer, Matthew J

    2008-01-01

    Background Overexpression of α-synuclein (SNCA) in families with multiplication mutations causes parkinsonism and subsequent dementia, characterized by diffuse Lewy Body disease post-mortem. Genetic variability in SNCA contributes to risk of idiopathic Parkinson's disease (PD), possibly as a result of overexpression. SNCA downregulation is therefore a valid therapeutic target for PD. Results We have identified human and murine-specific siRNA molecules which reduce SNCA in vitro. As a proof of concept, we demonstrate that direct infusion of chemically modified (naked), murine-specific siRNA into the hippocampus significantly reduces SNCA levels. Reduction of SNCA in the hippocampus and cortex persists for a minimum of 1 week post-infusion with recovery nearing control levels by 3 weeks post-infusion. Conclusion We have developed naked gene-specific siRNAs that silence expression of SNCA in vivo. This approach may prove beneficial toward our understanding of the endogenous functional equilibrium of SNCA, its role in disease, and eventually as a therapeutic strategy for α-synucleinopathies resulting from SNCA overexpression. PMID:18976489

  5. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo.

    Directory of Open Access Journals (Sweden)

    Elodie Angot

    Full Text Available Several people with Parkinson's disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10-22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.

  6. Early and progressive microstructural brain changes in mice overexpressing human alpha-Synuclein detected by diffusion kurtosis imaging

    Czech Academy of Sciences Publication Activity Database

    Khairnar, A.; Rudá-Kučerová, J.; Szabó, N.; Dražanová, Eva; Arab, A.; Hutter-Paier, B.; Neddens, J.; Latta, P.; Starčuk jr., Zenon; Rektorová, I.

    2017-01-01

    Roč. 61, MAR (2017), s. 197-208 ISSN 0889-1591 R&D Projects: GA MŠk(CZ) LO1212; GA MŠk(CZ) LM2015062; GA MŠk ED0017/01/01 Institutional support: RVO:68081731 Keywords : MRI * diffusion kurtosis imaging * substantia nigra * sriatum * thalamus * TNWT-61 * parkinson's disease * transgenic mice * animal model Subject RIV: BH - Optics, Masers, Lasers OBOR OECD: 1.7 Other natural sciences Impact factor: 5.964, year: 2016

  7. In parkinsonian substantia nigra, alpha-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity.

    Science.gov (United States)

    Shamoto-Nagai, M; Maruyama, W; Hashizume, Y; Yoshida, M; Osawa, T; Riederer, P; Naoi, M

    2007-01-01

    alpha-Synuclein (alphaSYN) plays a central role in the neural degeneration of Parkinson's disease (PD) through its conformational change. In PD, alphaSYN, released from the membrane, accumulates in the cytoplasm and forms Lewy body. However, the mechanism behind the translocation and conformational change of alphaSYN leading to the cell death has not been well elucidated. This paper reports that in the dopamine neurons of the substantia nigra containing neuromelanin from PD patients, alphaSYN was modified with acrolein (ACR), an aldehyde product of lipid peroxidation. Histopathological observation confirmed the co-localization of protein immunoreactive to anti-alphaSYN and ACR antibody. By Western blot analyses of samples precipitated with either anti-alphaSYN or anti-ACR antibody, increase in ACR-modified alphaSYN was confirmed in PD brain. Modification of recombinant alphaSYN by ACR enhanced its oligomerization, and at higher ACR concentrations alphaSYN was fragmented and polymerized forming a smear pattern in SDS-PAGE. ACR reduced 20S proteasome activity through the direct modification of the proteasome proteins and the production of polymerized ACR-modified proteins, which inhibited proteasome activity in vitro. These results suggest that ACR may initiate vicious cycle of modification and aggregation of proteins, including alphaSYN, and impaired proteolysis system, to cause neuronal death in PD.

  8. Deuterium isotope shifts for backbone {sup 1}H, {sup 15}N and {sup 13}C nuclei in intrinsically disordered protein {alpha}-synuclein

    Energy Technology Data Exchange (ETDEWEB)

    Maltsev, Alexander S.; Ying Jinfa; Bax, Ad, E-mail: bax@nih.gov [National Institutes of Health, Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases (United States)

    2012-10-15

    Intrinsically disordered proteins (IDPs) are abundant in nature and characterization of their potential structural propensities remains a widely pursued but challenging task. Analysis of NMR secondary chemical shifts plays an important role in such studies, but the output of such analyses depends on the accuracy of reference random coil chemical shifts. Although uniform perdeuteration of IDPs can dramatically increase spectral resolution, a feature particularly important for the poorly dispersed IDP spectra, the impact of deuterium isotope shifts on random coil values has not yet been fully characterized. Very precise {sup 2}H isotope shift measurements for {sup 13}C{sup {alpha}}, {sup 13}C{sup {beta}}, {sup 13}C Prime , {sup 15}N, and {sup 1}H{sup N} have been obtained by using a mixed sample of protonated and uniformly perdeuterated {alpha}-synuclein, a protein with chemical shifts exceptionally close to random coil values. Decomposition of these isotope shifts into one-bond, two-bond and three-bond effects as well as intra- and sequential residue contributions shows that such an analysis, which ignores conformational dependence, is meaningful but does not fully describe the total isotope shift to within the precision of the measurements. Random coil {sup 2}H isotope shifts provide an important starting point for analysis of such shifts in structural terms in folded proteins, where they are known to depend strongly on local geometry.

  9. The different faces of the p. A53T alpha-synuclein mutation: A screening of Greek patients with parkinsonism and/or dementia.

    Science.gov (United States)

    Breza, Marianthi; Koutsis, Georgios; Karadima, Georgia; Potagas, Constantin; Kartanou, Chrisoula; Papageorgiou, Sokratis G; Paraskevas, George P; Kapaki, Elisabeth; Stefanis, Leonidas; Panas, Marios

    2018-04-13

    The p. A53T mutation in the alpha-synuclein (SNCA) gene is a rare cause of autosomal dominant Parkinson's disease (PD). Although generally rare, it is particularly common in the Greek population due to a founder effect. A53T-positive PD patients often develop dementia during disease course and may very rarely present with dementia. We screened for the p. A53T SNCA mutation a total of 347 cases of Greek origin with parkinsonism and/or dementia, collected over 15 years at the Neurogenetics Unit, Eginition Hospital, University of Athens. Cases were classified into: "pure parkinsonism", "pure dementia" and "parkinsonism plus dementia". In total, 4 p. A53T SNCA mutation carriers were identified. All had autosomal dominant family history and early onset. Screening of the "pure parkinsonism" category revealed 2 cases with typical PD. The other two mutation carriers were identified in the "parkinsonism plus dementia" category. One had a diagnosis of PD dementia and the other of behavioral variant frontotemporal dementia. Screening of patients with "pure dementia" failed to identify any further A53T-positive cases. Our results confirm that the p. A53T SNCA mutation is relatively common in Greek patients with PD or PD plus dementia, particularly in cases with early onset and/or autosomal dominant family history. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Evidence for Intramolecular Antiparallel Beta-Sheet Structure in Alpha-Synuclein Fibrils from a Combination of Two-Dimensional Infrared Spectroscopy and Atomic Force Microscopy

    Science.gov (United States)

    Roeters, Steven J.; Iyer, Aditya; Pletikapić, Galja; Kogan, Vladimir; Subramaniam, Vinod; Woutersen, Sander

    2017-01-01

    The aggregation of the intrinsically disordered protein alpha-synuclein (αS) into amyloid fibrils is thought to play a central role in the pathology of Parkinson’s disease. Using a combination of techniques (AFM, UV-CD, XRD, and amide-I 1D- and 2D-IR spectroscopy) we show that the structure of αS fibrils varies as a function of ionic strength: fibrils aggregated in low ionic-strength buffers ([NaCl] ≤ 25 mM) have a significantly different structure than fibrils grown in higher ionic-strength buffers. The observations for fibrils aggregated in low-salt buffers are consistent with an extended conformation of αS molecules, forming hydrogen-bonded intermolecular β-sheets that are loosely packed in a parallel fashion. For fibrils aggregated in high-salt buffers (including those prepared in buffers with a physiological salt concentration) the measurements are consistent with αS molecules in a more tightly-packed, antiparallel intramolecular conformation, and suggest a structure characterized by two twisting stacks of approximately five hydrogen-bonded intermolecular β-sheets each. We find evidence that the high-frequency peak in the amide-I spectrum of αS fibrils involves a normal mode that differs fundamentally from the canonical high-frequency antiparallel β-sheet mode. The high sensitivity of the fibril structure to the ionic strength might form the basis of differences in αS-related pathologies.

  11. Drp-1 dependent mitochondrial fragmentation and protective autophagy in dopaminergic SH-SY5Y cells overexpressing alpha-synuclein.

    Science.gov (United States)

    Martinez, Jimena Hebe; Alaimo, Agustina; Gorojod, Roxana Mayra; Porte Alcon, Soledad; Fuentes, Federico; Coluccio Leskow, Federico; Kotler, Mónica Lidia

    2018-04-01

    Parkinson's disease is a neurodegenerative movement disorder caused by the loss of dopaminergic neurons from substantia nigra. It is characterized by the accumulation of aggregated α-synuclein as the major component of the Lewy bodies. Additional common features of this disease are the mitochondrial dysfunction and the activation/inhibition of autophagy both events associated to the intracellular accumulation of α-synuclein. The mechanism by which these events contribute to neural degeneration remains unknown. In the present work we investigated the effect of α-synuclein on mitochondrial dynamics and autophagy/mitophagy in SH-SY5Y cells, an in vitro model of Parkinson disease. We demonstrated that overexpression of wild type α-synuclein causes moderated toxicity, ROS generation and mitochondrial dysfunction. In addition, α-synuclein induces the mitochondrial fragmentation on a Drp-1-dependent fashion. Overexpression of the fusion protein Opa-1 prevented both mitochondrial fragmentation and cytotoxicity. On the other hand, cells expressing α-synuclein showed activated autophagy and particularly mitophagy. Employing a genetic strategy we demonstrated that autophagy is triggered in order to protect cells from α-synuclein-induced cell death. Our results clarify the role of Opa-1 and Drp-1 in mitochondrial dynamics and cell survival, a controversial α-synuclein research issue. The findings presented point to the relevance of mitochondrial homeostasis and autophagy in the pathogenesis of PD. Better understanding of the molecular interaction between these processes could give rise to novel therapeutic methods for PD prevention and amelioration. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Solt, Anna C; Henríquez-Roldán, Carlos; Torres-Jardón, Ricardo; Nuse, Bryan; Herritt, Lou; Villarreal-Calderón, Rafael; Osnaya, Norma; Stone, Ida; García, Raquel; Brooks, Diane M; González-Maciel, Angelica; Reynoso-Robles, Rafael; Delgado-Chávez, Ricardo; Reed, William

    2008-02-01

    Air pollution is a serious environmental problem. We investigated whether residency in cities with high air pollution is associated with neuroinflammation/neurodegeneration in healthy children and young adults who died suddenly. We measured mRNA cyclooxygenase-2, interleukin-1beta, and CD14 in target brain regions from low (n = 12) or highly exposed residents (n = 35) aged 25.1 +/- 1.5 years. Upregulation of cyclooxygenase-2, interleukin-1beta, and CD14 in olfactory bulb, frontal cortex, substantia nigrae and vagus nerves; disruption of the blood-brain barrier; endothelial activation, oxidative stress, and inflammatory cell trafficking were seen in highly exposed subjects. Amyloid beta42 (Abeta42) immunoreactivity was observed in 58.8% of apolipoprotein E (APOE) 3/3 < 25 y, and 100% of the APOE 4 subjects, whereas alpha-synuclein was seen in 23.5% of < 25 y subjects. Particulate material (PM) was seen in olfactory bulb neurons, and PM < 100 nm were observed in intraluminal erythrocytes from lung, frontal, and trigeminal ganglia capillaries. Exposure to air pollution causes neuroinflammation, an altered brain innate immune response, and accumulation of Abeta42 and alpha-synuclein starting in childhood. Exposure to air pollution should be considered a risk factor for Alzheimer's and Parkinson's diseases, and carriers of the APOE 4 allele could have a higher risk of developing Alzheimer's disease if they reside in a polluted environment.

  13. Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases.

    Science.gov (United States)

    Desplats, Paula; Spencer, Brian; Coffee, Elizabeth; Patel, Pruthul; Michael, Sarah; Patrick, Christina; Adame, Anthony; Rockenstein, Edward; Masliah, Eliezer

    2011-03-18

    DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.

  14. Photobiomodulation Suppresses Alpha-Synuclein-Induced Toxicity in an AAV-Based Rat Genetic Model of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Abid Oueslati

    Full Text Available Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM, may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human α-synuclein (α-syn in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD. In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated α-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies.

  15. TRIGGER

    CERN Multimedia

    Wesley Smith

    Level-1 Trigger Hardware and Software The hardware of the trigger components has been mostly finished. The ECAL Endcap Trigger Concentrator Cards (TCC) are in production while Barrel TCC firmware has been upgraded, and the Trigger Primitives can now be stored by the Data Concentrator Card for readout by the DAQ. The Regional Calorimeter Trigger (RCT) system is complete, and the timing is being finalized. All 502 HCAL trigger links to RCT run without error. The HCAL muon trigger timing has been equalized with DT, RPC, CSC and ECAL. The hardware and firmware for the Global Calorimeter Trigger (GCT) jet triggers are being commissioned and data from these triggers is available for readout. The GCT energy sums from rings of trigger towers around the beam pipe beam have been changed to include two rings from both sides. The firmware for Drift Tube Track Finder, Barrel Sorter and Wedge Sorter has been upgraded, and the synchronization of the DT trigger is satisfactory. The CSC local trigger has operated flawlessly u...

  16. TRIGGER

    CERN Multimedia

    Roberta Arcidiacono

    2013-01-01

    Trigger Studies Group (TSG) The Trigger Studies Group has just concluded its third 2013 workshop, where all POGs presented the improvements to the physics object reconstruction, and all PAGs have shown their plans for Trigger development aimed at the 2015 High Level Trigger (HLT) menu. The Strategy for Trigger Evolution And Monitoring (STEAM) group is responsible for Trigger menu development, path timing, Trigger performance studies coordination, HLT offline DQM as well as HLT release, menu and conditions validation – this last task in collaboration with PdmV (Physics Data and Monte Carlo Validation group). In the last months the group has delivered several HLT rate estimates and comparisons, using the available data and Monte Carlo samples. The studies were presented at the Trigger workshops in September and December, and STEAM has contacted POGs and PAGs to understand the origin of the discrepancies observed between 8 TeV data and Monte Carlo simulations. The most recent results show what the...

  17. SMG1 identified as a regulator of Parkinson's disease-associated alpha-synuclein through siRNA screening.

    Directory of Open Access Journals (Sweden)

    Adrienne Henderson-Smith

    Full Text Available Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129 compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson's disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn. Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB and Parkinson's disease with dementia (PDD. These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.

  18. Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson’s Disease Patients

    Science.gov (United States)

    Mu, Liancai; Chen, Jingming; Sobotka, Stanislaw; Nyirenda, Themba; Benson, Brian; Gupta, Fiona; Sanders, Ira; Adler, Charles H.; Caviness, John N.; Shill, Holly A.; Sabbagh, Marwan; Samanta, Johan E.; Sue, Lucia I.; Beach, Thomas G.

    2015-01-01

    Dysphagia is common in Parkinson’s disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia. PMID:26041249

  19. Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

    Science.gov (United States)

    Mu, Liancai; Chen, Jingming; Sobotka, Stanislaw; Nyirenda, Themba; Benson, Brian; Gupta, Fiona; Sanders, Ira; Adler, Charles H; Caviness, John N; Shill, Holly A; Sabbagh, Marwan; Samanta, Johan E; Sue, Lucia I; Beach, Thomas G

    2015-08-01

    Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

  20. TRIGGER

    CERN Multimedia

    Wesley Smith

    Level-1 Trigger Hardware and Software The trigger synchronization procedures for running with cosmic muons and operating with the LHC were reviewed during the May electronics week. Firmware maintenance issues were also reviewed. Link tests between the new ECAL endcap trigger concentrator cards (TCC48) and the Regional Calorimeter Trigger have been performed. Firmware for the energy sum triggers and an upgraded tau trigger of the Global Calorimeter Triggers has been developed and is under test. The optical fiber receiver boards for the Track-Finder trigger theta links of the DT chambers are now all installed. The RPC trigger is being made more robust by additional chamber and cable shielding and also by firmware upgrades. For the CSC’s the front-end and trigger motherboard firmware have been updated. New RPC patterns and DT/CSC lookup tables taking into account phi asymmetries in the magnetic field configuration are under study. The motherboard for the new pipeline synchronizer of the Global Trigg...

  1. TRIGGER

    CERN Multimedia

    W. Smith

    2012-01-01

      Level-1 Trigger The Level-1 Trigger group is ready to deploy improvements to the L1 Trigger algorithms for 2012. These include new high-PT patterns for the RPC endcap, an improved CSC PT assignment, a new PT-matching algorithm for the Global Muon Trigger, and new calibrations for ECAL, HCAL, and the Regional Calorimeter Trigger. These should improve the efficiency, rate, and stability of the L1 Trigger. The L1 Trigger group also is migrating the online systems to SLC5. To make the data transfer from the Global Calorimeter Trigger to the Global Trigger more reliable and also to allow checking the data integrity online, a new optical link system has been developed by the GCT and GT groups and successfully tested at the CMS electronics integration facility in building 904. This new system is now undergoing further tests at Point 5 before being deployed for data-taking this year. New L1 trigger menus have recently been studied and proposed by Emmanuelle Perez and the L1 Detector Performance Group...

  2. Alpha synuclein in Parkinson's disease

    DEFF Research Database (Denmark)

    Kragh, Christine Lund; Romero-Ramos, Marina; Halliday, Glenda M

    2014-01-01

    The perception of Parkinson’s disease (PD) as a disease centered on dopaminergic striatonigral neurodegeneration has changed fundamentally since 1997 when the first mutation in the SNCA gene (PARK1) encoding a-synuclein was discovered (Polymeropoulos et al. 1997). This discovery formed the basis...

  3. TRIGGER

    CERN Multimedia

    W. Smith

    At the March meeting, the CMS trigger group reported on progress in production, tests in the Electronics Integration Center (EIC) in Prevessin 904, progress on trigger installation in the underground counting room at point 5, USC55, the program of trigger pattern tests and vertical slice tests and planning for the Global Runs starting this summer. The trigger group is engaged in the final stages of production testing, systems integration, and software and firmware development. Most systems are delivering final tested electronics to CERN. The installation in USC55 is underway and integration testing is in full swing. A program of orderly connection and checkout with subsystems and central systems has been developed. This program includes a series of vertical subsystem slice tests providing validation of a portion of each subsystem from front-end electronics through the trigger and DAQ to data captured and stored. After full checkout, trigger subsystems will be then operated in the CMS Global Runs. Continuous...

  4. TRIGGER

    CERN Multimedia

    Wesley Smith

    Level-1 Trigger Hardware and Software The production of the trigger hardware is now basically finished, and in time for the turn-on of the LHC. The last boards produced are the Trigger Concentrator Cards for the ECAL Endcaps (TCC-EE). After the recent installation of the four EE Dees, the TCC-EE prototypes were used for their commissioning. Production boards are arriving and are being tested continuously, with the last ones expected in November. The Regional Calorimeter Trigger hardware is fully integrated after installation of the last EE cables. Pattern tests from the HCAL up to the GCT have been performed successfully. The HCAL triggers are fully operational, including the connection of the HCAL-outer and forward-HCAL (HO/HF) technical triggers to the Global Trigger. The HCAL Trigger and Readout (HTR) board firmware has been updated to permit recording of the tower “feature bit” in the data. The Global Calorimeter Trigger hardware is installed, but some firmware developments are still n...

  5. TRIGGER

    CERN Multimedia

    by Wesley Smith

    2010-01-01

    Level-1 Trigger Hardware and Software The overall status of the L1 trigger has been excellent and the running efficiency has been high during physics fills. The timing is good to about 1%. The fine-tuning of the time synchronization of muon triggers is ongoing and will be completed after more than 10 nb-1 of data have been recorded. The CSC trigger primitive and RPC trigger timing have been refined. A new configuration for the CSC Track Finder featured modified beam halo cuts and improved ghost cancellation logic. More direct control was provided for the DT opto-receivers. New RPC Cosmic Trigger (RBC/TTU) trigger algorithms were enabled for collision runs. There is further work planned during the next technical stop to investigate a few of the links from the ECAL to the Regional Calorimeter Trigger (RCT). New firmware and a new configuration to handle trigger rate spikes in the ECAL barrel are also being tested. A board newly developed by the tracker group (ReTRI) has been installed and activated to block re...

  6. TRIGGER

    CERN Multimedia

    W. Smith

    2010-01-01

    Level-1 Trigger Hardware and Software The Level-1 Trigger hardware has performed well during both the recent proton-proton and heavy ion running. Efforts were made to improve the visibility and handling of alarms and warnings. The tracker ReTRI boards that prevent fixed frequencies of Level-1 Triggers are now configured through the Trigger Supervisor. The Global Calorimeter Trigger (GCT) team has introduced a buffer cleanup procedure at stops and a reset of the QPLL during configuring to ensure recalibration in case of a switch from the LHC clock to the local clock. A device to test the cables between the Regional Calorimeter Trigger and the GCT has been manufactured. A wrong charge bit was fixed in the CSC Trigger. The ECAL group is improving crystal masking and spike suppression in the trigger primitives. New firmware for the Drift Tube Track Finder (DTTF) sorters was developed to improve fake track tagging and sorting. Zero suppression was implemented in the DT Sector Collector readout. The track finder b...

  7. TRIGGER

    CERN Multimedia

    Wesley Smith

    Trigger Hardware The status of the trigger components was presented during the September CMS Week and Annual Review and at the monthly trigger meetings in October and November. Procedures for cold and warm starts (e.g. refreshing of trigger parameters stored in registers) of the trigger subsystems have been studied. Reviews of parts of the Global Calorimeter Trigger (GCT) and the Global Trigger (GT) have taken place in October and November. The CERN group summarized the status of the Trigger Timing and Control (TTC) system. All TTC crates and boards are installed in the underground counting room, USC55. The central clock system will be upgraded in December (after the Global Run at the end of November GREN) to the new RF2TTC LHC machine interface timing module. Migration of subsystem's TTC PCs to SLC4/ XDAQ 3.12 is being prepared. Work is on going to unify the access to Local Timing Control (LTC) and TTC CMS interface module (TTCci) via SOAP (Simple Object Access Protocol, a lightweight XML-based messaging ...

  8. TRIGGER

    CERN Multimedia

    W. Smith from contributions of C. Leonidopoulos

    2010-01-01

    Level-1 Trigger Hardware and Software Since nearly all of the Level-1 (L1) Trigger hardware at Point 5 has been commissioned, activities during the past months focused on the fine-tuning of synchronization, particularly for the ECAL and the CSC systems, on firmware upgrades and on improving trigger operation and monitoring. Periodic resynchronizations or hard resets and a shortened luminosity section interval of 23 seconds were implemented. For the DT sector collectors, an automatic power-off was installed in case of high temperatures, and the monitoring capabilities of the opto-receivers and the mini-crates were enhanced. The DTTF and the CSCTF now have improved memory lookup tables. The HCAL trigger primitive logic implemented a new algorithm providing better stability of the energy measurement in the presence of any phase misalignment. For the Global Calorimeter Trigger, additional Source Cards have been manufactured and tested. Testing of the new tau, missing ET and missing HT algorithms is underw...

  9. TRIGGER

    CERN Multimedia

    Wesley Smith

    Level-1 Trigger Hardware and Software The final parts of the Level-1 trigger hardware are now being put in place. For the ECAL endcaps, more than half of the Trigger Concentrator Cards for the ECAL Endcap (TCC-EE) are now available at CERN, such that one complete endcap can be covered. The Global Trigger now correctly handles ECAL calibration sequences, without being influenced by backpressure. The Regional Calorimeter Trigger (RCT) hardware is complete and working in USC55. Intra-crate tests of all 18 RCT crates and the Global Calorimeter Trigger (GCT) are regularly taking place. Pattern tests have successfully captured data from HCAL through RCT to the GCT Source Cards. HB/HE trigger data are being compared with emulator results to track down the very few remaining hardware problems. The treatment of hot and dead cells, including their recording in the database, has been defined. For the GCT, excellent agreement between the emulator and data has been achieved for jets and HF ET sums. There is still som...

  10. TRIGGER

    CERN Multimedia

    W. Smith

    Level-1 Trigger Hardware and Software The trigger system has been constantly in use in cosmic and commissioning data taking periods. During CRAFT running it delivered 300 million muon and calorimeter triggers to CMS. It has performed stably and reliably. During the abort gaps it has also provided laser and other calibration triggers. Timing issues, namely synchronization and latency issues, have been solved. About half of the Trigger Concentrator Cards for the ECAL Endcap (TCC-EE) are installed, and the firmware is being worked on. The production of the other half has started. The HCAL Trigger and Readout (HTR) card firmware has been updated, and new features such as fast parallel zero-suppression have been included. Repairs of drift tube (DT) trigger mini-crates, optical links and receivers of sector collectors are under way and have been completed on YB0. New firmware for the optical receivers of the theta links to the drift tube track finder is being installed. In parallel, tests with new eta track finde...

  11. TRIGGER

    CERN Multimedia

    R. Carlin with contributions from D. Acosta

    2012-01-01

    Level-1 Trigger Data-taking continues at cruising speed, with high availability of all components of the Level-1 trigger. We have operated the trigger up to a luminosity of 7.6E33, where we approached 100 kHz using the 7E33 prescale column.  Recently, the pause without triggers in case of an automatic "RESYNC" signal (the "settle" and "recover" time) was reduced in order to minimise the overall dead-time. This may become very important when the LHC comes back with higher energy and luminosity after LS1. We are also preparing for data-taking in the proton-lead run in early 2013. The CASTOR detector will make its comeback into CMS and triggering capabilities are being prepared for this. Steps to be taken include improved cooperation with the TOTEM trigger system and using the LHC clock during the injection and ramp phases of LHC. Studies are being finalised that will have a bearing on the Trigger Technical Design Report (TDR), which is to be rea...

  12. TRIGGER

    CERN Multimedia

    W. Smith

    At the December meeting, the CMS trigger group reported on progress in production, tests in the Electronics Integration Center (EIC) in Prevessin 904, progress on trigger installation in the underground counting room at point 5, USC55, and results from the Magnet Test and Cosmic Challenge (MTCC) phase II. The trigger group is engaged in the final stages of production testing, systems integration, and software and firmware development. Most systems are delivering final tested electronics to CERN. The installation in USC55 is underway and moving towards integration testing. A program of orderly connection and checkout with subsystems and central systems has been developed. This program includes a series of vertical subsystem slice tests providing validation of a portion of each subsystem from front-end electronics through the trigger and DAQ to data captured and stored. This is combined with operations and testing without beam that will continue until startup. The plans for start-up, pilot and early running tri...

  13. TRIGGER

    CERN Multimedia

    Wesley Smith

    2011-01-01

    Level-1 Trigger Hardware and Software New Forward Scintillating Counters (FSC) for rapidity gap measurements have been installed and integrated into the Trigger recently. For the Global Muon Trigger, tuning of quality criteria has led to improvements in muon trigger efficiencies. Several subsystems have started campaigns to increase spares by recovering boards or producing new ones. The barrel muon sector collector test system has been reactivated, new η track finder boards are in production, and φ track finder boards are under revision. In the CSC track finder, an η asymmetry problem has been corrected. New pT look-up tables have also improved efficiency. RPC patterns were changed from four out of six coincident layers to three out of six in the barrel, which led to a significant increase in efficiency. A new PAC firmware to trigger on heavy stable charged particles allows looking for chamber hit coincidences in two consecutive bunch-crossings. The redesign of the L1 Trigger Emulator...

  14. TRIGGER

    CERN Multimedia

    W. Smith, from contributions of D. Acosta

    2012-01-01

      The L1 Trigger group deployed several major improvements this year. Compared to 2011, the single-muon trigger rate has been reduced by a factor of 2 and the η coverage has been restored to 2.4, with high efficiency. During the current technical stop, a higher jet seed threshold will be applied in the Global Calorimeter Trigger in order to significantly reduce the strong pile-up dependence of the HT and multi-jet triggers. The currently deployed L1 menu, with the “6E33” prescales, has a total rate of less than 100 kHz and operates with detector readout dead time of less than 3% for luminosities up to 6.5 × 1033 cm–2s–1. Further prescale sets have been created for 7 and 8 × 1033 cm–2s–1 luminosities. The L1 DPG is evaluating the performance of the Trigger for upcoming conferences and publication. Progress on the Trigger upgrade was reviewed during the May Upgrade Week. We are investigating scenarios for stagin...

  15. TRIGGER

    CERN Multimedia

    W. Smith from contributions of C. Leonidopoulos, I. Mikulec, J. Varela and C. Wulz.

    Level-1 Trigger Hardware and Software Over the past few months, the Level-1 trigger has successfully recorded data with cosmic rays over long continuous stretches as well as LHC splash events, beam halo, and collision events. The L1 trigger hardware, firmware, synchronization, performance and readiness for beam operation were reviewed in October. All L1 trigger hardware is now installed at Point 5, and most of it is completely commissioned. While the barrel ECAL Trigger Concentrator Cards are fully operational, the recently delivered endcap ECAL TCC system is still being commissioned. For most systems there is a sufficient number of spares available, but for a few systems additional reserve modules are needed. It was decided to increase the overall L1 latency by three bunch crossings to increase the safety margin for trigger timing adjustments. In order for CMS to continue data taking during LHC frequency ramps, the clock distribution tree needs to be reset. The procedures for this have been tested. A repl...

  16. TRIGGER

    CERN Multimedia

    R. Arcidiacono

    2013-01-01

      In 2013 the Trigger Studies Group (TSG) has been restructured in three sub-groups: STEAM, for the development of new HLT menus and monitoring their performance; STORM, for the development of HLT tools, code and actual configurations; and FOG, responsible for the online operations of the High Level Trigger. The Strategy for Trigger Evolution And Monitoring (STEAM) group is responsible for Trigger Menu development, path timing, trigger performance studies coordination, HLT offline DQM as well as HLT release, menu and conditions validation – in collaboration and with the technical support of the PdmV group. Since the end of proton-proton data taking, the group has started preparing for 2015 data taking, with collisions at 13 TeV and 25 ns bunch spacing. The reliability of the extrapolation to higher energy is being evaluated comparing the trigger rates on 7 and 8 TeV Monte Carlo samples with the data taken in the past two years. The effect of 25 ns bunch spacing is being studied on the d...

  17. TRIGGER

    CERN Multimedia

    W. Smith

    Level-1 Trigger Hardware and Software The road map for the final commissioning of the level-1 trigger system has been set. The software for the trigger subsystems is being upgraded to run under CERN Scientific Linux 4 (SLC4). There is also a new release for the Trigger Supervisor (TS 1.4), which implies upgrade work by the subsystems. As reported by the CERN group, a campaign to tidy the Trigger Timing and Control (TTC) racks has begun. The machine interface was upgraded by installing the new RF2TTC module, which receives RF signals from LHC Point 4. Two Beam Synchronous Timing (BST) signals, one for each beam, can now be received in CMS. The machine group will define the exact format of the information content shortly. The margin on the locking range of the CMS QPLL is planned for study for different subsystems in the next Global Runs, using a function generator. The TTC software has been successfully tested on SLC4. Some TTC subsystems have already been upgraded to SLC4. The TTCci Trigger Supervisor ...

  18. TRIGGER

    CERN Multimedia

    by Wesley Smith

    2011-01-01

    Level-1 Trigger Hardware and Software After the winter shutdown minor hardware problems in several subsystems appeared and were corrected. A reassessment of the overall latency has been made. In the TTC system shorter cables between TTCci and TTCex have been installed, which saved one bunch crossing, but which may have required an adjustment of the RPC timing. In order to tackle Pixel out-of-syncs without influencing other subsystems, a special hardware/firmware re-sync protocol has been introduced in the Global Trigger. The link between the Global Calorimeter Trigger and the Global Trigger with the new optical Global Trigger Interface and optical receiver daughterboards has been successfully tested in the Electronics Integration Centre in building 904. New firmware in the GCT now allows a setting to remove the HF towers from energy sums. The HF sleeves have been replaced, which should lead to reduced rates of anomalous signals, which may allow their inclusion after this is validated. For ECAL, improvements i...

  19. TRIGGER

    CERN Multimedia

    W. Smith

    2011-01-01

    Level-1 Trigger Hardware and Software Overall the L1 trigger hardware has been running very smoothly during the last months of proton running. Modifications for the heavy-ion run have been made where necessary. The maximal design rate of 100 kHz can be sustained without problems. All L1 latencies have been rechecked. The recently installed Forward Scintillating Counters (FSC) are being used in the heavy ion run. The ZDC scintillators have been dismantled, but the calorimeter itself remains. We now send the L1 accept signal and other control signals to TOTEM. Trigger cables from TOTEM to CMS will be installed during the Christmas shutdown, so that the TOTEM data can be fully integrated within the CMS readout. New beam gas triggers have been developed, since the BSC-based trigger is no longer usable at high luminosities. In particular, a special BPTX signal is used after a quiet period with no collisions. There is an ongoing campaign to provide enough spare modules for the different subsystems. For example...

  20. TRIGGER

    CERN Multimedia

    J. Alimena

    2013-01-01

    Trigger Strategy Group The Strategy for Trigger Evolution And Monitoring (STEAM) group is responsible for the development of future High-Level Trigger menus, as well as of its DQM and validation, in collaboration and with the technical support of the PdmV group. Taking into account the beam energy and luminosity expected in 2015, a rough estimate of the trigger rates indicates a factor four increase with respect to 2012 conditions. Assuming that a factor two can be tolerated thanks to the increase in offline storage and processing capabilities, a toy menu has been developed using the new OpenHLT workflow to estimate the transverse energy/momentum thresholds that would halve the current trigger rates. The CPU time needed to run the HLT has been compared between data taken with 25 ns and 50 ns bunch spacing, for equivalent pile-up: no significant difference was observed on the global time per event distribution at the only available data point, corresponding to a pile-up of about 10 interactions. Using th...

  1. TRIGGER

    CERN Multimedia

    W. Smith

    Level-1 Trigger Hardware The CERN group is working on the TTC system. Seven out of nine sub-detector TTC VME crates with all fibers cabled are installed in USC55. 17 Local Trigger Controller (LTC) boards have been received from production and are in the process of being tested. The RF2TTC module replacing the TTCmi machine interface has been delivered and will replace the TTCci module used to mimic the LHC clock. 11 out of 12 crates housing the barrel ECAL off-detector electronics have been installed in USC55 after commissioning at the Electronics Integration Centre in building 904. The cabling to the Regional Calorimeter Trigger (RCT) is terminated. The Lisbon group has completed the Synchronization and Link mezzanine board (SLB) production. The Palaiseau group has fully tested and installed 33 out of 40 Trigger Concentrator Cards (TCC). The seven remaining boards are being remade. The barrel TCC boards have been tested at the H4 test beam, and good agreement with emulator predictions were found. The cons...

  2. Human papilloma virus infection and psoriasis: Did human papilloma virus infection trigger psoriasis?

    Science.gov (United States)

    Jain, Sonia P; Gulhane, Sachin; Pandey, Neha; Bisne, Esha

    2015-01-01

    Psoriasis is an autoimmune chronic inflammatory skin disease known to be triggered by streptococcal and HIV infections. However, human papilloma virus infection (HPV) as a triggering factor for the development of psoriasis has not been reported yet. We, hereby report a case of plaque type with inverse psoriasis which probably could have been triggered by genital warts (HPV infection) and discuss the possible pathomechanisms for their coexistence and its management.

  3. Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering.

    Science.gov (United States)

    Chaabane, Wiem; Cieślar-Pobuda, Artur; El-Gazzah, Mohamed; Jain, Mayur V; Rzeszowska-Wolny, Joanna; Rafat, Mehrdad; Stetefeld, Joerg; Ghavami, Saeid; Los, Marek J

    2014-09-01

    The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

  4. The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease Mutação G209A no gene da alfa-sinucleína em famílias brasileiras com doença de Parkinson

    Directory of Open Access Journals (Sweden)

    Hélio A.G. Teive

    2001-09-01

    Full Text Available A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD. The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.Recentemente foi detectada mutação missense G209A no gene da alfa-sinucleína em uma grande família com doença de Parkinson (DP de Contursi, Itália. Este estudo tem o objetivo de determinar se a mutação G209A está presente em 10 famílias brasileiras com DP. Pacientes com DP foram recrutados em clínicas de distúrbio do movimento no Brasil. O critério de inclusão no estudo foi à presença de dois ou mais familiares acometidos pela DP. A mutação G209A do gene da alfa-sinucleína foi pesquisada usando a técnica de reação em cadeia de polimerase e a enzima de restrição Tsp45I. Foram estudados 10 pacientes de famílias não-relacionadas. A idade média do início dos sintomas da DP foi 42,7 anos. Não encontramos a mutação estudada neste grupo de pacientes. Nossos resultados sugerem que a mutação G209A é incomum em famílias brasileiras com DP.

  5. Social Laughter Triggers Endogenous Opioid Release in Humans.

    Science.gov (United States)

    Manninen, Sandra; Tuominen, Lauri; Dunbar, Robin I; Karjalainen, Tomi; Hirvonen, Jussi; Arponen, Eveliina; Hari, Riitta; Jääskeläinen, Iiro P; Sams, Mikko; Nummenmaa, Lauri

    2017-06-21

    The size of human social networks significantly exceeds the network that can be maintained by social grooming or touching in other primates. It has been proposed that endogenous opioid release after social laughter would provide a neurochemical pathway supporting long-term relationships in humans (Dunbar, 2012), yet this hypothesis currently lacks direct neurophysiological support. We used PET and the μ-opioid-receptor (MOR)-specific ligand [ 11 C]carfentanil to quantify laughter-induced endogenous opioid release in 12 healthy males. Before the social laughter scan, the subjects watched laughter-inducing comedy clips with their close friends for 30 min. Before the baseline scan, subjects spent 30 min alone in the testing room. Social laughter increased pleasurable sensations and triggered endogenous opioid release in thalamus, caudate nucleus, and anterior insula. In addition, baseline MOR availability in the cingulate and orbitofrontal cortices was associated with the rate of social laughter. In a behavioral control experiment, pain threshold-a proxy of endogenous opioidergic activation-was elevated significantly more in both male and female volunteers after watching laughter-inducing comedy versus non-laughter-inducing drama in groups. Modulation of the opioidergic activity by social laughter may be an important neurochemical pathway that supports the formation, reinforcement, and maintenance of human social bonds. SIGNIFICANCE STATEMENT Social contacts are vital to humans. The size of human social networks significantly exceeds the network that can be maintained by social grooming in other primates. Here, we used PET to show that endogenous opioid release after social laughter may provide a neurochemical mechanism supporting long-term relationships in humans. Participants were scanned twice: after a 30 min social laughter session and after spending 30 min alone in the testing room (baseline). Endogenous opioid release was stronger after laughter versus the

  6. Assays for alpha-synuclein aggregation

    DEFF Research Database (Denmark)

    Giehm, Lise; Lorenzen, Nikolai; Otzen, Daniel

    2011-01-01

    Over the last few decades, protein aggregation gone from being an irritating side product in the test tube to becoming a subject of great interest. This has been stimulated by the realization that a large and growing number of diseases is associated with the formation and accumulation of proteins...

  7. Human behaviour can trigger large carnivore attacks in developed countries.

    Science.gov (United States)

    Penteriani, Vincenzo; Delgado, María del Mar; Pinchera, Francesco; Naves, Javier; Fernández-Gil, Alberto; Kojola, Ilpo; Härkönen, Sauli; Norberg, Harri; Frank, Jens; Fedriani, José María; Sahlén, Veronica; Støen, Ole-Gunnar; Swenson, Jon E; Wabakken, Petter; Pellegrini, Mario; Herrero, Stephen; López-Bao, José Vicente

    2016-02-03

    The media and scientific literature are increasingly reporting an escalation of large carnivore attacks on humans in North America and Europe. Although rare compared to human fatalities by other wildlife, the media often overplay large carnivore attacks on humans, causing increased fear and negative attitudes towards coexisting with and conserving these species. Although large carnivore populations are generally increasing in developed countries, increased numbers are not solely responsible for the observed rise in the number of attacks by large carnivores. Here we show that an increasing number of people are involved in outdoor activities and, when doing so, some people engage in risk-enhancing behaviour that can increase the probability of a risky encounter and a potential attack. About half of the well-documented reported attacks have involved risk-enhancing human behaviours, the most common of which is leaving children unattended. Our study provides unique insight into the causes, and as a result the prevention, of large carnivore attacks on people. Prevention and information that can encourage appropriate human behaviour when sharing the landscape with large carnivores are of paramount importance to reduce both potentially fatal human-carnivore encounters and their consequences to large carnivores.

  8. Incorporating human-triggered earthquake risks into energy and water policies

    Science.gov (United States)

    Klose, C. D.; Seeber, L.; Jacob, K. H.

    2010-12-01

    A comprehensive understanding of earthquake risks in urbanized regions requires an accurate assessment of both urban vulnerabilities and hazards from earthquakes, including ones whose timing might be affected by human activities. Socioeconomic risks associated with human-triggered earthquakes are often misconstrued and receive little scientific, legal, and public attention. Worldwide, more than 200 damaging earthquakes, associated with industrialization and urbanization, were documented since the 20th century. Geomechanical pollution due to large-scale geoengineering activities can advance the clock of earthquakes, trigger new seismic events or even shot down natural background seismicity. Activities include mining, hydrocarbon production, fluid injections, water reservoir impoundments and deep-well geothermal energy production. This type of geohazard has impacts on human security on a regional and national level. Some planned or considered future engineering projects raise particularly strong concerns about triggered earthquakes, such as for instance, sequestration of carbon dioxide by injecting it deep underground and large-scale natural gas production in the Marcellus shale in the Appalacian basin. Worldwide examples of earthquakes are discussed, including their associated losses of human life and monetary losses (e.g., 1989 Newcastle and Volkershausen earthquakes, 2001 Killari earthquake, 2006 Basel earthquake, 2010 Wenchuan earthquake). An overview is given on global statistics of human-triggered earthquakes, including depths and time delay of triggering. Lastly, strategies are described, including risk mitigation measures such as urban planning adaptations and seismic hazard mapping.

  9. Are human endogenous retroviruses triggers of autoimmune diseases?

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Villesen, Palle; Nissen, Kari K

    2016-01-01

    factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian...... manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus...

  10. Triggered activity and automaticity in ventricular trabeculae of failing human and rabbit hearts

    NARCIS (Netherlands)

    Vermeulen, J. T.; McGuire, M. A.; Opthof, T.; Coronel, R.; de Bakker, J. M.; Klöpping, C.; Janse, M. J.

    1994-01-01

    The aim of the study was to assess the occurrence of triggered activity and automaticity in ventricular trabeculae from failing human hearts and normal and failing rabbit hearts during exposure to a normal and altered extracellular environment. Ventricular trabeculae were harvested from failing

  11. Scientific, Engineering, and Financial Factors of the 1989 Human-Triggered Newcastle Earthquake in Australia

    Science.gov (United States)

    Klose, C. D.

    2006-12-01

    This presentation emphasizes the dualism of natural resources exploitation and economic growth versus geomechanical pollution and risks of human-triggered earthquakes. Large-scale geoengineering activities, e.g., mining, reservoir impoundment, oil/gas production, water exploitation or fluid injection, alter pre-existing lithostatic stress states in the earth's crust and are anticipated to trigger earthquakes. Such processes of in- situ stress alteration are termed geomechanical pollution. Moreover, since the 19th century more than 200 earthquakes have been documented worldwide with a seismic moment magnitude of 4.5losses of triggered earthquakes. An hazard assessment, based on a geomechanical crust model, shows that only four deep coal mines were responsible for triggering this severe earthquake. A small-scale economic risk assessment identifies that the financial loss due to earthquake damage has reduced mining profits that have been re-invested in the Newcastle region for over two centuries beginning in 1801. Furthermore, large-scale economic risk assessment reveals that the financial loss is equivalent to 26% of the Australian Gross Domestic Product (GDP) growth in 1988/89. These costs account for 13% of the total costs of all natural disasters (e.g., flooding, drought, wild fires) and 94% of the costs of all earthquakes recorded in Australia between 1967 and 1999. In conclusion, the increasing number and size of geoengineering activities, such as coal mining near Newcastle or planned carbon dioxide Geosequestration initiatives, represent a growing hazard potential, which can negatively affect socio-economic growth and sustainable development. Finally, hazard and risk degrees, based on geomechanical-mathematical models, can be forecasted in space and over time for urban planning in order to prevent economic losses of human-triggered earthquakes in the future.

  12. What Does It Mean to Understand Human Rights as Essentially ‘Triggers for Intervention’?

    Directory of Open Access Journals (Sweden)

    Hawre Hasan Hama

    2017-12-01

    Full Text Available Traditional theories of human rights regard human rights to be equivalent to universal moral rights. They also claim that human rights are justified by an appeal to some valuable aspect of human nature. These approaches, however, have been strongly challenged by the political theory of human rights. The latter derived from John Rawls’s conception of human rights in his famous work, Law of Peoples, argues that human rights are not equivalent to our universal moral rights, but are a subset of those rights: they are those rights that once violated lead to an erosion of state sovereignty, thus acting as ‘triggers for intervention’. This article mainly discusses the political conception of human rights to explain this question; what does it mean to understand human rights in the ways that their violations lead to intervention? Furthermore, the article strongly argues that such understanding of human rights is neither accurate nor helpful for reasons that will be mentioned in chapter two.

  13. Contextual reminders fail to trigger memory reconsolidation in aged rats and aged humans.

    Science.gov (United States)

    Jones, Bethany J; Pest, Stacey M; Vargas, Iliana M; Glisky, Elizabeth L; Fellous, Jean-Marc

    2015-04-01

    There is strong evidence that hippocampal memory returns to a labile state upon reactivation, initiating a reconsolidation process that restabilizes it and allows for its updating. Normal aging is associated with deficits in episodic memory processes. However, the effects of aging on memory reconsolidation and its neural substrate remain largely unknown, and an animal model is lacking. In this study we investigated the effects of aging on context-dependent reconsolidation using an episodic set-learning task in humans and an analogous set-learning spatial task in rats. In both tasks, young and older subjects learned a set of objects (humans) or feeder locations (rats; Set 1) in Context A on Day 1. On Day 2, a different set (Set 2) was learned in either Context A (Reminder condition) or Context B (No Reminder condition). On Day 3, subjects were instructed (humans) or cued (rats) to recall Set 1. Young rats and humans in the Reminder condition falsely recalled significantly more items from Set 2 than those in the No Reminder condition, suggesting that the reminder context triggered a reactivation of Set 1 on Day 2 and allowed the integration of Set 2 items into Set 1. In both species, older subjects displayed a different pattern of results than young subjects. In aged rats, there was no difference between conditions in the level of falsely recalled Set 2 items (intrusions). Older humans in the No Reminder condition made significantly more intrusions than those in the Reminder condition. Follow-up control experiments in aged rats suggested that intrusions in older animals reflected general interference, independent of context manipulations. We conclude that contextual reminders are not sufficient to trigger memory updating in aged rats or aged humans, unlike in younger individuals. Future studies using this animal model should further our understanding of the role of the hippocampus in memory maintenance and updating during normal aging. Copyright © 2015 Elsevier Inc

  14. Climate change and human colonization triggered habitat loss and fragmentation in Madagascar

    DEFF Research Database (Denmark)

    Salmona, Jordi; Heller, Rasmus; Quéméré, Erwan

    2017-01-01

    The relative effect of past climate fluctuations and anthropogenic activities on current biome distribution is subject to increasing attention, notably in biodiversity hot spots. In Madagascar, where humans arrived in the last ~4 to 5,000 years, the exact causes of the demise of large vertebrates......-Holocene transition. While mid-Holocene climate change probably triggered major demographic changes in the two lemur species range and connectivity, human settlements that expanded over the last four millennia in northern Madagascar likely played a role in the loss and fragmentation of the forest cover.......—Propithecus tattersalli and Propithecus perrieri—using population genetic analyses. Our results highlight the necessity to consider population structure and changes in connectivity in demographic history inferences. We show that both species underwent demographic fluctuations which most likely occurred after the mid...

  15. Airborne polycyclic aromatic hydrocarbons trigger human skin cells aging through aryl hydrocarbon receptor.

    Science.gov (United States)

    Qiao, Yuan; Li, Qiang; Du, Hong-Yang; Wang, Qiao-Wei; Huang, Ye; Liu, Wei

    2017-07-01

    Accumulating evidence suggests that polycyclic aromatic hydrocarbons (PAH) which adsorbed on the surface of ambient air particulate matters (PM), are the major toxic compound to cause cardiovascular and respiratory diseases, even cancer. However, its detrimental effects on human skin cell remain unclear. Here, we demonstrated that SRM1649b, a reference urban dust material of PAH, triggers human skin cells aging through cell cycle arrest, cell growth inhibition and apoptosis. Principally, SRM1649b facilitated Aryl hydrocarbon receptor (AhR) translocated into nucleus, subsequently activated ERK/MAPK signaling pathway, and upregulated aging-related genes expression. Most important, we found that AhR antagonist efficiently revert the aging of skin cells. Thus our novel findings firstly revealed the mechanism of skin aging under PAH contamination and provided potential strategy for clinical application. Copyright © 2017. Published by Elsevier Inc.

  16. Climate change and human colonization triggered habitat loss and fragmentation in Madagascar.

    Science.gov (United States)

    Salmona, Jordi; Heller, Rasmus; Quéméré, Erwan; Chikhi, Lounès

    2017-10-01

    The relative effect of past climate fluctuations and anthropogenic activities on current biome distribution is subject to increasing attention, notably in biodiversity hot spots. In Madagascar, where humans arrived in the last ~4 to 5,000 years, the exact causes of the demise of large vertebrates that cohabited with humans are yet unclear. The prevailing narrative holds that Madagascar was covered with forest before human arrival and that the expansion of grasslands was the result of human-driven deforestation. However, recent studies have shown that vegetation and fauna structure substantially fluctuated during the Holocene. Here, we study the Holocene history of habitat fragmentation in the north of Madagascar using a population genetics approach. To do so, we infer the demographic history of two northern Madagascar neighbouring, congeneric and critically endangered forest dwelling lemur species-Propithecus tattersalli and Propithecus perrieri-using population genetic analyses. Our results highlight the necessity to consider population structure and changes in connectivity in demographic history inferences. We show that both species underwent demographic fluctuations which most likely occurred after the mid-Holocene transition. While mid-Holocene climate change probably triggered major demographic changes in the two lemur species range and connectivity, human settlements that expanded over the last four millennia in northern Madagascar likely played a role in the loss and fragmentation of the forest cover. © 2017 John Wiley & Sons Ltd.

  17. Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells.

    Science.gov (United States)

    Kuffer, Christian; Kuznetsova, Anastasia Yurievna; Storchová, Zuzana

    2013-08-01

    Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

  18. Elevated temperature triggers human respiratory syncytial virus F protein six-helix bundle formation

    International Nuclear Information System (INIS)

    Yunus, Abdul S.; Jackson, Trent P.; Crisafi, Katherine; Burimski, Irina; Kilgore, Nicole R.; Zoumplis, Dorian; Allaway, Graham P.; Wild, Carl T.; Salzwedel, Karl

    2010-01-01

    Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection in infants, immunocompromised patients, and the elderly. The RSV fusion (F) protein mediates fusion of the viral envelope with the target cell membrane during virus entry and is a primary target for antiviral drug and vaccine development. The F protein contains two heptad repeat regions, HR1 and HR2. Peptides corresponding to these regions form a six-helix bundle structure that is thought to play a critical role in membrane fusion. However, characterization of six-helix bundle formation in native RSV F protein has been hindered by the fact that a trigger for F protein conformational change has yet to be identified. Here we demonstrate that RSV F protein on the surface of infected cells undergoes a conformational change following exposure to elevated temperature, resulting in the formation of the six-helix bundle structure. We first generated and characterized six-helix bundle-specific antibodies raised against recombinant peptides modeling the RSV F protein six-helix bundle structure. We then used these antibodies as probes to monitor RSV F protein six-helix bundle formation in response to a diverse array of potential triggers of conformational changes. We found that exposure of 'membrane-anchored' RSV F protein to elevated temperature (45-55 deg. C) was sufficient to trigger six-helix bundle formation. Antibody binding to the six-helix bundle conformation was detected by both flow cytometry and cell-surface immunoprecipitation of the RSV F protein. None of the other treatments, including interaction with a number of potential receptors, resulted in significant binding by six-helix bundle-specific antibodies. We conclude that native, untriggered RSV F protein exists in a metastable state that can be converted in vitro to the more stable, fusogenic six-helix bundle conformation by an increase in thermal energy. These findings help to better define the mechanism of

  19. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells.

    Science.gov (United States)

    Zhou, Weibo; Simpson, P Jeanette; McFadden, Jill M; Townsend, Craig A; Medghalchi, Susan M; Vadlamudi, Aravinda; Pinn, Michael L; Ronnett, Gabriele V; Kuhajda, Francis P

    2003-11-01

    C75, an inhibitor of fatty acid synthase (FAS), induces apoptosis in cultured human cancer cells. Its proposed mechanism of action linked high levels of malonyl-CoA after FAS inhibition to potential downstream effects including inhibition of carnitine palmitoyltransferase-1 (CPT-1) with resultant inhibition of fatty acid oxidation. Recent data has shown that C75 directly stimulates CPT-1 increasing fatty acid oxidation in MCF-7 human breast cancer cells despite inhibitory concentrations of malonyl-CoA. In light of these findings, we have studied fatty acid metabolism in MCF7 human breast cancer cells to elucidate the mechanism of action of C75. We now report that: (a) in the setting of increased fatty acid oxidation, C75 inhibits fatty acid synthesis; (b) C273, a reduced form of C75, is unable to inhibit fatty acid synthesis and is nontoxic to MCF7 cells; (c) C75 and 5-(tetradecyloxy)-2-furoic acid (TOFA), an inhibitor of acetyl-CoA carboxylase, both cause a significant reduction of fatty acid incorporation into phosphatidylcholine, the major membrane phospholipid, within 2 h; (d) pulse chase studies with [(14)C]acetate labeling of membrane lipids show that both C75 and TOFA accelerate the decay of (14)C-labeled lipid from membranes within 2 h; (e) C75 also promotes a 2-3-fold increase in oxidation of membrane lipids within 2 h; and (f) because interference with phospholipid synthesis during S phase is known to trigger apoptosis in cycling cells, we performed double-labeled terminal deoxynucleotidyltransferase-mediated nick end labeling and BrdUrd analysis with both TOFA and C75. C75 triggered apoptosis during S phase, whereas TOFA did not. Moreover, application of TOFA 2 h before C75 blocked the C75 induced apoptosis, whereas etomoxir did not. Taken together these data indicate that FAS inhibition and its downstream inhibition of phospholipid production is a necessary part of the mechanism of action of C75. CPT-1 stimulation does not likely play a role in the

  20. The role of stress as a trigger for epileptic seizures: a narrative review of evidence from human and animal studies.

    Science.gov (United States)

    Novakova, Barbora; Harris, Peter R; Ponnusamy, Athi; Reuber, Markus

    2013-11-01

    Stress is one of the most frequently self-identified seizure triggers in patients with epilepsy; however, most previous publications on stress and epilepsy have focused on the role of stress in the initial development of epilepsy. This narrative review explores the causal role of stress in triggering seizures in patients with existing epilepsy. Findings from human studies of psychological stress, as well as of physiologic stress responses in humans and animals, and evidence from nonpharmacologic interventions for epilepsy are considered. The evidence from human studies for stress as a trigger of epileptic seizures is inconclusive. Although retrospective self-report studies show that stress is the most common patient-perceived seizure precipitant, prospective studies have yielded mixed results and studies of life events suggest that stressful experiences only trigger seizures in certain individuals. There is limited evidence suggesting that autonomic arousal can precede seizures. Interventions designed to improve coping with stress reduce seizures in some individuals. Studies of physiologic stress using animal epilepsy models provide more convincing evidence. Exposure to exogenous and endogenous stress mediators has been found to increase epileptic activity in the brain and trigger overt seizures, especially after repeated exposure. In conclusion, stress is likely to exacerbate the susceptibility to epileptic seizures in a subgroup of individuals with epilepsy and may play a role in triggering "spontaneous" seizures. However, there is currently no strong evidence for a close link between stress and seizures in the majority of people with epilepsy, although animal research suggests that such links are likely. Further research is needed into the relationship between stress and seizures and into interventions designed to reduce perceived stress and improve quality of life with epilepsy. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

  1. Staphylococcus aureus lipoproteins trigger human corneal epithelial innate response through toll-like receptor-2.

    Science.gov (United States)

    Li, Qiong; Kumar, Ashok; Gui, Jian-Fang; Yu, Fu-Shin X

    2008-05-01

    Bacterial lipoproteins (LP) are a family of cell wall components found in a wide variety of bacteria. In this study, we characterized the response of HUCL, a telomerase-immortalized human corneal epithelial cell (HCEC) line, to LP isolated from Staphylococcus (S) aureus. S. aureus LP (saLP) prepared by Triton X-114 extraction stimulated the activation of NF-kappaB, JNK, and P38 signaling pathways in HUCL cells. The extracts failed to stimulate NF-kappaB activation in HUCL cells after lipoprotein lipase treatment and in cell lines expressing TLR4 or TLR9, but not TLR2, indicating lipoprotein nature of the extracts. saLP induced the up-regulation of a variety of inflammatory cytokines and chemokines (IL-6, IL-8, ICAM-1), antimicrobial molecules (hBD-2, LL-37, and iNOS), and homeostasis genes (Mn-SOD) at both the mRNA level and protein level. Similar inflammatory response to saLP was also observed in primarily cultured HCECs using the production of IL-6 as readout. Moreover, TLR2 neutralizing antibody blocked the saLP-induced secretion of IL-6, IL-8 and hBD2 in HUCL cells. Our findings suggest that saLP activates TLR2 and triggers innate immune response in the cornea to S. aureus infection via production of proinflammatory cytokines and defense molecules.

  2. Structural and functional characterization of two alpha-synuclein strains

    Science.gov (United States)

    Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma; Gath, Julia; Jensen, Poul Henning; Habenstein, Birgit; Madiona, Karine; Olieric, Vincent; Böckmann, Anja; Meier, Beat H.; Melki, Ronald

    2013-10-01

    α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.

  3. Antibodies against alpha-synuclein reduce oligomerization in living cells.

    Directory of Open Access Journals (Sweden)

    Thomas Näsström

    Full Text Available Recent research implicates soluble aggregated forms of α-synuclein as neurotoxic species with a central role in the pathogenesis of Parkinson's disease and related disorders. The pathway by which α-synuclein aggregates is believed to follow a step-wise pattern, in which dimers and smaller oligomers are initially formed. Here, we used H4 neuroglioma cells expressing α-synuclein fused to hemi:GFP constructs to study the effects of α-synuclein monoclonal antibodies on the early stages of aggregation, as quantified by Bimolecular Fluorescence Complementation assay. Widefield and confocal microscopy revealed that cells treated for 48 h with monoclonal antibodies internalized antibodies to various degrees. C-terminal and oligomer-selective α-synuclein antibodies reduced the extent of α-synuclein dimerization/oligomerization, as indicated by decreased GFP fluorescence signal. Furthermore, ELISA measurements on lysates and conditioned media from antibody treated cells displayed lower α-synuclein levels compared to untreated cells, suggesting increased protein turnover. Taken together, our results propose that extracellular administration of monoclonal antibodies can modify or inhibit early steps in the aggregation process of α-synuclein, thus providing further support for passive immunization against diseases with α-synuclein pathology.

  4. Mechanisms of alpha-Synuclein Aggregation and Toxicity

    Science.gov (United States)

    2006-09-01

    Alegre, J., Gomez-Esteban, J.C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares , B., Llorens, V., Tortosa, E.G...192 (2005) 244–250 245chromosome 17. The tau isoforms prevalent in the sarkosyl- insoluble fraction, and the physical characteristics of the tau...Similarities between a-synuclein, tau, and b-amyloid. Tau and a-synuclein share many physical and biochemical properties (Dickson, 1999; Lee et al., 2004

  5. Retrieval per se is not sufficient to trigger reconsolidation of human fear memory.

    Science.gov (United States)

    Sevenster, Dieuwke; Beckers, Tom; Kindt, Merel

    2012-03-01

    Ample evidence suggests that consolidated memories, upon their retrieval, enter a labile state, in which they might be susceptible to change. It has been proposed that memory labilization allows for the integration of relevant information in the established memory trace (memory updating). Memory labilization and reconsolidation do not necessarily occur when a memory is being reactivated, but only when there is something to be learned during memory retrieval (prediction error). Thus, updating of a fear memory trace should not occur under retrieval conditions in which the outcome is fully predictable (no prediction error). Here, we addressed this issue, using a human differential fear conditioning procedure, by eliminating the very possibility of reinforcement of the reminder cue. A previously established fear memory (picture-shock pairings) was reactivated with shock-electrodes attached (Propranolol group, n=18) or unattached (Propranolol No-Shock Expectation group, n=19). We additionally tested a placebo-control group with the shock-electrodes attached (Placebo group, n=18). Reconsolidation was not triggered when nothing could be learned during the reminder trial, as noradrenergic blockade did not affect expression of the fear memory 24h later in the Propranolol No-Shock Expectation group. Only when the outcome of the retrieval cue was not fully predictable, propranolol, contrary to placebo, reduced the startle fear response and prevented the return of fear (reinstatement) the following day. In line with previous studies, skin conductance response and shock expectancies were not affected by propranolol. Remarkably, a double dissociation emerged between the emotional (startle response) and more cognitive expression (expectancies, SCR) of the fear memory. Our findings have important implications for reconsolidation blockade as treatment strategy for emotional disorders. First, fear reducing procedures that target the emotional component of fear memory do not

  6. Right Hemispheric Dominance in Gaze-Triggered Reflexive Shift of Attention in Humans

    Science.gov (United States)

    Okada, Takashi; Sato, Wataru; Toichi, Motomi

    2006-01-01

    Recent findings suggest a right hemispheric dominance in gaze-triggered shifts of attention. The aim of this study was to clarify the dominant hemisphere in the gaze processing that mediates attentional shift. A target localization task, with preceding non-predicative gaze cues presented to each visual field, was undertaken by 44 healthy subjects,…

  7. Traditional Acupuncture Triggers a Local Increase in Adenosine in Human Subjects

    OpenAIRE

    Takano, Takahiro; Chen, Xiaolin; Luo, Fang; Fujita, Takumi; Ren, Zeguang; Goldman, Nanna; Zhao, Yuanli; Markman, John D.; Nedergaard, Maiken

    2012-01-01

    Acupuncture is a form of Eastern medicine that has been practiced for centuries. Despite its long history and worldwide application, the biological mechanisms of acupuncture in relieving pain have been poorly defined. Recent studies in mice, however, demonstrate that acupuncture triggers increases in interstitial adenosine, which reduces the severity of chronic pain through adenosine A1 receptors, suggesting that adenosine-mediated antinociception contributes to the clinical benefits of acupu...

  8. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

    Science.gov (United States)

    Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina

    2009-03-01

    HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.

  9. Bypass of cell cycle arrest induced by transient DNMT1 post-transcriptional silencing triggers aneuploidy in human cells

    Directory of Open Access Journals (Sweden)

    Barra Viviana

    2012-02-01

    Full Text Available Abstract Background Aneuploidy has been acknowledged as a major source of genomic instability in cancer, and it is often considered the result of chromosome segregation errors including those caused by defects in genes controlling the mitotic spindle assembly, centrosome duplication and cell-cycle checkpoints. Aneuploidy and chromosomal instability has been also correlated with epigenetic alteration, however the molecular basis of this correlation is poorly understood. Results To address the functional connection existing between epigenetic changes and aneuploidy, we used RNA-interference to silence the DNMT1 gene, encoding for a highly conserved member of the DNA methyl-transferases. DNMT1 depletion slowed down proliferation of near-diploid human tumor cells (HCT116 and triggered G1 arrest in primary human fibroblasts (IMR90, by inducing p53 stabilization and, in turn, p21waf1 transactivation. Remarkably, p53 increase was not caused by DNA damage and was not observed after p14-ARF post-transcriptional silencing. Interestingly, DNMT1 silenced cells with p53 or p14-ARF depleted did not arrest in G1 but, instead, underwent DNA hypomethylation and became aneuploid. Conclusion Our results suggest that DNMT1 depletion triggers a p14ARF/p53 dependent cell cycle arrest to counteract the aneuploidy induced by changes in DNA methylation.

  10. Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes

    International Nuclear Information System (INIS)

    Hasegawa, Tatsuya; Nakashima, Masaya; Suzuki, Yoshiharu

    2016-01-01

    Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1β production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1β, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE_2. In addition, inhibition of DNA damage repair by knockdown of XPA, which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes. - Highlights: • UVB radiation induces NLRP3 inflammasome activation in human keratinocytes. • NLRP3 knockdown suppresses production of UVB-induced inflammatory mediators. • UVB-induced DNA damage triggers NLRP3 inflammasome activation. • NLRP3 expression in human epidermis is elevated in response to UV radiation.

  11. Nuclear DNA damage-triggered NLRP3 inflammasome activation promotes UVB-induced inflammatory responses in human keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa, Tatsuya, E-mail: tatsuya.hasegawa@to.shiseido.co.jp; Nakashima, Masaya; Suzuki, Yoshiharu

    2016-08-26

    Ultraviolet (UV) radiation in sunlight can result in DNA damage and an inflammatory reaction of the skin commonly known as sunburn, which in turn can lead to cutaneous tissue disorders. However, little has been known about how UV-induced DNA damage mediates the release of inflammatory mediators from keratinocytes. Here, we show that UVB radiation intensity-dependently increases NLRP3 gene expression and IL-1β production in human keratinocytes. Knockdown of NLRP3 with siRNA suppresses UVB-induced production of not only IL-1β, but also other inflammatory mediators, including IL-1α, IL-6, TNF-α, and PGE{sub 2}. In addition, inhibition of DNA damage repair by knockdown of XPA, which is a major component of the nucleotide excision repair system, causes accumulation of cyclobutane pyrimidine dimer (CPD) and activation of NLRP3 inflammasome. In vivo immunofluorescence analysis confirmed that NLRP3 expression is also elevated in UV-irradiated human epidermis. Overall, our findings indicate that UVB-induced DNA damage initiates NLRP3 inflammasome activation, leading to release of various inflammatory mediators from human keratinocytes. - Highlights: • UVB radiation induces NLRP3 inflammasome activation in human keratinocytes. • NLRP3 knockdown suppresses production of UVB-induced inflammatory mediators. • UVB-induced DNA damage triggers NLRP3 inflammasome activation. • NLRP3 expression in human epidermis is elevated in response to UV radiation.

  12. Trigger finger

    Science.gov (United States)

    ... digit; Trigger finger release; Locked finger; Digital flexor tenosynovitis ... cut or hand Yellow or green drainage from the cut Hand pain or discomfort Fever If your trigger finger returns, call your surgeon. You may need another surgery.

  13. Interleukin-6 triggers human cerebral endothelial cells proliferation and migration: The role for KDR and MMP-9

    International Nuclear Information System (INIS)

    Yao, Jianhua S.; Zhai Wenwu; Young, William L.; Yang Guoyuan

    2006-01-01

    Interleukin-6 (IL-6) is involved in angiogenesis. However, the underlying mechanisms are unknown. Using human cerebral endothelial cell (HCEC), we report for First time that IL-6 triggers HCEC proliferation and migration in a dose-dependent manner, specifically associated with enhancement of VEGF expression, up-regulated and phosphorylated VEGF receptor-2 (KDR), and stimulated MMP-9 secretion. We investigated the signal pathway of IL-6/IL-6R responsible for KDR's regulation. Pharmacological inhibitor of PI3K failed to inhibit IL-6-mediated VEGF overexpression, while blocking ERK1/2 with PD98059 could abolish IL-6-induced KDR overexpression. Further, neutralizing endogenous VEGF attenuated KDR expression and phosphorylation, suggesting that IL-6-induced KDR activation is independent of VEGF stimulation. MMP-9 inhibitor GM6001 significantly decreases HCEC proliferation and migration (p < 0.05), indicating the crucial function of MMP-9 in promoting angiogenic changes in HCECs. We conclude that IL-6 triggers VEGF-induced angiogenic activity through increasing VEGF release, up-regulates KDR expression and phosphorylation through activating ERK1/2 signaling, and stimulates MMP-9 overexpression

  14. A stable aspirin-triggered lipoxin A4 analog blocks phosphorylation of leukocyte-specific protein 1 in human neutrophils.

    Science.gov (United States)

    Ohira, Taisuke; Bannenberg, Gerard; Arita, Makoto; Takahashi, Minoru; Ge, Qingyuan; Van Dyke, Thomas E; Stahl, Gregory L; Serhan, Charles N; Badwey, John A

    2004-08-01

    Lipoxins and their aspirin-triggered 15-epimers are endogenous anti-inflammatory agents that block neutrophil chemotaxis in vitro and inhibit neutrophil influx in several models of acute inflammation. In this study, we examined the effects of 15-epi-16-(p-fluoro)-phenoxy-lipoxin A(4) methyl ester, an aspirin-triggered lipoxin A(4)-stable analog (ATLa), on the protein phosphorylation pattern of human neutrophils. Neutrophils stimulated with the chemoattractant fMLP were found to exhibit intense phosphorylation of a 55-kDa protein that was blocked by ATLa (10-50 nM). This 55-kDa protein was identified as leukocyte-specific protein 1, a downstream component of the p38-MAPK cascade in neutrophils, by mass spectrometry, Western blotting, and immunoprecipitation experiments. ATLa (50 nM) also reduced phosphorylation/activation of several components of the p38-MAPK pathway in these cells (MAPK kinase 3/MAPK kinase 6, p38-MAPK, MAPK-activated protein kinase-2). These results indicate that ATLa exerts its anti-inflammatory effects, at least in part, by blocking activation of the p38-MAPK cascade in neutrophils, which is known to promote chemotaxis and other proinflammatory responses by these cells.

  15. Fipronil is a powerful uncoupler of oxidative phosphorylation that triggers apoptosis in human neuronal cell line SHSY5Y.

    Science.gov (United States)

    Vidau, Cyril; González-Polo, Rosa A; Niso-Santano, Mireia; Gómez-Sánchez, Rubén; Bravo-San Pedro, José M; Pizarro-Estrella, Elisa; Blasco, Rafael; Brunet, Jean-Luc; Belzunces, Luc P; Fuentes, José M

    2011-12-01

    Fipronil is a phenylpyrazole insecticide known to elicit neurotoxicity via an interaction with ionotropic receptors, namely GABA and glutamate receptors. Recently, we showed that fipronil and other phenylpyrazole compounds trigger cell death in Caco-2 cells. In this study, we investigated the mode of action and the type of cell death induced by fipronil in SH-SY5Y human neuroblastoma cells. Flow cytometric and western blot analyses demonstrated that fipronil induces cellular events belonging to the apoptosis process, such as mitochondrial potential collapse, cytochrome c release, caspase-3 activation, nuclear condensation and phosphatidylserine externalization. In addition, fipronil induces a rapid ATP depletion with concomitant activation of anaerobic glycolysis. This cellular response is characteristic of mitochondrial injury associated with a defect of the respiration process. Therefore, we also investigated the effect of fipronil on the oxygen consumption in isolated mitochondria. Interestingly, we show for the first time that fipronil is a strong uncoupler of oxidative phosphorylation at relative low concentrations. Thus in this study, we report a new mode of action by which the insecticide fipronil could triggers apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Nanomelatonin triggers superior anticancer functionality in a human malignant glioblastoma cell line

    Science.gov (United States)

    Yadav, Sanjeev Kumar; Srivastava, Anup Kumar; Dev, Atul; Kaundal, Babita; Choudhury, Subhasree Roy; Karmakar, Surajit

    2017-09-01

    Melatonin (MEL) has promising medicinal value as an anticancer agent in a variety of malignancies, but there are difficulties in achieving a therapeutic dose due to its short half-life, low bioavailability, poor solubility and extensive first-pass metabolism. In this study chitosan/tripolyphosphate (TPP) nanoparticles were prepared by an ionic gelation method to overcome the therapeutic challenges of melatonin and to improve its anticancer efficacy. Characterization of the melatonin-loaded chitosan (MEL-CS) nanoformulation was performed using transmission and scanning electron microscopies, dynamic light scattering, Fourier transform infrared spectroscopy, Raman spectroscopy and x-ray diffraction. In vitro release, cellular uptake and efficacy studies were tested for their enhanced anticancer potential in human U87MG glioblastoma cells. Confocal studies revealed higher cellular uptake of MEL-CS nanoparticles and enhanced anticancer efficacy in human malignant glioblastoma cancer cells than in healthy non-malignant human HEK293T cells in mono- and co-culture models. Our study has shown for the first time that MEL-CS nanocomposites are therapeutically more effective as compared to free MEL at inducing functional anticancer efficacy in the human brain tumour U87MG cell line.

  17. Derivation of mouse embryonic stem cell lines from tyrosine hydroxylase reporter mice crossed with a human SNCA transgenic mouse model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Margarita Chumarina

    2017-03-01

    Full Text Available Mouse embryonic stem cell (mESC lines were derived by crossing heterozygous transgenic (tg mice expressing green fluorescent protein (GFP under the control of the rat tyrosine hydroxylase (TH promoter, with homozygous alpha-synuclein (aSYN mice expressing human mutant SNCAA53T under the control of the mouse Prion promoter (MoPrP, or wildtype (WT mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity. These mESC lines can help to study the impact of human aSYN expression in neurons and oligodendrocytes, and also trace GFP-expressing midbrain neurons.

  18. The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation.

    Science.gov (United States)

    Dong, Chen; He, Mingyuan; Tu, Wenzhi; Konishi, Teruaki; Liu, Weili; Xie, Yuexia; Dang, Bingrong; Li, Wenjian; Uchihori, Yukio; Hei, Tom K; Shao, Chunlin

    2015-07-10

    The abscopal effect could be an underlying factor in evaluating prognosis of radiotherapy. This study established an in vitro system to examine whether tumor-generated bystander signals could be transmitted by macrophages to further trigger secondary cellular responses after different irradiations, where human lung cancer NCI-H446 cells were irradiated with either γ-rays or carbon ions and co-cultured with human macrophage U937 cells, then these U937 cells were used as a bystander signal transmitter and co-cultured with human bronchial epithelial cells BEAS-2B. Results showed that U937 cells were only activated by γ-irradiated NCI-H446 cells so that the secondary injuries in BEAS-2B cells under carbon ion irradiation were weaker than γ-rays. Both TNF-α and IL-1α were involved in the γ-irradiation induced secondary bystander effect but only TNF-α contributed to the carbon ion induced response. Further assay disclosed that IL-1α but not TNF-α was largely responsible for the activation of macrophages and the formation of micronucleus in BEAS-2B cells. These data suggest that macrophages could transfer secondary bystander signals and play a key role in the secondary bystander effect of photon irradiation, while carbon ion irradiation has conspicuous advantage due to its reduced secondary injury. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Barnase as a new therapeutic agent triggering apoptosis in human cancer cells.

    Directory of Open Access Journals (Sweden)

    Evelina Edelweiss

    Full Text Available BACKGROUND: RNases are currently studied as non-mutagenic alternatives to the harmful DNA-damaging anticancer drugs commonly used in clinical practice. Many mammalian RNases are not potent toxins due to the strong inhibition by ribonuclease inhibitor (RI presented in the cytoplasm of mammalian cells. METHODOLOGY/PRINCIPAL FINDINGS: In search of new effective anticancer RNases we studied the effects of barnase, a ribonuclease from Bacillus amyloliquefaciens, on human cancer cells. We found that barnase is resistant to RI. In MTT cell viability assay, barnase was cytotoxic to human carcinoma cell lines with half-inhibitory concentrations (IC(50 ranging from 0.2 to 13 microM and to leukemia cell lines with IC(50 values ranging from 2.4 to 82 microM. Also, we characterized the cytotoxic effects of barnase-based immunoRNase scFv 4D5-dibarnase, which consists of two barnase molecules serially fused to the single-chain variable fragment (scFv of humanized antibody 4D5 that recognizes the extracellular domain of cancer marker HER2. The scFv 4D5-dibarnase specifically bound to HER2-positive cells and was internalized via receptor-mediated endocytosis. The intracellular localization of internalized scFv 4D5-dibarnase was determined by electronic microscopy. The cytotoxic effect of scFv 4D5-dibarnase on HER2-positive human ovarian carcinoma SKOV-3 cells (IC(50 = 1.8 nM was three orders of magnitude greater than that of barnase alone. Both barnase and scFv 4D5-dibarnase induced apoptosis in SKOV-3 cells accompanied by internucleosomal chromatin fragmentation, membrane blebbing, the appearance of phosphatidylserine on the outer leaflet of the plasma membrane, and the activation of caspase-3. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that barnase is a potent toxic agent for targeting to cancer cells.

  20. Staphylococcus aureus lipoproteins trigger human corneal epithelial innate response through toll-like receptor-2

    OpenAIRE

    Li, Qiong; Kumar, Ashok; Gui, Jian-Fang; Yu, Fu-Shin X.

    2007-01-01

    Bacterial lipoproteins (LP) are a family of cell wall components found in a wide variety of bacteria. In this study, we characterized the response of HUCL, a telomerase-immortalized human corneal epithelial cell (HCEC) line, to LP isolated from Staphylococcus (S) aureus. S. aureus LP (saLP) prepared by Triton X-114 extraction stimulated the activation of NF-κB, JNK, and P38 signaling pathways in HUCL cells. The extracts failed to stimulate NF-κB activation in HUCL cells after lipoprotein lipa...

  1. ERK-dependent and -independent pathways trigger human neural progenitor cell migration

    International Nuclear Information System (INIS)

    Moors, Michaela; Cline, Jason E.; Abel, Josef; Fritsche, Ellen

    2007-01-01

    Besides differentiation and apoptosis, cell migration is a basic process in brain development in which neural cells migrate several centimeters within the developing brain before reaching their proper positions and forming the right connections. For identifying signaling events that control neural migration and are therefore potential targets of chemicals to disturb normal brain development, we developed a human neurosphere-based migration assay based on normal human neural progenitor (NHNP) cells, in which the distance is measured that cells wander over time. Applying this assay, we investigated the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the regulation of NHNP cell migration. Exposure to model substances like ethanol or phorbol 12-myristate 13-acetate (PMA) revealed a correlation between ERK1/2 activation and cell migration. The participation of phospho-(P-) ERK1/2 was confirmed by exposure of the cells to the MEK inhibitor PD98059, which directly prohibits ERK1/2 phosphorylation and inhibited cell migration. We identified protein kinase C (PKC) and epidermal growth factor receptor (EGFR) as upstream signaling kinases governing ERK1/2 activation, thereby controlling NHNP cell migration. Additionally, treatments with src kinase inhibitors led to a diminished cell migration without affecting ERK1/2 phosphorylation. Based on these results, we postulate that migration of NHNP cells is controlled via ERK1/2-dependent and -independent pathways

  2. Melatonin synthesis in the human ciliary body triggered by TRPV4 activation: Involvement of AANAT phosphorylation.

    Science.gov (United States)

    Alkozi, Hanan Awad; Perez de Lara, María J; Pintor, Jesús

    2017-09-01

    Melatonin is a substance synthesized in the pineal gland as well as in other organs. This substance is involved in many ocular functions, giving its synthesis in numerous eye structures. Melatonin is synthesized from serotonin through two enzymes, the first limiting step into the synthesis of melatonin being aralkylamine N-acetyltransferase (AANAT). In this current study, AANAT phosphorylation after the activation of TRPV4 was studied using human non-pigmented epithelial ciliary body cells. Firstly, it was necessary to determine the adequate time and dose of the TRPV4 agonist GSK1016790A to reach the maximal phosphorylation of AANAT. An increase of 72% was observed after 5 min incubation with 10 nM GSK (**p melatonin synthesis. The involvement of a TRPV4 channel in melatonin synthesis was verified by antagonist and siRNA studies as a previous step to studying intracellular signalling. Studies performed on the second messengers involved in GSK induced AANAT phosphorylation were carried out by inhibiting several pathways. In conclusion, the activation of calmodulin and calmodulin-dependent protein kinase II was confirmed, as shown by the cascade seen in AANAT phosphorylation (***p melatonin levels. In conclusion, the activation of a TRPV4 present in human ciliary body epithelial cells produced an increase in AANAT phosphorylation and a further melatonin increase by a mechanism in which Ca-calmodulin and the calmodulin-dependent protein kinase II are involved. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Biomaterials trigger endothelial cell activation when co-incubated with human whole blood.

    Science.gov (United States)

    Herklotz, Manuela; Hanke, Jasmin; Hänsel, Stefanie; Drichel, Juliane; Marx, Monique; Maitz, Manfred F; Werner, Carsten

    2016-10-01

    Endothelial cell activation resulting from biomaterial contact or biomaterial-induced blood activation may in turn also affect hemostasis and inflammatory processes in the blood. Current in vitro hemocompatibility assays typically ignore these modulating effects of the endothelium. This study describes a co-incubation system of human whole blood, biomaterial and endothelial cells (ECs) that was developed to overcome this limitation. First, human endothelial cells were characterized in terms of their expression of coagulation- and inflammation-relevant markers in response to various activators. Subsequently, their capacity to regulate hemostasis as well as complement and granulocyte activation was monitored in a hemocompatibility assay. After blood contact, quiescent ECs exhibited anticoagulant and anti-inflammatory properties. When they were co-incubated with surfaces exhibiting pro-coagulant or pro-inflammatory characteristics, the ECs down-regulated coagulation but not complement or leukocyte activation. Analysis of intracellular levels of the endothelial activation markers E-selectin and tissue factor showed that co-incubation with model surfaces and blood significantly increased the activation state of ECs. Finally, the coagulation- and inflammation-modulating properties of the ECs were tested after blood/biomaterial exposure. Pre-activation of ECs by biomaterials in the blood induced a pro-coagulant and pro-inflammatory state of the ECs, wherein the pro-coagulant response was higher for biomaterial/blood pre-activated ECs than for TNF-α-pre-activated cells. This work provides evidence that biomaterials, even without directly contacting the endothelium, affect the endothelial activation state with and have consequences for plasmatic and cellular reactions in the blood. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

    Science.gov (United States)

    Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

    2001-12-01

    Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

  5. Glucocerebrosidase expression patterns in the non-human primate brain

    OpenAIRE

    Dopeso-Reyes, Iria G.; Sucunza, Diego; Rico, Alberto J.; Pignataro, Diego; Marín-Ramos, David; Roda, Elvira; Rodríguez-Pérez, Ana I.; Labandeira-García, José L.; Lanciego, José L.

    2017-01-01

    Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene. Mutations in GBA1 gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson’s disease (PD) and dementia with Lewy bodies. However, it is also worth noting that a direct link between GBA1 mutations and alpha-synuclein aggregation indicating cause and e...

  6. Vitamin K3 triggers human leukemia cell death through hydrogen peroxide generation and histone hyperacetylation.

    Science.gov (United States)

    Lin, Changjun; Kang, Jiuhong; Zheng, Rongliang

    2005-10-01

    Vitamin K3 (VK3) is a well-known anticancer agent, but its mechanism remains elusive. In the present study, VK3 was found to simultaneously induce cell death, reactive oxygen species (ROS) generation, including superoxide anion (O2*-) and hydrogen peroxide (H2O2) generation, and histone hyperacetylation in human leukemia HL-60 cells in a concentration- and time-dependent manner. Catalase (CAT), an antioxidant enzyme that specifically scavenges H2O2, could significantly diminish both histone acetylation increase and cell death caused by VK3, whereas superoxide dismutase (SOD), an enzyme that specifically eliminates O2*-, showed no effect on both of these, leading to the conclusion that H2O2 generation, but not O2*- generation, contributes to VK3-induced histone hyperacetylation and cell death. This conclusion was confirmed by the finding that enhancement of VK3-induced H2O2 generation by vitamin C (VC) could significantly promote both the histone hyperacetylation and cell death. Further studies suggested that histone hyperacetylation played an important role in VK3-induced cell death, since sodium butyrate, a histone deacetylase (HDAC) inhibitor, showed no effect on ROS generation, but obviously potentiated VK3-induced histone hyperacetylation and cell death. Collectively, these results demonstrate a novel mechanism for the anticancer activity of VK3, i.e., VK3 induced tumor cell death through H2O2 generation, which then further induced histone hyperacetylation.

  7. The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells.

    Directory of Open Access Journals (Sweden)

    Kateřina Voráčová

    Full Text Available Oxadiazines are heterocyclic compounds containing N-N-O or N-N-C-O system within a six membered ring. These structures have been up to now exclusively prepared via organic synthesis. Here, we report the discovery of a natural oxadiazine nocuolin A (NoA that has a unique structure based on 1,2,3-oxadiazine. We have identified this compound in three independent cyanobacterial strains of genera Nostoc, Nodularia, and Anabaena and recognized the putative gene clusters for NoA biosynthesis in their genomes. Its structure was characterized using a combination of NMR, HRMS and FTIR methods. The compound was first isolated as a positive hit during screening for apoptotic inducers in crude cyanobacterial extracts. We demonstrated that NoA-induced cell death has attributes of caspase-dependent apoptosis. Moreover, NoA exhibits a potent anti-proliferative activity (0.7-4.5 μM against several human cancer lines, with p53-mutated cell lines being even more sensitive. Since cancers bearing p53 mutations are resistant to several conventional anti-cancer drugs, NoA may offer a new scaffold for the development of drugs that have the potential to target tumor cells independent of their p53 status. As no analogous type of compound was previously described in the nature, NoA establishes a novel class of bioactive secondary metabolites.

  8. Triggering Avoidance: Dissociable Influences of Aversive Pavlovian Conditioned Stimuli on Human Instrumental Behavior.

    Science.gov (United States)

    Garofalo, Sara; Robbins, Trevor W

    2017-01-01

    The present study investigates human aversive Pavlovian-to-Instrumental Transfer (PIT) and possible influences of outcome devaluation and instrumental overtraining on this effect. PIT measures the extent to which a Pavlovian conditioned stimulus (CS) can increase instrumental responses independently paired with the same (outcome-specific transfer) or a different (general transfer) reinforcer. Two measures of PIT were obtained: the percentage of instrumental responses and the vigor of such responses. Thirty-eight volunteers performed a standard PIT task sequence. Results showed a double dissociation between outcome-specific and general transfer: the first selectively expressed in the amount of responses, the second in the vigor measure solely. Furthermore, outcome-specific transfer was enhanced by overtraining, but not affected by devaluation. General transfer, on the other hand, was affected by neither overtraining, nor devaluation. A positive correlation between general transfer and sensitivity to punishments was found. Findings are discussed in terms of hypothetically different underlying neurobehavioral mechanisms and their relations to habits and goal-directed behavior.

  9. Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.

    Science.gov (United States)

    Misra, Uma Kant; Pizzo, Salvatore Vincent

    2015-04-10

    Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2-3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2-3-fold increase in lipogenesis as determined by 6-[(14)C]glucose or 1-[(14)C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [(14)CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Periodontal bacteria in human carotid atherothrombosis as a potential trigger for neutrophil activation.

    Science.gov (United States)

    Rangé, Hélène; Labreuche, Julien; Louedec, Liliane; Rondeau, Philippe; Planesse, Cynthia; Sebbag, Uriel; Bourdon, Emmanuel; Michel, Jean-Baptiste; Bouchard, Philippe; Meilhac, Olivier

    2014-10-01

    Epidemiological, biological and clinical links between periodontal and cardiovascular diseases are now well established. Several human studies have detected bacterial DNA corresponding to periodontal pathogens in cardiovascular samples. Intraplaque hemorrhage has been associated with a higher risk of atherosclerotic plaque rupture, potentially mediated by neutrophil activation. In this study, we hypothesized that plaque composition may be related to periodontal pathogens. Carotid culprit plaque samples were collected from 157 patients. Macroscopic characterization was performed at the time of collection: presence of blood, lipid core, calcification and fibrosis. Markers of neutrophil activation released by carotid samples were quantified (myeloperoxidase or MPO, cell-free DNA and DNA-MPO complexes). PCR analysis using specific primers for Porphyromonas gingivalis, Aggregatibacter actinomycetemcommitans, Treponema denticola, Prevotella intermedia and Tannerella forsythia was used to detect DNA from periodontal pathogens in carotid tissues. In addition, bacterial lipopolysaccharide (LPS) and Immunoglobulins G against T. forsythia were quantified in atherosclerotic carotid conditioned medium. Intraplaque hemorrhage was present in 73/157 carotid samples and was associated with neutrophil activation, reflected by the release of MPO, cell-free DNA and MPO-DNA complexes. LPS levels were also linked to intraplaque hemorrhage but not with the neutrophil activation markers. Seventy-three percent of the carotid samples were positive for periodontal bacterial DNA. Furthermore, hemoglobin levels were associated with the detection of T. forsythia and neutrophil activation/inflammation markers. This study suggests a potential role of periodontal microorganisms, especially T. forsythia, in neutrophil activation within hemorrhagic atherosclerotic carotid plaques. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Pseudomonas aeruginosa outer membrane vesicles triggered by human mucosal fluid and lysozyme can prime host tissue surfaces for bacterial adhesion

    Directory of Open Access Journals (Sweden)

    Matteo Maria Emiliano Metruccio

    2016-06-01

    Full Text Available Pseudomonas aeruginosa is a leading cause of human morbidity and mortality that often targets epithelial surfaces. Host immunocompromise, or the presence of indwelling medical devices, including contact lenses, can predispose to infection. While medical devices are known to accumulate bacterial biofilms, it is not well understood why resistant epithelial surfaces become susceptible to P. aeruginosa. Many bacteria, including P. aeruginosa, release Outer Membrane Vesicles (OMVs in response to stress that can fuse with host cells to alter their function. Here, we tested the hypothesis that mucosal fluid can trigger OMV release to compromise an epithelial barrier. This was tested using tear fluid and corneal epithelial cells in vitro and in vivo. After 1 h both human tear fluid, and the tear component lysozyme, greatly enhanced OMV release from P. aeruginosa strain PAO1 compared to PBS controls (~100 fold. TEM and SDS-PAGE showed tear fluid and lysozyme-induced OMVs were similar in size and protein composition, but differed from biofilm-harvested OMVs, the latter smaller with fewer proteins. Lysozyme-induced OMVs were cytotoxic to human corneal epithelial cells in vitro and murine corneal epithelium in vivo. OMV exposure in vivo enhanced Ly6G/C expression at the corneal surface, suggesting myeloid cell recruitment, and primed the cornea for bacterial adhesion (~4-fold, P < 0.01. Sonication disrupted OMVs retained cytotoxic activity, but did not promote adhesion, suggesting the latter required OMV-mediated events beyond cell killing. These data suggest that mucosal fluid induced P. aeruginosa OMVs could contribute to loss of epithelial barrier function during medical device-related infections.

  12. Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

    Science.gov (United States)

    Singh, Jagmohan; Kumar, Sumit; Phillips, Benjamin

    2015-01-01

    The extracellular signal that triggers activation of rho-associated kinase (RhoA/ROCK), the major molecular determinant of basal internal anal sphincter (IAS) smooth muscle tone, is not known. Using human IAS tissues, we identified the presence of the biosynthetic machineries for angiotensin II (ANG II), thromboxane A2 (TXA2), and prostaglandin F2α (PGF2α). These end products of the renin-angiotensin system (RAS) (ANG II) and arachidonic acid (TXA2 and PGF2α) pathways and their effects in human IAS vs. rectal smooth muscle (RSM) were studied. A multipronged approach utilizing immunocytochemistry, Western blot analyses, and force measurements was implemented. Additionally, in a systematic analysis of the effects of respective inhibitors along different steps of biosynthesis and those of antagonists, their end products were evaluated either individually or in combination. To further describe the molecular mechanism for the IAS tone via these pathways, we monitored RhoA/ROCK activation and its signal transduction cascade. Data showed characteristically higher expression of biosynthetic machineries of RAS and AA pathways in the IAS compared with the RSM. Additionally, specific inhibition of the arachidonic acid (AA) pathway caused ∼80% decrease in the IAS tone, whereas that of RAS lead to ∼20% decrease. Signal transduction studies revealed that the end products of both AA and RAS pathways cause increase in the IAS tone via activation of RhoA/ROCK. Both AA and RAS (via the release of their end products TXA2, PGF2α, and ANG II, respectively), provide extracellular signals which activate RhoA/ROCK for the maintenance of the basal tone in human IAS. PMID:25882611

  13. Recruitment of motor units in the medial gastrocnemius muscle during human quiet standing: is recruitment intermittent? What triggers recruitment?

    Science.gov (United States)

    Vieira, Taian M M; Loram, Ian D; Muceli, Silvia; Merletti, Roberto; Farina, Dario

    2012-01-01

    The recruitment and the rate of discharge of motor units are determinants of muscle force. Within a motoneuron pool, recruitment and rate coding of individual motor units might be controlled independently, depending on the circumstances. In this study, we tested whether, during human quiet standing, the force of the medial gastrocnemius (MG) muscle is predominantly controlled by recruitment or rate coding. If MG control during standing was mainly due to recruitment, then we further asked what the trigger mechanism is. Is it determined internally, or is it related to body kinematics? While seven healthy subjects stood quietly, intramuscular electromyograms were recorded from the MG muscle with three pairs of wire electrodes. The number of active motor units and their mean discharge rate were compared for different sway velocities and positions. Motor unit discharges occurred more frequently when the body swayed faster and forward (Pearson R = 0.63; P motor unit potentials was explained chiefly by the recruitment of additional units. During forward body shifts, the median number of units detected increased from 3 to 11 (P motor units did not discharge continuously throughout standing. They were recruited within individual, forward sways and intermittently, with a modal rate of two recruitments per second. This modal rate is consistent with previous circumstantial evidence relating the control of standing to an intrinsic, higher level planning process.

  14. Trigger Finger

    Science.gov (United States)

    ... in a bent position. People whose work or hobbies require repetitive gripping actions are at higher risk ... developing trigger finger include: Repeated gripping. Occupations and hobbies that involve repetitive hand use and prolonged gripping ...

  15. Triggering Artefacts

    DEFF Research Database (Denmark)

    Mogensen, Preben Holst; Robinson, Mike

    1995-01-01

    and adapting them to specific situations need not be ad hoc.Triggering artefacts are a way of systematically challenging both designers' preunderstandings and the conservatism of work practice. Experiences from the Great Belt tunnel and bridge project are used to illustrate howtriggering artefacts change...

  16. DMS triggers apoptosis associated with the inhibition of SPHK1/NF-κB activation and increase in intracellular Ca2+ concentration in human cancer cells.

    Science.gov (United States)

    Chen, Kan; Pan, Qiuwei; Gao, Ying; Yang, Xinyan; Wang, Shibing; Peppelenbosch, Maikel P; Kong, Xiangdong

    2014-01-01

    N,N-Dimethyl-D-erythro-sphingosine (DMS) is known to induce cell apoptosis by specifically inhibiting sphingosine kinase 1 (SPHK1) and modulating the activity of cellular ceramide levels. The present study investigated the effects and the mechanism(s) of action of DMS in human lung cancer cells. We found that DMS dose-dependently suppressed cell proliferation and induced cell apoptosis in the human lung cancer cell line, A549. Mechanistically, treatment with DMS suppressed the activation of SPHK1 and nuclear factor-κB (NF-κB) p65, but increased intracellular [Ca2+]i in A549 cells. This study demonstrates that DMS triggers the apoptosis of human lung cancer cells through the modulation of SPHK1, NF-κB and calcium signaling. These molecules may represent targets for anticancer drug design.

  17. Triggering ovulation with gonadotropin-releasing hormone agonist versus human chorionic gonadotropin in polycystic ovarian syndrome. A randomized trial

    Directory of Open Access Journals (Sweden)

    Amr Hassaan Farag

    2015-12-01

    Full Text Available Objectives: To compare GnRH agonist to hCG for triggering ovulation in polycystic ovarian syndrome treated with clomiphene citrate. Study design: Prospective randomized study. Materials & methods: Eighty five infertile women with PCOS participated in a randomized allocation concealed prospective trial and had induction of ovulation with clomiphene citrate. GnRH agonist 0.2 mg subcutaneously (group 1 or hCG 10,000 IU intramuscularly (group 2 was given to trigger ovulation. Primary outcome was mid-luteal serum progesterone, while secondary outcomes were ovulation rates and clinical pregnancy rates along 3 cycles. Results: No difference was found between group 1 and group 2 regarding mean serum progesterone and clinical pregnancy rates in each cycle. Cumulative pregnancy rates were similar (17.14% versus 20% respectively; P = 0.332. Ovulation rates were 80% versus 68.6% (P = 0.413; 94.3% versus 90.9% (P = 0.669; 97.1% versus 93.7% (P = 0.603 in the two groups respectively. However, a significant rise in number of patients with mid-luteal serum progesterone >10 ng/mL was noted in the 3rd cycle between both groups, (P < 0.0001 for group 1 while P = 0.007 for group 2. Conclusion: Triggering ovulation with GnRH-a after treatment with clomiphene citrate in PCOS, in view of its known protective effect against OHSS, may be an effective physiological alternative to conventional hCG without compromising luteal function and pregnancy rates after repeated cycles of treatment.

  18. Trigger circuit

    International Nuclear Information System (INIS)

    Verity, P.R.; Chaplain, M.D.; Turner, G.D.J.

    1984-01-01

    A monostable trigger circuit comprises transistors TR2 and TR3 arranged with their collectors and bases interconnected. The collector of the transistor TR2 is connected to the base of transistor TR3 via a capacitor C2 the main current path of a grounded base transistor TR1 and resistive means R2,R3. The collector of transistor TR3 is connected to the base of transistor TR2 via resistive means R6, R7. In the stable state all the transistors are OFF, the capacitor C2 is charged, and the output is LOW. A positive pulse input to the base of TR2 switches it ON, which in turn lowers the voltage at points A and B and so switches TR1 ON so that C2 can discharge via R2, R3, which in turn switches TR3 ON making the output high. Thus all three transistors are latched ON. When C2 has discharged sufficiently TR1 switches OFF, followed by TR3 (making the output low again) and TR2. The components C1, C3 and R4 serve to reduce noise, and the diode D1 is optional. (author)

  19. In vivo measurements of relaxation process in the human liver by MRI. The role of respiratory gating/triggering

    DEFF Research Database (Denmark)

    Thomsen, C; Henriksen, O; Ring, P

    1988-01-01

    In vivo estimation of relaxation processes in the liver by magnetic resonance imaging (MRI) may be helpful for characterization of various pathological conditions in the liver. However, such measurements may be significantly hampered by movement of the liver with the respiration. The effect...... of synchronization of data acquisition to the respiratory cycle on measured T1- and T2-relaxation curves was studied in normal subjects, patients with diffuse liver disease, and patients with focal liver pathology. Multi spin echo sequences with five different repetition times were used. The measurements were...... carried out with and without respiratory gating/triggering. In the healthy subjects as well as in the patients with diffuse liver diseases respiratory synchronization did not alter the obtained relaxation curves. However, in the patients with focal pathology the relaxation curves were significantly...

  20. Activation of Triggering Receptor Expressed on Myeloid Cells-1 on Human Neutrophils by Marburg and Ebola Viruses

    National Research Council Canada - National Science Library

    Mohamadzadeh, Mansour; Coberley, Sadie S; Olinger, Gene G; Kalina, Warren V; Ruthel, Gordon; Fullter, Claudette L; Swenson, Dana L; Pratt, William D; Kuhns, Douglas B; Schmaljohn, Alan L

    2006-01-01

    .... Here, we report that MARV and EBOV activate TREM-1 on human neutrophils, resulting in DAP12 phosphorylation, TREM-1 shedding, mobilization of intracellular calcium, secretion of proinflammatory...

  1. Climate warming and humans played different roles in triggering Late Quaternary extinctions in east and west Eurasia.

    Science.gov (United States)

    Wan, Xinru; Zhang, Zhibin

    2017-03-29

    Climate change and humans are proposed as the two key drivers of total extinction of many large mammals in the Late Pleistocene and Early Holocene, but disentangling their relative roles remains challenging owing to a lack of quantitative evaluation of human impact and climate-driven distribution changes on the extinctions of these large mammals in a continuous temporal-spatial dimension. Here, our analyses showed that temperature change had significant effects on mammoth (genus Mammuthus ), rhinoceros (Rhinocerotidae), horse (Equidae) and deer (Cervidae). Rapid global warming was the predominant factor driving the total extinction of mammoths and rhinos in frigid zones from the Late Pleistocene and Early Holocene. Humans showed significant, negative effects on extirpations of the four mammalian taxa, and were the predominant factor causing the extinction or major extirpations of rhinos and horses. Deer survived both rapid climate warming and extensive human impacts. Our study indicates that both the current rates of warming and range shifts of species are much faster than those from the Late Pleistocene to Holocene. Our results provide new insight into the extinction of Late Quaternary megafauna by demonstrating taxon-, period- and region-specific differences in extinction drivers of climate change and human disturbances, and some implications about the extinction risk of animals by recent and ongoing climate warming. © 2017 The Author(s).

  2. Role for the disulfide-bonded region of human immunodeficiency virus type 1 gp41 in receptor-triggered activation of membrane fusion function

    International Nuclear Information System (INIS)

    Bellamy-McIntyre, Anna K.; Baer, Severine; Ludlow, Louise; Drummer, Heidi E.; Poumbourios, Pantelis

    2010-01-01

    The conserved disulfide-bonded region (DSR) of the human immunodeficiency virus type 1 (HIV-1) fusion glycoprotein, gp41, mediates association with the receptor-binding glycoprotein, gp120. Interactions between gp120, CD4 and chemokine receptors activate the fusion activity of gp41. The introduction of W596L and W610F mutations to the DSR of HIV-1 QH1549.13 blocked viral entry and hemifusion without affecting gp120-gp41 association. The fusion defect correlated with inhibition of CD4-triggered gp41 pre-hairpin formation, consistent with the DSR mutations having decoupled receptor-induced conformational changes in gp120 from gp41 activation. Our data implicate the DSR in sensing conformational changes in the gp120-gp41 complex that lead to fusion activation.

  3. Lawrence Livermore National Laboratory- Completing the Human Genome Project and Triggering Nearly $1 Trillion in U.S. Economic Activity

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, Jeffrey S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-07-28

    The success of the Human Genome project is already nearing $1 Trillion dollars of U.S. economic activity. Lawrence Livermore National Laboratory (LLNL) was a co-leader in one of the biggest biological research effort in history, sequencing the Human Genome Project. This ambitious research effort set out to sequence the approximately 3 billion nucleotides in the human genome, an effort many thought was nearly impossible. Deoxyribonucleic acid (DNA) was discovered in 1869, and by 1943 came the discovery that DNA was a molecule that encodes the genetic instructions used in the development and functioning of living organisms and many viruses. To make full use of the information, scientists needed to first sequence the billions of nucleotides to begin linking them to genetic traits and illnesses, and eventually more effective treatments. New medical discoveries and improved agriculture productivity were some of the expected benefits. While the potential benefits were vast, the timeline (over a decade) and cost ($3.8 Billion) exceeded what the private sector would normally attempt, especially when this would only be the first phase toward the path to new discoveries and market opportunities. The Department of Energy believed its best research laboratories could meet this Grand Challenge and soon convinced the National Institute of Health to formally propose the Human Genome project to the federal government. The U.S. government accepted the risk and challenge to potentially create new healthcare and food discoveries that could benefit the world and the U.S. Industry.

  4. Tumor necrosis factor related apoptosis inducing ligand triggers apoptosis in dividing but not in differentiating human epidermal keratinocytes

    NARCIS (Netherlands)

    Jansen, Bastiaan J. H.; van Ruissen, Fred; Cerneus, Stefanie; Cloin, Wendy; Bergers, Mieke; van Erp, Piet E. J.; Schalkwijk, Joost

    2003-01-01

    Using serial analysis of gene expression we have previously identified the expression of several pro-apoptotic and anti-apoptotic genes in cultured human primary epidermal keratinocytes, including tumor necrosis factor related apoptosis inducing ligand (TRAIL). TRAIL is a potent inducer of apoptosis

  5. Rhein triggers apoptosis via induction of endoplasmic reticulum stress, caspase-4 and intracellular calcium in primary human hepatic HL-7702 cells

    Energy Technology Data Exchange (ETDEWEB)

    KoraMagazi, Arouna [Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu (China); Wang, Dandan [Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu (China); Yousef, Bashir; Guerram, Mounia [Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu (China); Yu, Feng, E-mail: yufengcpu14@yahoo.com [Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu (China); Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu (China); Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, Jiangsu (China)

    2016-04-22

    Rhein is an active component of rhubarb; a traditional Chinese medicine reported to induce apoptosis and cause liver toxicity. However, rhein's apoptotic-inducing effects, as well as its molecular mechanisms of action on hepatic cells need to be further explored. In the present study, rhein was found to trigger apoptosis in primary human hepatic HL-7702 cells as showed by annexin V/PI double staining assay and nuclear morphological changes demonstrated by Hoechst 33258 staining. Moreover, it was observed that the mechanism implicated in rhein-induced apoptosis was caspase-dependent, presumably via ER-stress associated pathways, as illustrated by up-regulation of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase (PERK), C-Jun N-terminal kinase (JNK) and CCAAT/enhancer-binding protein homologous protein (CHOP). Meanwhile, caspase-4 as a hallmark of ER-stress, was also showed to be activated following by caspase-3 activation. Furthermore, rhein also promoted intracellular elevation of calcium that contributed in apoptosis induction. Interestingly, pre-treatment with calpain inhibitor I reduced the effects of rhein on apoptosis induction and JNK activation. These data suggested that rhein-induced apoptosis through ER-stress and elevated intracellular calcium level in HL-7702 cells. - Highlights: • Rhein triggers apoptotic cell death on primary human hepatic HL-7702 cells. • Rhein leads to caspase-4 activation in HL-7702 cells. • Rhein induces endoplasmic reticulum stress pathways in HL-7702 cells. • Rhein causes elevation of intracellular calcium concentrations in HL-7702 cells.

  6. Local and systemic immunomodulatory mechanisms triggered by Human Papillomavirus transformed cells: a potential role for G-CSF and neutrophils

    OpenAIRE

    Alvarez, Karla Lucia Fernandez; Beldi, Mariana Carmezim; Sarmanho, Fabiane; Rossetti, Renata Ariza Marques; Silveira, Caio Raony Farina; Mota, Giana Rabello; Andreoli, Maria Antonieta; Caruso, Eliana Dias de Carvalho; Kamillos, Marcia Ferreira; Souza, Ana Marta; Mastrocalla, Haydee; Clavijo-Salomon, Maria Alejandra; Barbuto, José Alexandre Marzagão; Lorenzi, Noely Paula; Longatto Filho, Adhemar

    2017-01-01

    Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by...

  7. The Brassica epithionitrile 1-cyano-2,3-epithiopropane triggers cell death in human liver cancer cells in vitro.

    Science.gov (United States)

    Hanschen, Franziska S; Herz, Corinna; Schlotz, Nina; Kupke, Franziska; Bartolomé Rodríguez, María M; Schreiner, Monika; Rohn, Sascha; Lamy, Evelyn

    2015-11-01

    Glucosinolates are secondary metabolites present in Brassica vegetables. Alkenyl glucosinolates are enzymatically degraded forming nitriles or isothiocyanates, but in the presence of epithiospecifier protein, epithionitriles are released. However, studies on the occurrence of epithionitriles in Brassica food and knowledge about their biological effects are scarce. Epithionitrile formation from glucosinolates of seven Brassica vegetables was analyzed using GC-MS and HPLC-DAD. Bioactivity of synthetic and plant-derived 1-cyano-2,3-epithiopropane (CETP) - the predominant epithionitrile in Brassica vegetables - in three human hepatocellular carcinoma (HCC) cell lines and primary murine hepatocytes was also evaluated. The majority of the Brassica vegetables were producers of nitriles or epithionitriles as hydrolysis products and not of isothiocyanates. For example, Brussels sprouts and savoy cabbage contained up to 0.8 μmol CETP/g vegetable. Using formazan dye assays, concentrations of 380-1500 nM CETP were observed to inhibit the mitochondrial dehydrogenase activity of human HCC cells without impairment of cell growth. At 100-fold higher CETP concentrations, cell death was observed. Presence of plant matrix increased CETP-based toxicity. These in vitro data provide no indication that epithionitriles will severely affect human health by Brassica consumption. In contrast to isothiocyanates, no evidence of selective toxicity against HCC cells was found. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Sulforaphane Induces Cell Death Through G2/M Phase Arrest and Triggers Apoptosis in HCT 116 Human Colon Cancer Cells.

    Science.gov (United States)

    Liu, Kuo-Ching; Shih, Ting-Ying; Kuo, Chao-Lin; Ma, Yi-Shih; Yang, Jiun-Long; Wu, Ping-Ping; Huang, Yi-Ping; Lai, Kuang-Chi; Chung, Jing-Gung

    2016-01-01

    Sulforaphane (SFN), an isothiocyanate, exists exclusively in cruciferous vegetables, and has been shown to possess potent antitumor and chemopreventive activity. However, there is no available information that shows SFN affecting human colon cancer HCT 116 cells. In the present study, we found that SFN induced cell morphological changes, which were photographed by contrast-phase microscopy, and decreased viability. SFN also induced G2/M phase arrest and cell apoptosis in HCT 116 cells, which were measured with flow cytometric assays. Western blotting indicated that SFN increased Cyclin A, cdk 2, Cyclin B and WEE1, but decreased Cdc 25C, cdk1 protein expressions that led to G2/M phase arrest. Apoptotic cell death was also confirmed by Annexin V/PI and DAPI staining and DNA gel electrophoresis in HCT 116 cells after exposure to SFN. The flow cytometric assay also showed that SFN induced the generation of reactive oxygen species (ROS) and Ca[Formula: see text] and decreased mitochondria membrane potential and increased caspase-8, -9 and -3 activities in HCT 116 cell. Western blotting also showed that SFN induced the release of cytochrome c, and AIF, which was confirmed by confocal microscopy examination. SFN induced ER stress-associated protein expression. Based on those observations, we suggest that SFN may be used as a novel anticancer agent for the treatment of human colon cancer in the future.

  9. Genetics and biochemistry of collagen binding-triggered glandular differentiation in a human colon carcinoma cell line

    International Nuclear Information System (INIS)

    Pignatelli, M.; Bodmer, W.F.

    1988-01-01

    The authors have examined the interaction between collagen binding and epithelial differentiation by using a human colon carcinoma cell line (SW1222) that can differentiate structurally when grown in a three-dimensional collagen gel to form glandular structures. As much as 66% inhibition of glandular differentiation can be achieved by addition to the culture of a synthetic peptide containing the Arg-Gly-Asp-Thr (RGDT) sequence, which is a cell recognition site found in collagen. Arg-Gly-Asp-Thr also inhibited the cell attachment to collagen-coated plates. Chromosome 15 was found in all human-mouse hybrid clones that could differentiate in the collagen gel and bind collagen. Both binding to collagen and glandular differentiation of the hybrid cells were also inhibited by Arg-Gly-Asp-Thr as for the parent cell line SW1222. The ability of SW1222 cells to express the differentiated phenotype appears, therefore, to be determined by an Arg-Gly-Asp-directed collagen receptor on the cell surface that is controlled by a gene on chromosome 15

  10. Lipophilic Chemicals from Diesel Exhaust Particles Trigger Calcium Response in Human Endothelial Cells via Aryl Hydrocarbon Receptor Non-Genomic Signalling

    Directory of Open Access Journals (Sweden)

    Bendik C. Brinchmann

    2018-05-01

    Full Text Available Exposure to diesel exhaust particles (DEPs affects endothelial function and may contribute to the development of atherosclerosis and vasomotor dysfunction. As intracellular calcium concentration [Ca2+]i is considered important in myoendothelial signalling, we explored the effects of extractable organic matter from DEPs (DEP-EOM on [Ca2+]i and membrane microstructure in endothelial cells. DEP-EOM of increasing polarity was obtained by pressurized sequential extraction of DEPs with n-hexane (n-Hex-EOM, dichloromethane (DCM-EOM, methanol, and water. Chemical analysis revealed that the majority of organic matter was extracted by the n-Hex- and DCM-EOM, with polycyclic aromatic hydrocarbons primarily occurring in n-Hex-EOM. The concentration of calcium was measured in human microvascular endothelial cells (HMEC-1 using micro-spectrofluorometry. The lipophilic n-Hex-EOM and DCM-EOM, but not the more polar methanol- and water-soluble extracts, induced rapid [Ca2+]i increases in HMEC-1. n-Hex-EOM triggered [Ca2+]i increase from intracellular stores, followed by extracellular calcium influx consistent with store operated calcium entry (SOCE. By contrast, the less lipophilic DCM-EOM triggered [Ca2+]i increase via extracellular influx alone, resembling receptor operated calcium entry (ROCE. Both extracts increased [Ca2+]i via aryl hydrocarbon receptor (AhR non-genomic signalling, verified by pharmacological inhibition and RNA-interference. Moreover, DCM-EOM appeared to induce an AhR-dependent reduction in the global plasma membrane order, as visualized by confocal fluorescence microscopy. DCM-EOM-triggered [Ca2+]i increase and membrane alterations were attenuated by the membrane stabilizing lipid cholesterol. In conclusion, lipophilic constituents of DEPs extracted by n-hexane and DCM seem to induce rapid AhR-dependent [Ca2+]i increase in HMEC-1 endothelial cells, possibly involving both ROCE and SOCE-mediated mechanisms. The semi-lipophilic fraction

  11. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading-deficiency is driven by suppression of mismatch repair

    Science.gov (United States)

    Campbell, Brittany B; Ungerleider, Nathan; Light, Nicholas; Wu, Tong; LeCompte, Kimberly G; Goksenin, A Yasemin; Bunnell, Bruce A; Tabori, Uri; Shlien, Adam

    2018-01-01

    Tumors defective for DNA polymerase (Pol) ε proofreading have the highest tumor mutation burden identified. A major unanswered question is whether loss of Pol ε proofreading by itself is sufficient to drive this mutagenesis, or whether additional factors are necessary. To address this, we used a combination of next generation sequencing and in vitro biochemistry on human cell lines engineered to have defects in Pol ε proofreading and mismatch repair. Absent mismatch repair, monoallelic Pol ε proofreading deficiency caused a rapid increase in a unique mutation signature, similar to that observed in tumors from patients with biallelic mismatch repair deficiency and heterozygous Pol ε mutations. Restoring mismatch repair was sufficient to suppress the explosive mutation accumulation. These results strongly suggest that concomitant suppression of mismatch repair, a hallmark of colorectal and other aggressive cancers, is a critical force for driving the explosive mutagenesis seen in tumors expressing exonuclease-deficient Pol ε. PMID:29488881

  12. Efficacy of Prompt Initiation of Antiretroviral Therapy in the Treatment of Hemophagocytic Lymphohistiocytosis Triggered by Uncontrolled Human Immunodeficiency Virus

    Directory of Open Access Journals (Sweden)

    Bryan P. Fitzgerald

    2017-01-01

    Full Text Available Hemophagocytic lymphohistiocytosis (HLH is a life-threatening, rapidly progressive hematologic disorder involving uncontrolled immune system activation. HLH has been associated with viral infections, including human immunodeficiency virus (HIV infections. We report a case of a critically ill 30-year-old female who was hospitalized with HIV-associated HLH, with a CD4 count of 4 cells/mL and HIV viral load of 1,842,730 copies/mL. After ruling out other potential infectious causes of HLH, antiretroviral therapy (ART was initiated with darunavir, ritonavir, tenofovir, and emtricitabine. Within one week of initiation of ART, the patient began to improve clinically and hematologically and was stable enough for discharge from the hospital three weeks after starting therapy. This case suggests that treatment with ART in patients with HIV-associated HLH should be considered even in critically ill patients with low CD4 counts.

  13. Poly(N-isopropylacrylamide) hydrogel-based shape-adjustable polyimide films triggered by near-human-body temperature.

    Science.gov (United States)

    Huanqing Cui; Xuemin Du; Juan Wang; Tianhong Tang; Tianzhun Wu

    2016-08-01

    Hydrogel-based shape-adjustable films were successfully fabricated via grafting poly(N-isopropylacrylamide) (PNIPAM) onto one side of polyimide (PI) films. The prepared PI-g-PNIPAM films exhibited rapid, reversible, and repeatable bending/unbending property by heating to near-human-body temperature (37 °C) or cooling to 25 °C. The excellent property of PI-g-PNIPAM films resulted from a lower critical solution temperature (LCST) of PNIPAM at about 32 °C. Varying the thickness of PNIPAM hydrogel layer regulated the thermo-responsive shape bending degree and response speed of PI-g-PNIPAM films. The thermo-induced shrinkage of hydrogel layers can tune the curvature of PI films, which have potential applications in the field of wearable and implantable devices.

  14. Potent antiproliferative cembrenoids accumulate in tobacco upon infection with Rhodococcus fascians and trigger unusual microtubule dynamics in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Aminata P Nacoulma

    Full Text Available AIMS: Though plant metabolic changes are known to occur during interactions with bacteria, these were rarely challenged for pharmacologically active compounds suitable for further drug development. Here, the occurrence of specific chemicals with antiproliferative activity against human cancer cell lines was evidenced in hyperplasia (leafy galls induced when plants interact with particular phytopathogens, such as the Actinomycete Rhodococcus fascians. METHODS: We examined leafy galls fraction F3.1.1 on cell proliferation, cell division and cytoskeletal disorganization of human cancer cell lines using time-lapse videomicroscopy imaging, combined with flow cytometry and immunofluorescence analysis. We determined the F3.1.1-fraction composition by gas chromatography coupled to mass spectrometry. RESULTS: The leafy galls induced on tobacco by R. fascians yielded fraction F3.1.1 which inhibited proliferation of glioblastoma U373 cells with an IC50 of 4.5 µg/mL, F.3.1.1 was shown to increase cell division duration, cause nuclear morphological deformations and cell enlargement, and, at higher concentrations, karyokinesis defects leading to polyploidization and apoptosis. F3.1.1 consisted of a mixture of isomers belonging to the cembrenoids. The cellular defects induced by F3.1.1 were caused by a peculiar cytoskeletal disorganization, with the occurrence of fragmented tubulin and strongly organized microtubule aggregates within the same cell. Colchicine, paclitaxel, and cembrene also affected U373 cell proliferation and karyokinesis, but the induced microtubule rearrangement was very different from that provoked by F3.1.1. Altogether our data indicate that the cembrenoid isomers in F3.1.1 have a unique mode of action and are able to simultaneously modulate microtubule polymerization and stability.

  15. Nonbilayer Phospholipid Arrangements Are Toll-Like Receptor-2/6 and TLR-4 Agonists and Trigger Inflammation in a Mouse Model Resembling Human Lupus

    Directory of Open Access Journals (Sweden)

    Carlos Wong-Baeza

    2015-01-01

    Full Text Available Systemic lupus erythematosus is characterized by dysregulated activation of T and B cells and autoantibodies to nuclear antigens and, in some cases, lipid antigens. Liposomes with nonbilayer phospholipid arrangements induce a disease resembling human lupus in mice, including IgM and IgG antibodies against nonbilayer phospholipid arrangements. As the effect of these liposomes on the innate immune response is unknown and innate immune system activation is necessary for efficient antibody formation, we evaluated the effect of these liposomes on Toll-like receptor (TLR signaling, cytokine production, proinflammatory gene expression, and T, NKT, dendritic, and B cells. Liposomes induce TLR-4- and, to a lesser extent, TLR-2/TLR-6-dependent signaling in TLR-expressing human embryonic kidney (HEK cells and bone marrow-derived macrophages. Mice with the lupus-like disease had increased serum concentrations of proinflammatory cytokines, C3a and C5a; they also had more TLR-4-expressing splenocytes, a higher expression of genes associated with TRIF-dependent TLR-4-signaling and complement activation, and a lower expression of apoptosis-related genes, compared to healthy mice. The percentage of NKT and the percentage and activation of dendritic and B2 cells were also increased. Thus, TLR-4 and TLR-2/TLR-6 activation by nonbilayer phospholipid arrangements triggers an inflammatory response that could contribute to autoantibody production and the generation of a lupus-like disease in mice.

  16. The LHCb trigger

    International Nuclear Information System (INIS)

    Korolko, I.

    1998-01-01

    This paper describes progress in the development of the LHCb trigger system since the letter of intent. The trigger philosophy has significantly changed, resulting in an increase of trigger efficiency for signal B events. It is proposed to implement a level-1 vertex topology trigger in specialised hardware. (orig.)

  17. Human Properdin Opsonizes Nanoparticles and Triggers a Potent Pro-inflammatory Response by Macrophages without Involving Complement Activation

    Science.gov (United States)

    Kouser, Lubna; Paudyal, Basudev; Kaur, Anuvinder; Stenbeck, Gudrun; Jones, Lucy A.; Abozaid, Suhair M.; Stover, Cordula M.; Flahaut, Emmanuel; Sim, Robert B.; Kishore, Uday

    2018-01-01

    Development of nanoparticles as tissue-specific drug delivery platforms can be considerably influenced by the complement system because of their inherent pro-inflammatory and tumorigenic consequences. The complement activation pathways, and its recognition subcomponents, can modulate clearance of the nanoparticles and subsequent inflammatory response and thus alter the intended translational applications. Here, we report, for the first time, that human properdin, an upregulator of the complement alternative pathway, can opsonize functionalized carbon nanotubes (CNTs) via its thrombospondin type I repeat (TSR) 4 and 5. Binding of properdin and TSR4+5 is likely to involve charge pattern/polarity recognition of the CNT surface since both carboxymethyl cellulose-coated carbon nanotubes (CMC-CNT) and oxidized (Ox-CNT) bound these proteins well. Properdin enhanced the uptake of CMC-CNTs by a macrophage cell line, THP-1, mounting a robust pro-inflammatory immune response, as revealed by qRT-PCR, multiplex cytokine array, and NF-κB nuclear translocation analyses. Properdin can be locally synthesized by immune cells in an inflammatory microenvironment, and thus, its interaction with nanoparticles is of considerable importance. In addition, recombinant TSR4+5 coated on the CMC-CNTs inhibited complement consumption by CMC-CNTs, suggesting that nanoparticle decoration with TSR4+5, can be potentially used as a complement inhibitor in a number of pathological contexts arising due to exaggerated complement activation. PMID:29483907

  18. Effects of Trehalose on Thermodynamic Properties of Alpha-synuclein Revealed through Synchrotron Radiation Circular Dichroism

    Directory of Open Access Journals (Sweden)

    Paolo Ruzza

    2015-05-01

    Full Text Available Many neurodegenerative diseases, including Huntington’s, Alzheimer’s and Parkinson’s diseases, are characterized by protein misfolding and aggregation. The capability of trehalose to interfere with protein misfolding and aggregation has been recently evaluated by several research groups. In the present work, we studied, by means of synchrotron radiation circular dichroism (SRCD spectroscopy, the dose-effect of trehalose on α-synuclein conformation and/or stability to probe the capability of this osmolyte to interfere with α-synuclein’s aggregation. Our study indicated that a low trehalose concentration stabilized α-synuclein folding much better than at high concentration by blocking in vitro α-synuclein’s polymerisation. These results suggested that trehalose could be associated with other drugs leading to a new approach for treating Parkinson’s and other brain-related diseases.

  19. Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation

    DEFF Research Database (Denmark)

    Betzer, Cristine; Lassen, Louise Berkhoudt; Olsen, Anders

    2018-01-01

    Aggregation of α-synuclein is a hallmark of Parkinson's disease and dementia with Lewy bodies. We here investigate the relationship between cytosolic Ca2+and α-synuclein aggregation. Analyses of cell lines and primary culture models of α-synuclein cytopathology reveal an early phase with reduced ...

  20. The Neuroprotective Role of Protein Quality Control in Halting the Development of Alpha-Synuclein Pathology

    Directory of Open Access Journals (Sweden)

    Destiny-Love Manecka

    2017-09-01

    Full Text Available Synucleinopathies are a family of neurodegenerative disorders that comprises Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Each of these disorders is characterized by devastating motor, cognitive, and autonomic consequences. Current treatments for synucleinopathies are not curative and are limited to improvement of quality of life for affected individuals. Although the underlying causes of these diseases are unknown, a shared pathological hallmark is the presence of proteinaceous inclusions containing the α-synuclein (α-syn protein in brain tissue. In the past few years, it has been proposed that these inclusions arise from the self-templated, prion-like spreading of misfolded and aggregated forms of α-syn throughout the brain, leading to neuronal dysfunction and death. In this review, we describe how impaired protein homeostasis is a prominent factor in the α-syn aggregation cascade, with alterations in protein quality control (PQC pathways observed in the brains of patients. We discuss how PQC modulates α-syn accumulation, misfolding and aggregation primarily through chaperoning activity, proteasomal degradation, and lysosome-mediated degradation. Finally, we provide an overview of experimental data indicating that targeting PQC pathways is a promising avenue to explore in the design of novel neuroprotective approaches that could impede the spreading of α-syn pathology and thus provide a curative treatment for synucleinopathies.

  1. Defining the Role of Alpha-Synuclein in Enteric Dysfunction in Parkinsons Disease

    Science.gov (United States)

    2017-10-01

    gastrointestinal pathology Gastrointestinal motility was evaluated monthly in rats following treatment by measuring fecal water content (A) and total...fecal output (B). A) Both PFF (black bars, n = 15) and monomer ( grey bars; n = 15) treated animals exhibited a significant decrease in fecal water ...assay. AAV-α-syn treatment (black circles) was associated with significant slowing of colonic motility as compared to AAV-GFP treated animals (n=6

  2. Rapid Self-assembly of alpha-Synuclein Observed by In Situ Atomic Force Microscopy

    NARCIS (Netherlands)

    Hoyer, Wolfgang; Cherny, Dmitry; Subramaniam, Vinod; Jovin, Thomas M.

    2004-01-01

    Self-assembly of α-synuclein resulting in protein aggregates of diverse morphology has been implicated in the pathogenesis of Parkinson's disease and other neurodegenerative disorders known as synucleinopathies. Apart from its biomedical relevance, this aggregation process is representative of the

  3. NMR of alpha-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation

    NARCIS (Netherlands)

    Fernández, Claudio O.; Hoyer, Wolfgang; Zweckstetter, Markus; Jares-Erijman, Elizabeth A.; Subramaniam, Vinod; Griesinger, Christian; Jovin, Thomas M.

    2004-01-01

    The aggregation of α-synuclein is characteristic of Parkinson's disease (PD) and other neurodegenerative synucleinopathies. The 140-aa protein is natively unstructured; thus, ligands binding to the monomeric form are of therapeutic interest. Biogenic polyamines promote the aggregation of α-synuclein

  4. Explorations of the application of cyanine dyes for quantitative alpha-synuclein detection

    NARCIS (Netherlands)

    Volkova, K.D.; Kovalska, V.B.; Segers-Nolten, Gezina M.J.; Veldhuis, G.; Veldhuis, G.J.; Subramaniam, Vinod; Yarmoluk, S.M.

    2009-01-01

    We examined the practical aspects of using fluorescent mono (T-284) and trimethinecyanine (SH-516) dyes for detecting and quantifying fibrillar α-synuclein (ASN). We studied the interaction of cyanine dyes with fibrillar proteins using fluorescence spectroscopy and atomic force microscopy. The

  5. Parkinson's disease induced pluripotent stem cells with triplication of the alpha-synuclein locus

    Czech Academy of Sciences Publication Activity Database

    Devine, M.J.; Ryten, M.; Vodička, Petr; Thomson, A.J.; Burdon, T.; Houlden, H.; Cavaleri, F.; Nagano, M.; Drummond, N.J.; Taanman, J.W.; Schapira, A.H.; Gwinn, K.; Hardy, J.; Lewis, P.A.; Kunath, T.

    2011-01-01

    Roč. 2, č. 440 (2011), s. 1-1 ISSN 2041-1723 Institutional research plan: CEZ:AV0Z50450515 Keywords : gene duplication * dementia * association Subject RIV: FH - Neurology Impact factor: 7.396, year: 2011

  6. An Efficient Procedure for Removal and Inactivation of Alpha-Synuclein Assemblies from Laboratory Materials.

    Science.gov (United States)

    Bousset, Luc; Brundin, Patrik; Böckmann, Anja; Meier, Beat; Melki, Ronald

    2016-01-01

    Preformed α-synuclein fibrils seed the aggregation of soluble α-synuclein in cultured cells and in vivo. This, and other findings, has kindled the idea that α-synuclein fibrils possess prion-like properties. As α-synuclein fibrils should not be considered as innocuous, there is a need for decontamination and inactivation procedures for laboratory benches and non-disposable laboratory material. We assessed the effectiveness of different procedures designed to disassemble α-synuclein fibrils and reduce their infectivity. We examined different commercially available detergents to remove α-synuclein assemblies adsorbed on materials that are not disposable and that are most found in laboratories (e.g. plastic, glass, aluminum or stainless steel surfaces). We show that methods designed to decrease PrP prion infectivity neither effectively remove α-synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency. In contrast, both commercial detergents and SDS detached α-synuclein assemblies from contaminated surfaces and disassembled the fibrils. We describe three cleaning procedures that effectively remove and disassemble α-synuclein seeds. The methods rely on the use of detergents that are compatible with most non-disposable tools in a laboratory. The procedures are easy to implement and significantly decrease any potential risks associated to handling α-synuclein assemblies.

  7. KLK6 proteolysis is implicated in the turnover and uptake of extracellular alpha-synuclein species.

    Science.gov (United States)

    Pampalakis, Georgios; Sykioti, Vasia-Samantha; Ximerakis, Methodios; Stefanakou-Kalakou, Ioanna; Melki, Ronald; Vekrellis, Kostas; Sotiropoulou, Georgia

    2017-02-28

    KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinant and naturally secreted KLK6 can readily cleave α-synuclein fibrils that have the potential for cell-to-cell propagation in "a prion-like mechanism". Importantly, KLK6-deficient primary cortical neurons have increased ability for α-synuclein fibril uptake. We also demonstrate that KLK6 activates proMMP2, which in turn can cleave α-synuclein. The repertoire of proteases activated by KLK6 in a neuronal environment was analyzed by degradomic profiling, which also identified ADAMTS19 and showed that KLK6 has a limited number of substrates indicating specific biological functions such as the regulation of α-synuclein turnover. We generated adenoviral vectors for KLK6 delivery and demonstrated that the levels of extracellular α-synuclein can be reduced by neuronally secreted KLK6. Our findings open the possibility to exploit KLK6 as a novel therapeutic target for Parkinson disease and other synucleinopathies.

  8. Long-term polarization of microglia upon alpha-synuclein overexpression in nonhuman primates

    DEFF Research Database (Denmark)

    Barkholt, Pernille; Sanchez-Guajardo, Vanesa Maria; Kirik, Denis

    2012-01-01

    We have previously shown that persistent ﰇ-sy- nuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) ﰇ-synuclein....

  9. Parkinson's disease: acid-glucocerebrosidase activity and alpha-synuclein clearance.

    Science.gov (United States)

    Blanz, Judith; Saftig, Paul

    2016-10-01

    The role of mutations in the gene GBA1 encoding the lysosomal hydrolase β-glucocerebrosidase for the development of synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, was only very recently uncovered. The knowledge obtained from the study of carriers or patients suffering from Gaucher disease (a common lysosomal storage disorder because of GBA1 mutations) is of particular importance for understanding the role of the enzyme and its catabolic pathway in the development of synucleinopathies. Decreased activity of β-glucocerebrosidase leads to lysosomal dysfunction and the accumulation of its substrate glucosylceramide and related lipid derivatives. Glucosylceramide is suggested to stabilize toxic oligomeric forms of α-synuclein that negatively influence the activity of β-glucocerebrosidase and to partially block export of newly synthesized β-glucocerebrosidase from the endoplasmic reticulum to late endocytic compartments, amplifying the pathological effects of α-synuclein and ultimately resulting in neuronal cell death. This pathogenic molecular feedback loop and most likely other factors (such as impaired endoplasmic reticulum-associated degradation, activation of the unfolded protein response and dysregulation of calcium homeostasis induced by misfolded GC mutants) are involved in shifting the cellular homeostasis from monomeric α-synuclein towards oligomeric neurotoxic and aggregated forms, which contribute to Parkinson's disease progression. From a therapeutic point of view, strategies aiming to increase either the expression, stability or delivery of the β-glucocerebrosidase to lysosomes are likely to decrease the α-synuclein burden and may be useful for an in depth evaluation at the organismal level. Lysosomes are critical for protein and lipid homeostasis. Recent research revealed that dysfunction of this organelle contributes to the development of neurodegenerative diseases such as Parkinson's disease (PD). Mutations in the lysosomal hydrolase β-glucocerebrosidase (GBA1) are a major risk factor for the development of PD and the molecular events linked to the reduced activity of GBA1 and the pathological accumulation of lipids and α-synuclein are just at the beginning to be understood. New therapeutic concepts in regards to how to increase the expression, stability, or delivery of β-glucocerebrosidase to lysosomes are currently developed. This article is part of a special issue on Parkinson disease. © 2016 International Society for Neurochemistry.

  10. Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis.

    Directory of Open Access Journals (Sweden)

    David Freeman

    Full Text Available α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of α-synuclein aggregates directly into cells as well as by cell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS in target cells. Finally, we observe that α-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of α-synuclein pathology in cells.

  11. Alpha-synuclein oligomers - neurotoxic molecules in Parkinson’s disease and other Lewy body disorders

    Directory of Open Access Journals (Sweden)

    Martin Ingelsson

    2016-09-01

    Full Text Available Adverse intra- and extracellular effects of toxic α-synuclein are believed to be central to the pathogenesis in Parkinson’s disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of α-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of α-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric α-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that α-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson’s disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against α-synuclein oligomers/protofibrils should be a particularly attractive treatment option.

  12. Multiple system atrophy: genetic risks and alpha-synuclein mutations [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Heather T Whittaker

    2017-11-01

    Full Text Available Multiple system atrophy (MSA is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings. Families with certain types of α-synuclein mutations develop diseases that mimic MSA, and the spectrum of clinical and pathological features in these families suggests a spectrum of severity, from late-onset Parkinson’s disease to MSA. Nonetheless, controversies persist, such as the role of common α-synuclein variants in MSA and whether this disorder shares a common mechanism of spreading pathology with other protein misfolding neurodegenerative diseases. Here, we review these issues, specifically focusing on α-synuclein mutations.

  13. Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain.

    Science.gov (United States)

    Yang, Weili; Wang, Guohao; Wang, Chuan-En; Guo, Xiangyu; Yin, Peng; Gao, Jinquan; Tu, Zhuchi; Wang, Zhengbo; Wu, Jing; Hu, Xintian; Li, Shihua; Li, Xiao-Jiang

    2015-05-27

    Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and >15 years of age to examine the expression of Parkin, PINK1, and α-synuclein, which are known to cause PD via loss- or gain-of-function mechanisms. We found that α-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of α-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant α-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD. Copyright © 2015 the authors 0270-6474/15/358345-14$15.00/0.

  14. Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages and Airway Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Bianca Maria Rotoli

    2018-03-01

    Full Text Available Lysinuric protein intolerance (LPI is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system y+L for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA, a significant induction of the expression and release of the inflammatory mediators IL1β and TNFα was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFκB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1β has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation.

  15. Azoxystrobin Induces Apoptosis of Human Esophageal Squamous Cell Carcinoma KYSE-150 Cells through Triggering of the Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    Xiao-ke Shi

    2017-05-01

    Full Text Available Recent studies indicate that mitochondrial pathways of apoptosis are potential chemotherapeutic target for the treatment of esophageal cancer. Azoxystrobin (AZOX, a methoxyacrylate derived from the naturally occurring strobilurins, is a known fungicide acting as a ubiquinol oxidation (Qo inhibitor of mitochondrial respiratory complex III. In this study, the effects of AZOX on human esophageal squamous cell carcinoma KYSE-150 cells were examined and the underlying mechanisms were investigated. AZOX exhibited inhibitory effects on the proliferation of KYSE-150 cells with inhibitory concentration 50% (IC50 of 2.42 μg/ml by 48 h treatment. Flow cytometry assessment revealed that the inhibitory effect of AZOX on KYSE-150 cell proliferation occurred with cell cycle arrest at S phase and increased cell apoptosis in time-dependent and dose-dependent manners. Cleaved poly ADP ribose polymerase (PARP, caspase-3 and caspase-9 were increased significantly by AZOX. It is worth noted that the Bcl-2/Bax ratios were decreased because of the down-regulated Bcl-2 and up-regulated Bax expression level. Meanwhile, the cytochrome c release was increased by AZOX in KYSE-150 cells. AZOX-induced cytochrome c expression and caspase-3 activation was significantly blocked by Bax Channel Blocker. Intragastric administration of AZOX effectively decreased the tumor size generated by subcutaneous inoculation of KYSE-150 cells in nude mice. Consistently, decreased Bcl-2 expression, increased cytochrome c and PARP level, and activated caspase-3 and caspase-9 were observed in the tumor samples. These results indicate that AZOX can effectively induce esophageal cancer cell apoptosis through the mitochondrial pathways of apoptosis, suggesting AZOX or its derivatives may be developed as potential chemotherapeutic agents for the treatment of esophageal cancer.

  16. Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection.

    Directory of Open Access Journals (Sweden)

    Martin S Davey

    2011-05-01

    Full Text Available Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8. In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN-γ and tumor necrosis factor (TNF-α. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP, requires cell-cell contact of Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1, and results in a TNF-α dependent proliferation of Vγ9/Vδ2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting γδ T cell responses in vitro. Patients with acute peritoneal-dialysis (PD-associated bacterial peritonitis--characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity--show a selective activation of local Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive γδ T cells in

  17. Human Neutrophil Clearance of Bacterial Pathogens Triggers Anti-Microbial γδ T Cell Responses in Early Infection

    Science.gov (United States)

    Roberts, Gareth W.; Heuston, Sinéad; Brown, Amanda C.; Chess, James A.; Toleman, Mark A.; Gahan, Cormac G. M.; Hill, Colin; Parish, Tanya; Williams, John D.; Davies, Simon J.; Johnson, David W.; Topley, Nicholas; Moser, Bernhard; Eberl, Matthias

    2011-01-01

    Human blood Vγ9/Vδ2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vγ9/Vδ2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vγ9/Vδ2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vγ9/Vδ2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-α dependent proliferation of Vγ9/Vδ2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting γδ T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vγ9/Vδ2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The γδ T cell-driven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of γδ T cells and TNF-α and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive γδ T cells in early

  18. Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial stromal cell responsiveness to interleukin 1: a new possible mechanism underlying embryo implantation.

    Science.gov (United States)

    Bourdiec, Amélie; Shao, Rong; Rao, C V; Akoum, Ali

    2012-09-01

    Deep functional changes occurring within the endometrium during implantation are orchestrated by embryonic and maternal signals. Human chorionic gonadotropin (hCG), a major embryonic signal, plays a critical role in the initiation and maintenance of pregnancy. Interleukin (IL) 1, one of the earliest embryonic signals, appears to exert a direct impact on the receptive endometrium and to induce major molecular changes that are essential for embryo implantation. Herein we investigate whether hCG can modulate endometrial stromal cell (ESC) receptivity to IL1 during the implantation window and assess the impact on angiogenesis in vitro. Primary cultures of ESCs from normal fertile women during the implantation window were treated for 24 h with different concentrations of hCG (0-100 ng/ml) and stimulated for 24 h with IL1B (0-0.1 ng/ml). IL1 receptors (IL1Rs), IL1R antagonist (IL1RA), and monocyte chemotactic protein (MCP) 1 were analyzed by real-time PCR, ELISA, and Western blotting. The angiogenic activity in vitro was studied using human microvascular endothelial cell line, scratch wound assay, and cell proliferation via BrdU incorporation into DNA. Human CG induced a dose-dependent imbalance in ESC receptivity to IL1 by significantly upregulating the functional signaling IL1R1 and concomitantly downregulating the decoy inhibitory IL1R2 and IL1RA upon subsequent exposure to IL1B. Prior exposure to hCG amplified MCP1 secretion by ESCs in response to IL1B and triggered the release of angiogenic activity in vitro in which MCP1 appeared to play a significant role. Overexpression of IL1R2 using cell transfection inhibited IL1 and hCG/IL1B-mediated MCP1 secretion. These findings suggest that hCG coordinates embryonic signal interaction with the maternal endometrium, and point to a new possible pathway by which it may promote embryonic growth.

  19. Ginsenoside Rh2 Induces Human Hepatoma Cell Apoptosisvia Bax/Bak Triggered Cytochrome C Release and Caspase-9/Caspase-8 Activation

    Directory of Open Access Journals (Sweden)

    Xiao-Xi Guo

    2012-11-01

    Full Text Available Ginsenoside Rh2 (G-Rh2 has been shown to induce apoptotic cell death in a variety of cancer cells. However, the details of the signal transduction cascade involved in G-Rh2-induced cell death is unclear. In this manuscript we elucidate the molecular mechanism of G-Rh2-induced apoptosis in human hepatoma SK-HEP-1 cells by demonstrating that G-Rh2 causes rapid and dramatic translocation of both Bak and Bax, which subsequently triggers mitochondrial cytochrome c release and consequent caspase activation. Interestingly, siRNA-based gene inactivation of caspase-8 effectively delays caspase-9 activation and apoptosis induced by G-Rh2, indicating that caspase-8 also plays an important role in the G-Rh2-induced apoptosis program. Taken together, our results indicate that G-Rh2 employs a multi pro-apoptotic pathway to execute cancer cell death, suggesting a potential role for G-Rh2 as a powerful chemotherapeutic agent.

  20. The Central Trigger Processor (CTP)

    CERN Multimedia

    Franchini, Matteo

    2016-01-01

    The Central Trigger Processor (CTP) receives trigger information from the calorimeter and muon trigger processors, as well as from other sources of trigger. It makes the Level-1 decision (L1A) based on a trigger menu.

  1. Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1

    Directory of Open Access Journals (Sweden)

    Federica Raggi

    2017-09-01

    Full Text Available Macrophages (Mf are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth. They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1 and alternatively activated (anti-inflammatory M2 subsets. We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment.

  2. Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1

    Science.gov (United States)

    Raggi, Federica; Pelassa, Simone; Pierobon, Daniele; Penco, Federica; Gattorno, Marco; Novelli, Francesco; Eva, Alessandra; Varesio, Luigi; Giovarelli, Mirella; Bosco, Maria Carla

    2017-01-01

    Macrophages (Mf) are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth. They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1) and alternatively activated (anti-inflammatory M2) subsets. We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment. PMID:28936211

  3. Oxidation of the tryptophan 32 residue of human superoxide dismutase 1 caused by its bicarbonate-dependent peroxidase activity triggers the non-amyloid aggregation of the enzyme.

    Science.gov (United States)

    Coelho, Fernando R; Iqbal, Asif; Linares, Edlaine; Silva, Daniel F; Lima, Filipe S; Cuccovia, Iolanda M; Augusto, Ohara

    2014-10-31

    The role of oxidative post-translational modifications of human superoxide dismutase 1 (hSOD1) in the amyotrophic lateral sclerosis (ALS) pathology is an attractive hypothesis to explore based on several lines of evidence. Among them, the remarkable stability of hSOD1(WT) and several of its ALS-associated mutants suggests that hSOD1 oxidation may precede its conversion to the unfolded and aggregated forms found in ALS patients. The bicarbonate-dependent peroxidase activity of hSOD1 causes oxidation of its own solvent-exposed Trp(32) residue. The resulting products are apparently different from those produced in the absence of bicarbonate and are most likely specific for simian SOD1s, which contain the Trp(32) residue. The aims of this work were to examine whether the bicarbonate-dependent peroxidase activity of hSOD1 (hSOD1(WT) and hSOD1(G93A) mutant) triggers aggregation of the enzyme and to comprehend the role of the Trp(32) residue in the process. The results showed that Trp(32) residues of both enzymes are oxidized to a similar extent to hSOD1-derived tryptophanyl radicals. These radicals decayed to hSOD1-N-formylkynurenine and hSOD1-kynurenine or to a hSOD1 covalent dimer cross-linked by a ditryptophan bond, causing hSOD1 unfolding, oligomerization, and non-amyloid aggregation. The latter process was inhibited by tempol, which recombines with the hSOD1-derived tryptophanyl radical, and did not occur in the absence of bicarbonate or with enzymes that lack the Trp(32) residue (bovine SOD1 and hSOD1(W32F) mutant). The results support a role for the oxidation products of the hSOD1-Trp(32) residue, particularly the covalent dimer, in triggering the non-amyloid aggregation of hSOD1. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Sterigmatocystin-induced DNA damage triggers G2 arrest via an ATM/p53-related pathway in human gastric epithelium GES-1 cells in vitro.

    Directory of Open Access Journals (Sweden)

    Donghui Zhang

    Full Text Available Sterigmatocystin (ST, which is commonly detected in food and feed commodities, is a mutagenic and carcinogenic mycotoxin that has been recognized as a possible human carcinogen. Our previous study showed that ST can induce G2 phase arrest in GES-1 cells in vitro and that the MAPK and PI3K signaling pathways are involved in the ST-induced G2 arrest. It is now widely accepted that DNA damage plays a critical role in the regulation of cell cycle arrest and apoptosis. In response to DNA damage, a complex signaling network is activated in eukaryotic cells to trigger cell cycle arrest and facilitate DNA repair. To further explore the molecular mechanism through which ST induces G2 arrest, the current study was designed to precisely dissect the role of DNA damage and the DNA damage sensor ataxia telangiectasia-mutated (ATM/p53-dependent pathway in the ST-induced G2 arrest in GES-1 cells. Using the comet assay, we determined that ST induces DNA damage, as evidenced by the formation of DNA comet tails, in GES-1 cells. We also found that ST induces the activation of ATM and its downstream molecules, Chk2 and p53, in GES-1 cells. The ATM pharmacological inhibitor caffeine was found to effectively inhibit the activation of the ATM-dependent pathways and to rescue the ST-induced G2 arrest in GES-1 cells, which indicating its ATM-dependent characteristic. Moreover, the silencing of the p53 expression with siRNA effectively attenuated the ST-induced G2 arrest in GES-1 cells. We also found that ST induces apoptosis in GES-1 cells. Thus, our results show that the ST-induced DNA damage activates the ATM/53-dependent signaling pathway, which contributes to the induction of G2 arrest in GES-1 cells.

  5. Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block.

    Science.gov (United States)

    Tan, Zhe; Dhande, Yogesh K; Reineke, Theresa M

    2017-12-20

    A series of 3-guanidinopropyl methacrylamide (GPMA)-based polymeric gene delivery vehicles were developed via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers have been evaluated for their cellular internalization ability, transfection efficiency, and cytotoxicity. Two homopolymers: P(GPMA 20 ), P(GPMA 34 ), were synthesized to study the effect of guanidium polymer length on delivery efficiency and toxicity. In addition, an N-acetyl-d-galactosamine (GalNAc)-based hydrophilic block was incorporated to produce diblock polymers, which provides a neutral hydrophilic block that sterically protects plasmid-polymer complexes (polyplexes) from colloidal aggregation and aids polyplex targeting to hepatocytes via binding to asialoglycoprotein receptors (ASGPRs). Polyplexes formed with P(GPMA x ) (x = 20, 34) homopolymers were shown to be internalized via both energy-dependent and independent pathways, whereas polyplexes formed with block polymers were internalized through endocytosis. Notably, P(GPMA x ) polyplexes enter cells very efficiently but are also very toxic to human hepatocellular carcinoma (HepG2) cells and triggered cell apoptosis. In comparison, the presence of a carbohydrate block in the polymer structures reduced the cytotoxicity of the polyplex formulations and increased gene delivery efficiency with HepG2 cells. Transfection efficiency and toxicity studies were also carried out with HEK 293T (human embryonic kidney) cells for comparison. Results showed that polyplexes formed with the P(GPMA x ) homopolymers exhibit much higher transfection efficiency and lower toxicity with HEK 293T cells. The presence of the carbohydrate block did not further increase transfection efficiency in comparison to the homopolymers with HEK 293T cells, likely due to the lack of ASGPRs on the HEK 293T cell line. This study revealed that although guanidinium-based polymers have high membrane permeability, their application as plasmid

  6. BAT Triggering Performance

    Science.gov (United States)

    McLean, Kassandra M.; Fenimore, E. E.; Palmer, D. M.; BAT Team

    2006-09-01

    The Burst Alert Telescope (BAT) onboard Swift has detected and located about 160 gamma-ray bursts (GRBs) in its first twenty months of operation. BAT employs two triggering systems to find GRBs: image triggering, which looks for a new point source in the field of view, and rate triggering, which looks for a significant increase in the observed counts. The image triggering system looks at 1 minute, 5 minute, and full pointing accumulations of counts in the detector plane in the energy range of 15-50 keV, with about 50 evaluations per pointing (about 40 minutes). The rate triggering system looks through 13 different time scales (from 4ms to 32s), 4 overlapping energy bins (covering 15-350 keV), 9 regions of the detector plane (from the full plane to individual quarters), and two background sampling models to search for GRBs. It evaluates 27000 trigger criteria in a second, for close to 1000 criteria. The image triggering system looks at 1, 5, and 40 minute accumulations of counts in the detector plane in the energy range of 15-50 keV. Both triggering systems are working very well with the settings from before launch and after we turned on BAT. However, we now have more than a year and a half of data to evaluate these triggering systems and tweak them for optimal performance, as well as lessons learned from these triggering systems.

  7. Stay away from asthma triggers

    Science.gov (United States)

    Asthma triggers - stay away from; Asthma triggers - avoiding; Reactive airway disease - triggers; Bronchial asthma - triggers ... clothes. They should leave the coat outside or away from your child. Ask people who work at ...

  8. Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling

    Energy Technology Data Exchange (ETDEWEB)

    Chiang, Jo-Hua [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Yang, Jai-Sing [Department of Pharmacology, China Medical University, Taichung 404, Taiwan (China); Lu, Chi-Cheng [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Hour, Mann-Jen; Chang, Shu-Jen [School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Lee, Tsung-Han, E-mail: thlee@email.nchu.edu.tw [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2013-06-01

    The current study aims to investigate the antiangiogenic responses and apoptotic death of human umbilical vein endothelial cells (HUVECs) by a newly synthesized compound named 2-(3′-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38). This work attempted to not only explore the effects of angiogenesis on in vivo and ex vivo studies but also hypothesize the implications for HUVECs (an ideal cell model for angiogenesis in vitro) and further undermined apoptotic experiments to verify the underlying molecular signaling by HMJ-38. Our results demonstrated that HMJ-38 significantly inhibited blood vessel growth and microvessel formation by the mouse Matrigel plug assay of angiogenesis, and the suppression of microsprouting from the rat aortic ring assay was observed after HMJ-38 exposure. In addition, HMJ-38 disrupted the tube formation and blocked the ability of HUVECs to migrate in response to VEGF. We also found that HMJ-38 triggered cell apoptosis of HUVECs in vitro. HMJ-38 concentration-dependently suppressed viability and induced apoptotic damage in HUVECs. HMJ-38-influenced HUVECs were performed by determining the oxidative stress (ROS production) and ATM/p53-modulated Fas and DR4/DR5 signals that were examined by flow cytometry, Western blotting, siRNA and real-time RT-PCR analyses, respectively. Our findings demonstrate that p53-regulated extrinsic pathway might fully contribute to HMJ-38-provoked apoptotic death in HUVECs. In view of these observations, we conclude that HMJ-38 reduces angiogenesis in vivo and ex vivo as well as induces apoptosis of HUVECs in vitro. Overall, HMJ-38 has a potent anti-neovascularization effect and could warrant being a vascular targeting agent in the future. - Highlights: • HMJ-38 suppresses angiogenic actions in vivo and ex vivo. • Inhibitions of blood vessel and microvessel formation by HMJ-38 are acted. • Cytotoxic effects of HUVECs occur by HMJ-38 challenge. • p53-modulated extrinsic pathway contributes to HMJ-38

  9. Lessons from (triggered) tremor

    Science.gov (United States)

    Gomberg, Joan

    2010-01-01

    I test a “clock-advance” model that implies triggered tremor is ambient tremor that occurs at a sped-up rate as a result of loading from passing seismic waves. This proposed model predicts that triggering probability is proportional to the product of the ambient tremor rate and a function describing the efficacy of the triggering wave to initiate a tremor event. Using data mostly from Cascadia, I have compared qualitatively a suite of teleseismic waves that did and did not trigger tremor with ambient tremor rates. Many of the observations are consistent with the model if the efficacy of the triggering wave depends on wave amplitude. One triggered tremor observation clearly violates the clock-advance model. The model prediction that larger triggering waves result in larger triggered tremor signals also appears inconsistent with the measurements. I conclude that the tremor source process is a more complex system than that described by the clock-advance model predictions tested. Results of this and previous studies also demonstrate that (1) conditions suitable for tremor generation exist in many tectonic environments, but, within each, only occur at particular spots whose locations change with time; (2) any fluid flow must be restricted to less than a meter; (3) the degree to which delayed failure and secondary triggering occurs is likely insignificant; and 4) both shear and dilatational deformations may trigger tremor. Triggered and ambient tremor rates correlate more strongly with stress than stressing rate, suggesting tremor sources result from time-dependent weakening processes rather than simple Coulomb failure.

  10. IL-6 Triggers IL-21 production by human CD4(+) T cells to drive STAT3-dependent plasma cell differentiation in B cells

    NARCIS (Netherlands)

    Diehl, Sean A.; Schmidlin, Heike; Nagasawa, Maho; Blom, Bianca; Spits, Hergen

    2012-01-01

    Interleukin (IL)-21-producing CD4(+) T cells are central to humoral immunity. Deciphering the signals that induce IL-21 production in CD4(+) T cells and those triggered by IL-21 in B cells are, therefore, of importance for understanding the generation of antibody (Ab) responses. Here, we show that

  11. Triggering trigeminal neuralgia

    DEFF Research Database (Denmark)

    Di Stefano, Giulia; Maarbjerg, Stine; Nurmikko, Turo

    2018-01-01

    Introduction Although it is widely accepted that facial pain paroxysms triggered by innocuous stimuli constitute a hallmark sign of trigeminal neuralgia, very few studies to date have systematically investigated the role of the triggers involved. In the recently published diagnostic classification...

  12. Triggering the GRANDE array

    International Nuclear Information System (INIS)

    Wilson, C.L.; Bratton, C.B.; Gurr, J.; Kropp, W.; Nelson, M.; Sobel, H.; Svoboda, R.; Yodh, G.; Burnett, T.; Chaloupka, V.; Wilkes, R.J.; Cherry, M.; Ellison, S.B.; Guzik, T.G.; Wefel, J.; Gaidos, J.; Loeffler, F.; Sembroski, G.; Goodman, J.; Haines, T.J.; Kielczewska, D.; Lane, C.; Steinberg, R.; Lieber, M.; Nagle, D.; Potter, M.; Tripp, R.

    1990-01-01

    A brief description of the Gamma Ray And Neutrino Detector Experiment (GRANDE) is presented. The detector elements and electronics are described. The trigger logic for the array is then examined. The triggers for the Gamma Ray and the Neutrino portions of the array are treated separately. (orig.)

  13. Trigger Menu in 2017

    CERN Document Server

    The ATLAS collaboration

    2018-01-01

    This document summarises the trigger menu deployed by the ATLAS experiment during 2017 data taking at proton-proton collision centre-of-mass energies of $\\sqrt{s}=13$ TeV and $\\sqrt{s}=5$ TeV at the LHC and describes the improvements with respect to the trigger system and menu used in 2016 data taking.

  14. Causality and headache triggers

    Science.gov (United States)

    Turner, Dana P.; Smitherman, Todd A.; Martin, Vincent T.; Penzien, Donald B.; Houle, Timothy T.

    2013-01-01

    Objective The objective of this study was to explore the conditions necessary to assign causal status to headache triggers. Background The term “headache trigger” is commonly used to label any stimulus that is assumed to cause headaches. However, the assumptions required for determining if a given stimulus in fact has a causal-type relationship in eliciting headaches have not been explicated. Methods A synthesis and application of Rubin’s Causal Model is applied to the context of headache causes. From this application the conditions necessary to infer that one event (trigger) causes another (headache) are outlined using basic assumptions and examples from relevant literature. Results Although many conditions must be satisfied for a causal attribution, three basic assumptions are identified for determining causality in headache triggers: 1) constancy of the sufferer; 2) constancy of the trigger effect; and 3) constancy of the trigger presentation. A valid evaluation of a potential trigger’s effect can only be undertaken once these three basic assumptions are satisfied during formal or informal studies of headache triggers. Conclusions Evaluating these assumptions is extremely difficult or infeasible in clinical practice, and satisfying them during natural experimentation is unlikely. Researchers, practitioners, and headache sufferers are encouraged to avoid natural experimentation to determine the causal effects of headache triggers. Instead, formal experimental designs or retrospective diary studies using advanced statistical modeling techniques provide the best approaches to satisfy the required assumptions and inform causal statements about headache triggers. PMID:23534872

  15. The LHCb trigger

    CERN Document Server

    Hernando Morata, Jose Angel

    2006-01-01

    The LHCb experiment relies on an efficient trigger to select a rate up to 2 kHz of events useful for physics analysis from an initial rate of 10 MHz of visible collisions. In this contribution, we describe the different LHCb trigger algorithms and present their expected performance.

  16. The NA27 trigger

    International Nuclear Information System (INIS)

    Bizzarri, R.; Di Capua, E.; Falciano, S.; Iori, M.; Marel, G.; Piredda, G.; Zanello, L.; Haupt, L.; Hellman, S.; Holmgren, S.O.; Johansson, K.E.

    1985-05-01

    We have designed and implemented a minimum bias trigger together with a fiducial volume trigger for the experiment NA27, performed at the CERN SPS. A total of more than 3 million bubble chamber pictures have been taken with a triggered cross section smaller than 75% of the total inelastic cross section. Events containing charm particles were triggered with an efficiency of 98 +2 sub(-3)%. With the fiducial volume trigger, the probability for a picture to contain an interaction in the visible hydrogen increased from 47.3% to 59.5%, reducing film cost and processing effort with about 20%. The improvement in data taking rate is shown to be negligible. (author)

  17. Validation of a commercially available enzyme-linked immunoabsorbent assay for the quantification of human α-Synuclein in cerebrospinal fluid.

    Science.gov (United States)

    Kruse, Niels; Mollenhauer, Brit

    2015-11-01

    The quantification of α-Synuclein in cerebrospinal fluid (CSF) as a biomarker has gained tremendous interest in the last years. Several commercially available immunoassays are emerging. We here describe the full validation of one commercially available ELISA assay for the quantification of α-Synuclein in human CSF (Covance alpha-Synuclein ELISA kit). The study was conducted within the BIOMARKAPD project in the European initiative Joint Program for Neurodegenerative Diseases (JPND). We investigated the effect of several pre-analytical and analytical confounders: i.e. (1) need for centrifugation of freshly drawn CSF, (2) sample stability, (3) delay of freezing, (4) volume of storage aliquots, (5) freeze/thaw cycles, (6) thawing conditions, (7) dilution linearity, (8) parallelism, (9) spike recovery, and (10) precision. None of these confounders influenced the levels of α-Synuclein in CSF significantly. We found a very high intra-assay precision. The inter-assay precision was lower than expected due to different performances of kit lots used. Overall the validated immunoassay is useful for the quantification of α-Synuclein in human CSF. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. LHCb Topological Trigger Reoptimization

    International Nuclear Information System (INIS)

    Likhomanenko, Tatiana; Khairullin, Egor; Rogozhnikov, Alex; Ustyuzhanin, Andrey; Ilten, Philip; Williams, Michael

    2015-01-01

    The main b-physics trigger algorithm used by the LHCb experiment is the so- called topological trigger. The topological trigger selects vertices which are a) detached from the primary proton-proton collision and b) compatible with coming from the decay of a b-hadron. In the LHC Run 1, this trigger, which utilized a custom boosted decision tree algorithm, selected a nearly 100% pure sample of b-hadrons with a typical efficiency of 60-70%; its output was used in about 60% of LHCb papers. This talk presents studies carried out to optimize the topological trigger for LHC Run 2. In particular, we have carried out a detailed comparison of various machine learning classifier algorithms, e.g., AdaBoost, MatrixNet and neural networks. The topological trigger algorithm is designed to select all ’interesting” decays of b-hadrons, but cannot be trained on every such decay. Studies have therefore been performed to determine how to optimize the performance of the classification algorithm on decays not used in the training. Methods studied include cascading, ensembling and blending techniques. Furthermore, novel boosting techniques have been implemented that will help reduce systematic uncertainties in Run 2 measurements. We demonstrate that the reoptimized topological trigger is expected to significantly improve on the Run 1 performance for a wide range of b-hadron decays. (paper)

  19. NOMAD Trigger Studies

    International Nuclear Information System (INIS)

    Varvell, K.

    1995-01-01

    The author reports on the status of an offline study of the NOMAD triggers, which has several motivations. Of primary importance is to demonstrate, using offline information recorded by the individual subdetectors comprising NOMAD, that the online trigger system is functioning as expected. Such an investigation serves to complement the extensive monitoring which is already carried out online. More specific to the needs of the offline software and analysis, the reconstruction of tracks and vertices in the detector requires some knowledge of the time at which the trigger has occurred, in order to locate relevant hits in the drift chambers and muon chambers in particular. The fact that the different triggers allowed by the MIOTRINO board take varying times to form complicates this task. An offline trigger algorithm may serve as a tool to shed light on situations where the online trigger status bits have not been recorded correctly, as happens in a small number of cases, or as an aid to studies with the aim of further refinement of the online triggers themselves

  20. Calo trigger acquisition system

    CERN Multimedia

    Franchini, Matteo

    2016-01-01

    Calo trigger acquisition system - Evolution of the acquisition system from a multiple boards system (upper, orange cables) to a single board one (below, light blue cables) where all the channels are collected in a single board.

  1. Calorimetry triggering in ATLAS

    CERN Document Server

    Igonkina, O; Adragna, P; Aharrouche, M; Alexandre, G; Andrei, V; Anduaga, X; Aracena, I; Backlund, S; Baines, J; Barnett, B M; Bauss, B; Bee, C; Behera, P; Bell, P; Bendel, M; Benslama, K; Berry, T; Bogaerts, A; Bohm, C; Bold, T; Booth, J R A; Bosman, M; Boyd, J; Bracinik, J; Brawn, I, P; Brelier, B; Brooks, W; Brunet, S; Bucci, F; Casadei, D; Casado, P; Cerri, A; Charlton, D G; Childers, J T; Collins, N J; Conde Muino, P; Coura Torres, R; Cranmer, K; Curtis, C J; Czyczula, Z; Dam, M; Damazio, D; Davis, A O; De Santo, A; Degenhardt, J; Delsart, P A; Demers, S; Demirkoz, B; Di Mattia, A; Diaz, M; Djilkibaev, R; Dobson, E; Dova, M, T; Dufour, M A; Eckweiler, S; Ehrenfeld, W; Eifert, T; Eisenhandler, E; Ellis, N; Emeliyanov, D; Enoque Ferreira de Lima, D; Faulkner, P J W; Ferland, J; Flacher, H; Fleckner, J E; Flowerdew, M; Fonseca-Martin, T; Fratina, S; Fhlisch, F; Gadomski, S; Gallacher, M P; Garitaonandia Elejabarrieta, H; Gee, C N P; George, S; Gillman, A R; Goncalo, R; Grabowska-Bold, I; Groll, M; Gringer, C; Hadley, D R; Haller, J; Hamilton, A; Hanke, P; Hauser, R; Hellman, S; Hidvgi, A; Hillier, S J; Hryn'ova, T; Idarraga, J; Johansen, M; Johns, K; Kalinowski, A; Khoriauli, G; Kirk, J; Klous, S; Kluge, E-E; Koeneke, K; Konoplich, R; Konstantinidis, N; Kwee, R; Landon, M; LeCompte, T; Ledroit, F; Lei, X; Lendermann, V; Lilley, J N; Losada, M; Maettig, S; Mahboubi, K; Mahout, G; Maltrana, D; Marino, C; Masik, J; Meier, K; Middleton, R P; Mincer, A; Moa, T; Monticelli, F; Moreno, D; Morris, J D; Mller, F; Navarro, G A; Negri, A; Nemethy, P; Neusiedl, A; Oltmann, B; Olvito, D; Osuna, C; Padilla, C; Panes, B; Parodi, F; Perera, V J O; Perez, E; Perez Reale, V; Petersen, B; Pinzon, G; Potter, C; Prieur, D P F; Prokishin, F; Qian, W; Quinonez, F; Rajagopalan, S; Reinsch, A; Rieke, S; Riu, I; Robertson, S; Rodriguez, D; Rogriquez, Y; Rhr, F; Saavedra, A; Sankey, D P C; Santamarina, C; Santamarina Rios, C; Scannicchio, D; Schiavi, C; Schmitt, K; Schultz-Coulon, H C; Schfer, U; Segura, E; Silverstein, D; Silverstein, S; Sivoklokov, S; Sjlin, J; Staley, R J; Stamen, R; Stelzer, J; Stockton, M C; Straessner, A; Strom, D; Sushkov, S; Sutton, M; Tamsett, M; Tan, C L A; Tapprogge, S; Thomas, J P; Thompson, P D; Torrence, E; Tripiana, M; Urquijo, P; Urrejola, P; Vachon, B; Vercesi, V; Vorwerk, V; Wang, M; Watkins, P M; Watson, A; Weber, P; Weidberg, T; Werner, P; Wessels, M; Wheeler-Ellis, S; Whiteson, D; Wiedenmann, W; Wielers, M; Wildt, M; Winklmeier, F; Wu, X; Xella, S; Zhao, L; Zobernig, H; de Seixas, J M; dos Anjos, A; Asman, B; Özcan, E

    2009-01-01

    The ATLAS experiment is preparing for data taking at 14 TeV collision energy. A rich discovery physics program is being prepared in addition to the detailed study of Standard Model processes which will be produced in abundance. The ATLAS multi-level trigger system is designed to accept one event in 2 105 to enable the selection of rare and unusual physics events. The ATLAS calorimeter system is a precise instrument, which includes liquid Argon electro-magnetic and hadronic components as well as a scintillator-tile hadronic calorimeter. All these components are used in the various levels of the trigger system. A wide physics coverage is ensured by inclusively selecting events with candidate electrons, photons, taus, jets or those with large missing transverse energy. The commissioning of the trigger system is being performed with cosmic ray events and by replaying simulated Monte Carlo events through the trigger and data acquisition system.

  2. BTeV Trigger

    International Nuclear Information System (INIS)

    Gottschalk, Erik E.

    2006-01-01

    BTeV was designed to conduct precision studies of CP violation in BB-bar events using a forward-geometry detector in a hadron collider. The detector was optimized for high-rate detection of beauty and charm particles produced in collisions between protons and antiprotons. The trigger was designed to take advantage of the main difference between events with beauty and charm particles and more typical hadronic events-the presence of detached beauty and charm decay vertices. The first stage of the BTeV trigger was to receive data from a pixel vertex detector, reconstruct tracks and vertices for every beam crossing, reject at least 98% of beam crossings in which neither beauty nor charm particles were produced, and trigger on beauty events with high efficiency. An overview of the trigger design and its evolution to include commodity networking and computing components is presented

  3. Calorimetry triggering in ATLAS

    International Nuclear Information System (INIS)

    Igonkina, O; Achenbach, R; Andrei, V; Adragna, P; Aharrouche, M; Bauss, B; Bendel, M; Alexandre, G; Anduaga, X; Aracena, I; Backlund, S; Bogaerts, A; Baines, J; Barnett, B M; Bee, C; P, Behera; Bell, P; Benslama, K; Berry, T; Bohm, C

    2009-01-01

    The ATLAS experiment is preparing for data taking at 14 TeV collision energy. A rich discovery physics program is being prepared in addition to the detailed study of Standard Model processes which will be produced in abundance. The ATLAS multi-level trigger system is designed to accept one event in 2 | 10 5 to enable the selection of rare and unusual physics events. The ATLAS calorimeter system is a precise instrument, which includes liquid Argon electro-magnetic and hadronic components as well as a scintillator-tile hadronic calorimeter. All these components are used in the various levels of the trigger system. A wide physics coverage is ensured by inclusively selecting events with candidate electrons, photons, taus, jets or those with large missing transverse energy. The commissioning of the trigger system is being performed with cosmic ray events and by replaying simulated Monte Carlo events through the trigger and data acquisition system.

  4. Calorimetry Triggering in ATLAS

    International Nuclear Information System (INIS)

    Igonkina, O.; Achenbach, R.; Adragna, P.; Aharrouche, M.; Alexandre, G.; Andrei, V.; Anduaga, X.; Aracena, I.; Backlund, S.; Baines, J.; Barnett, B.M.; Bauss, B.; Bee, C.; Behera, P.; Bell, P.; Bendel, M.; Benslama, K.; Berry, T.; Bogaerts, A.; Bohm, C.; Bold, T.; Booth, J.R.A.; Bosman, M.; Boyd, J.; Bracinik, J.; Brawn, I.P.; Brelier, B.; Brooks, W.; Brunet, S.; Bucci, F.; Casadei, D.; Casado, P.; Cerri, A.; Charlton, D.G.; Childers, J.T.; Collins, N.J.; Conde Muino, P.; Coura Torres, R.; Cranmer, K.; Curtis, C.J.; Czyczula, Z.; Dam, M.; Damazio, D.; Davis, A.O.; De Santo, A.; Degenhardt, J.

    2011-01-01

    The ATLAS experiment is preparing for data taking at 14 TeV collision energy. A rich discovery physics program is being prepared in addition to the detailed study of Standard Model processes which will be produced in abundance. The ATLAS multi-level trigger system is designed to accept one event in 2/10 5 to enable the selection of rare and unusual physics events. The ATLAS calorimeter system is a precise instrument, which includes liquid Argon electro-magnetic and hadronic components as well as a scintillator-tile hadronic calorimeter. All these components are used in the various levels of the trigger system. A wide physics coverage is ensured by inclusively selecting events with candidate electrons, photons, taus, jets or those with large missing transverse energy. The commissioning of the trigger system is being performed with cosmic ray events and by replaying simulated Monte Carlo events through the trigger and data acquisition system.

  5. Calorimetry triggering in ATLAS

    Energy Technology Data Exchange (ETDEWEB)

    Igonkina, O [Nikhef National Institute for Subatomic Physics, Amsterdam (Netherlands); Achenbach, R; Andrei, V [Kirchhoff Institut fuer Physik, Universitaet Heidelberg, Heidelberg (Germany); Adragna, P [Physics Department, Queen Mary, University of London, London (United Kingdom); Aharrouche, M; Bauss, B; Bendel, M [Institut fr Physik, Universitt Mainz, Mainz (Germany); Alexandre, G [Section de Physique, Universite de Geneve, Geneva (Switzerland); Anduaga, X [Universidad Nacional de La Plata, La Plata (Argentina); Aracena, I [Stanford Linear Accelerator Center (SLAC), Stanford (United States); Backlund, S; Bogaerts, A [European Laboratory for Particle Physics (CERN), Geneva (Switzerland); Baines, J; Barnett, B M [STFC Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxon (United Kingdom); Bee, C [Centre de Physique des Particules de Marseille, IN2P3-CNRS, Marseille (France); P, Behera [Iowa State University, Ames, Iowa (United States); Bell, P [School of Physics and Astronomy, University of Manchester, Manchester (United Kingdom); Benslama, K [University of Regina, Regina (Canada); Berry, T [Department of Physics, Royal Holloway and Bedford New College, Egham (United Kingdom); Bohm, C [Fysikum, Stockholm University, Stockholm (Sweden)

    2009-04-01

    The ATLAS experiment is preparing for data taking at 14 TeV collision energy. A rich discovery physics program is being prepared in addition to the detailed study of Standard Model processes which will be produced in abundance. The ATLAS multi-level trigger system is designed to accept one event in 2 | 10{sup 5} to enable the selection of rare and unusual physics events. The ATLAS calorimeter system is a precise instrument, which includes liquid Argon electro-magnetic and hadronic components as well as a scintillator-tile hadronic calorimeter. All these components are used in the various levels of the trigger system. A wide physics coverage is ensured by inclusively selecting events with candidate electrons, photons, taus, jets or those with large missing transverse energy. The commissioning of the trigger system is being performed with cosmic ray events and by replaying simulated Monte Carlo events through the trigger and data acquisition system.

  6. LHCb Topological Trigger Reoptimization

    CERN Document Server

    INSPIRE-00400931; Ilten, Philip; Khairullin, Egor; Rogozhnikov, Alex; Ustyuzhanin, Andrey; Williams, Michael

    2015-12-23

    The main b-physics trigger algorithm used by the LHCb experiment is the so-called topological trigger. The topological trigger selects vertices which are a) detached from the primary proton-proton collision and b) compatible with coming from the decay of a b-hadron. In the LHC Run 1, this trigger, which utilized a custom boosted decision tree algorithm, selected a nearly 100% pure sample of b-hadrons with a typical efficiency of 60-70%; its output was used in about 60% of LHCb papers. This talk presents studies carried out to optimize the topological trigger for LHC Run 2. In particular, we have carried out a detailed comparison of various machine learning classifier algorithms, e.g., AdaBoost, MatrixNet and neural networks. The topological trigger algorithm is designed to select all "interesting" decays of b-hadrons, but cannot be trained on every such decay. Studies have therefore been performed to determine how to optimize the performance of the classification algorithm on decays not used in the training. ...

  7. Topological Trigger Developments

    CERN Multimedia

    Likhomanenko, Tatiana

    2015-01-01

    The main b-physics trigger algorithm used by the LHCb experiment is the so-called topological trigger. The topological trigger selects vertices which are a) detached from the primary proton-proton collision and b) compatible with coming from the decay of a b-hadron. In the LHC Run 1, this trigger utilized a custom boosted decision tree algorithm, selected an almost 100% pure sample of b-hadrons with a typical efficiency of 60-70%, and its output was used in about 60% of LHCb papers. This talk presents studies carried out to optimize the topological trigger for LHC Run 2. In particular, we have carried out a detailed comparison of various machine learning classifier algorithms, e.g., AdaBoost, MatrixNet and uBoost. The topological trigger algorithm is designed to select all "interesting" decays of b-hadrons, but cannot be trained on every such decay. Studies have therefore been performed to determine how to optimize the performance of the classification algorithm on decays not used in the training. These inclu...

  8. CMS Trigger Performance

    CERN Document Server

    Donato, Silvio

    2017-01-01

    During its second run of operation (Run 2) which started in 2015, the LHC will deliver a peak instantaneous luminosity that may reach $2 \\cdot 10^{34}$ cm$^{-2}$s$^{-1}$ with an average pile-up of about 55, far larger than the design value. Under these conditions, the online event selection is a very challenging task. In CMS, it is realized by a two-level trigger system the Level-1 (L1) Trigger, implemented in custom-designed electronics, and the High Level Trigger (HLT), a streamlined version of the offline reconstruction software running on a computer farm. In order to face this challenge, the L1 trigger has been through a major upgrade compared to Run 1, whereby all electronic boards of the system have been replaced, allowing more sophisticated algorithms to be run online. Its last stage, the global trigger, is now able to perform complex selections and to compute high-level quantities, like invariant masses. Likewise, the algorithms that run in the HLT go through big improvements; in particular, new appr...

  9. The ATLAS Tau Trigger

    CERN Document Server

    Dam, M; The ATLAS collaboration

    2009-01-01

    The ATLAS experiment at CERN’s LHC has implemented a dedicated tau trigger system to select hadronically decaying tau leptons from the enormous background of QCD jets. This promises a significant increase in the discovery potential to the Higgs boson and in searches for physics beyond the Standard Model. The three level trigger system has been optimised for effciency and good background rejection. The first level uses information from the calorimeters only, while the two higher levels include also information from the tracking detectors. Shower shape variables and the track multiplicity are important variables to distinguish taus from QCD jets. At the initial lumonosity of 10^31 cm^−2 s^−1, single tau triggers with a transverse energy threshold of 50 GeV or higher can be run standalone. Below this level, the tau signatures will be combined with other event signature

  10. The ATLAS Tau Trigger

    CERN Document Server

    Rados, PK; The ATLAS collaboration

    2014-01-01

    Physics processes involving tau leptons play a crucial role in understanding particle physics at the high energy frontier. The ability to efficiently trigger on events containing hadronic tau decays is therefore of particular importance to the ATLAS experiment. During the 2012 run, the Large Hadronic Collder (LHC) reached instantaneous luminosities of nearly $10^{34} cm^{-2}s^{-1}$ with bunch crossings occurring every $50 ns$. This resulted in a huge event rate and a high probability of overlapping interactions per bunch crossing (pile-up). With this in mind it was necessary to design an ATLAS tau trigger system that could reduce the event rate to a manageable level, while efficiently extracting the most interesting physics events in a pile-up robust manner. In this poster the ATLAS tau trigger is described, its performance during 2012 is presented, and the outlook for the LHC Run II is briefly summarized.

  11. Triggering of final oocyte maturation with gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Live birth after frozen-thawed embryo replacement cycles

    DEFF Research Database (Denmark)

    Griesinger, Georg; Kolibianakis, E M; Papanikolaou, E G

    2007-01-01

    OBJECTIVE: To report the outcome of frozen-thawed embryo replacement cycles after GnRH-agonist triggering of final oocyte maturation in the collecting cycle with GnRH-antagonist. DESIGN: Prospective, observational, multicentric clinical study. SETTING: Tertiary university-affiliated IVF centers...... a total of 228 participants. Surplus embryos or oocytes at the pronuclear stage were cryopreserved in 53 patients after hCG administration and 32 patients after GnRH-agonist administration on the basis of patient choice, pronuclear/embryo availability, and local laws. INTERVENTION(S): Transfer of frozen......-thawed embryos. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): Thirty-one and 23 patients after administration of hCG and GnRH-agonist, respectively, started a frozen-embryo replacement cycle by September 2005, with 25 and 16 patients eventually undergoing at least one frozen-thawed ET. Live birth rate per...

  12. ALICE High Level Trigger

    CERN Multimedia

    Alt, T

    2013-01-01

    The ALICE High Level Trigger (HLT) is a computing farm designed and build for the real-time, online processing of the raw data produced by the ALICE detectors. Events are fully reconstructed from the raw data, analyzed and compressed. The analysis summary together with the compressed data and a trigger decision is sent to the DAQ. In addition the reconstruction of the events allows for on-line monitoring of physical observables and this information is provided to the Data Quality Monitor (DQM). The HLT can process event rates of up to 2 kHz for proton-proton and 200 Hz for Pb-Pb central collisions.

  13. Trigger and decision processors

    International Nuclear Information System (INIS)

    Franke, G.

    1980-11-01

    In recent years there have been many attempts in high energy physics to make trigger and decision processes faster and more sophisticated. This became necessary due to a permanent increase of the number of sensitive detector elements in wire chambers and calorimeters, and in fact it was possible because of the fast developments in integrated circuits technique. In this paper the present situation will be reviewed. The discussion will be mainly focussed upon event filtering by pure software methods and - rather hardware related - microprogrammable processors as well as random access memory triggers. (orig.)

  14. The STAR trigger

    International Nuclear Information System (INIS)

    Bieser, F.S.; Crawford, H.J.; Engelage, J.; Eppley, G.; Greiner, L.C.; Judd, E.G.; Klein, S.R.; Meissner, F.; Minor, R.; Milosevich, Z.; Mutchler, G.; Nelson, J.M.; Schambach, J.; VanderMolen, A.S.; Ward, H.; Yepes, P.

    2003-01-01

    We describe the trigger system that we designed and implemented for the STAR detector at RHIC. This is a 10 MHz pipelined system based on fast detector output that controls the event selection for the much slower tracking detectors. Results from the first run are presented and new detectors for the 2001 run are discussed

  15. Asthma Triggers: Gain Control

    Science.gov (United States)

    ... harm people too. Try to use pest management methods that pose less of a risk. Keep counters, sinks, tables and floors clean and ... with pest challenges in your home and other environments. [EPA ... pests while reducing pesticide risks; roaches are often asthma triggers and shouldn’t ...

  16. Physics issues on triggering

    Indian Academy of Sciences (India)

    The detectors at the ILC are planned to run without hardware trigger. The ... as not coming from the interaction point and not matching to the silicon detectors ... electrons so that additional dE/dx cuts can help, making also here a factor 10 or.

  17. AIDS radio triggers.

    Science.gov (United States)

    Elias, A M

    1991-07-01

    In April 1991, the Ethnic Communities' Council of NSW was granted funding under the Community AIDS Prevention and Education Program through the Department of Community Services and Health, to produce a series of 6x50 second AIDS radio triggers with a 10-second tag line for further information. The triggers are designed to disseminate culturally-sensitive information about HIV/AIDS in English, Italian, Greek, Spanish, Khmer, Turkish, Macedonian, Serbo-Croatian, Arabic, Cantonese, and Vietnamese, with the goal of increasing awareness and decreasing the degree of misinformation about HIV/AIDS among people of non-English-speaking backgrounds through radio and sound. The 6 triggers cover the denial that AIDS exists in the community, beliefs that words and feelings do not protect one from catching HIV, encouraging friends to be compassionate, compassion within the family, AIDS information for a young audience, and the provision of accurate and honest information on HIV/AIDS. The triggers are slated to be completed by the end of July 1991 and will be broadcast on all possible community, ethnic, and commercial radio networks across Australia. They will be available upon request in composite form with an information kit for use by health care professionals and community workers.

  18. Dealing with Asthma Triggers

    Science.gov (United States)

    ... one trigger that you shouldn't avoid because exercise is important for your health. Your doctor will want you to be active, so talk with him or her about what to do before playing ... or 15 minutes before you exercise or play sports. And, of course, you'll ...

  19. Trigger Finger (Stenosing Tenosynovitis)

    Science.gov (United States)

    ... All Topics A-Z Videos Infographics Symptom Picker Anatomy Bones Joints Muscles Nerves Vessels Tendons About Hand Surgery What is a Hand Surgeon? What is a Hand Therapist? Media Find a Hand Surgeon Home Anatomy Trigger Finger Email to a friend * required fields ...

  20. Inhibition of CLIC4 enhances autophagy and triggers mitochondrial and ER stress-induced apoptosis in human glioma U251 cells under starvation.

    Directory of Open Access Journals (Sweden)

    Jiateng Zhong

    Full Text Available CLIC4/mtCLIC, a chloride intracellular channel protein, localizes to mitochondria, endoplasmic reticulum (ER, nucleus and cytoplasm, and participates in the apoptotic response to stress. Apoptosis and autophagy, the main types of the programmed cell death, seem interconnected under certain stress conditions. However, the role of CLIC4 in autophagy regulation has yet to be determined. In this study, we demonstrate upregulation and nuclear translocation of the CLIC4 protein following starvation in U251 cells. CLIC4 siRNA transfection enhanced autophagy with increased LC3-II protein and puncta accumulation in U251 cells under starvation conditions. In that condition, the interaction of the 14-3-3 epsilon isoform with CLIC4 was abolished and resulted in Beclin 1 overactivation, which further activated autophagy. Moreover, inhibiting the expression of CLIC4 triggered both mitochondrial apoptosis involved in Bax/Bcl-2 and cytochrome c release under starvation and endoplasmic reticulum stress-induced apoptosis with CHOP and caspase-4 upregulation. These results demonstrate that CLIC4 nuclear translocation is an integral part of the cellular response to starvation. Inhibiting the expression of CLIC4 enhances autophagy and contributes to mitochondrial and ER stress-induced apoptosis under starvation.

  1. The ATLAS Tau Trigger

    International Nuclear Information System (INIS)

    Rados, Petar Kevin

    2013-06-01

    The tau lepton plays a crucial role in understanding particle physics at the Tera scale. One of the most promising probes of the Higgs boson coupling to fermions is with detector signatures involving taus. In addition, many theories beyond the Standard Model, such as supersymmetry and exotic particles (W' and Z'), predict new physics with large couplings to taus. The ability to trigger on hadronic tau decays is therefore critical to achieving the physics goals of the ATLAS experiment. The higher instantaneous luminosities of proton-proton collisions achieved by the Large Hadron Collider (LHC) in 2012 resulted in a larger probability of overlap (pile-up) between bunch crossings, and so it was critical for ATLAS to have an effective tau trigger strategy. The details of this strategy are summarized in this paper, and the results of the latest performance measurements are presented. (authors)

  2. The LPS trigger system

    International Nuclear Information System (INIS)

    Benotto, F.; Costa, M.; Staiano, A.; Zampieri, A.; Bollito, M.; Isoardi, P.; Pernigotti, E.; Sacchi, R.; Trapani, P.P.; Larsen, H.; Massam, T.; Nemoz, C.

    1996-03-01

    The Leading Proton Spectrometer (LPS) has been equipped with microstrip silicon detectors specially designed to trigger events with high values of x L vertical stroke anti p' p vertical stroke / vertical stroke anti p p vertical stroke ≥0.95 where vertical stroke anti p' p vertical stroke and vertical stroke anti p p vertical stroke are respectively the momenta of outgoing and incoming protons. The LPS First Level Trigger can provide a clear tag for very high momentum protons in a kinematical region never explored before. In the following we discuss the physics motivation in tagging very forward protons and present a detailed description of the detector design, the front end electronics, the readout electronics, the Monte Carlo simulation and some preliminary results from 1995 data taking. (orig.)

  3. Minimum risk trigger indices

    International Nuclear Information System (INIS)

    Tingey, F.H.

    1979-01-01

    A viable safeguards system includes among other things the development and use of indices which trigger various courses of action. The usual limit of error calculation provides such an index. The classical approach is one of constructing tests which, under certain assumptions, make the likelihood of a false alarm small. Of concern also is the test's failure to indicate a loss (diversion) when in fact one has occurred. Since false alarms are usually costly and losses both costly and of extreme strategic sinificance, there remains the task of balancing the probability of false alarm and its consequences against the probability of undetected loss and its consequences. The application of other than classical hypothesis testing procedures are considered in this paper. Using various consequence models, trigger indices are derived which have certain optimum properties. Application of the techniques would enhance the material control function

  4. Overexpression of miR-183/-96/-182 triggers neuronal cell fate in Human Retinal Pigment Epithelial (hRPE) cells in culture.

    Science.gov (United States)

    Davari, Maliheh; Soheili, Zahra-Soheila; Samiei, Shahram; Sharifi, Zohreh; Pirmardan, Ehsan Ranaei

    2017-01-29

    miR-183 cluster, composed of miR-183/-96/-182 genes, is highly expressed in the adult retina, particularly in photoreceptors. It involves in development, maturation and normal function of neuroretina. Ectopic overexpression of miR-183/-96/-182 genes was performed to assess reprogramming of hRPE cells. They were amplified from genomic DNA and cloned independently or in tandem configuration into pAAV.MCS vector. hRPE cells were then transfected with the recombinant constructs. Real-Time PCR was performed to measure the expression levels of miR-183/-96/-182 and that of several retina-specific neuronal genes such as OTX2, NRL, PDC and DCT. The transfected cells also were immunocytochemically examined for retina-specific neuronal markers, including Rhodopsin, red opsin, CRX, Thy1, CD73, recoverin and PKCα, to determine the cellular fate of the transfected hRPE cells. Data showed that upon miR-183/-96/-182 overexpression in hRPE cultures, the expression of neuronal genes including OTX2, NRL, PDC and DCT was also upregulated. Moreover, miR-183 cluster-treated hRPE cells were immunoreactive for neuronal markers such as Rhodopsin, red opsin, CRX and Thy1. Both transcriptional and translational upregulation of neuronal genes in miR-183 cluster-treated hRPE cells suggests that in vitro overexpression of miR-183 cluster could trigger reprogramming of hRPE cells to retinal neuron fate. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Neural networks for triggering

    International Nuclear Information System (INIS)

    Denby, B.; Campbell, M.; Bedeschi, F.; Chriss, N.; Bowers, C.; Nesti, F.

    1990-01-01

    Two types of neural network beauty trigger architectures, based on identification of electrons in jets and recognition of secondary vertices, have been simulated in the environment of the Fermilab CDF experiment. The efficiencies for B's and rejection of background obtained are encouraging. If hardware tests are successful, the electron identification architecture will be tested in the 1991 run of CDF. 10 refs., 5 figs., 1 tab

  6. The ARGUS vertex trigger

    International Nuclear Information System (INIS)

    Koch, N.; Kolander, M.; Kolanoski, H.; Siegmund, T.; Bergter, J.; Eckstein, P.; Schubert, K.R.; Waldi, R.; Imhof, M.; Ressing, D.; Weiss, U.; Weseler, S.

    1995-09-01

    A fast second level trigger has been developed for the ARGUS experiment which recognizes tracks originating from the interaction region. The processor compares the hits in the ARGUS Micro Vertex Drift Chamber to 245760 masks stored in random access memories. The masks which are fully defined in three dimensions are able to reject tracks originating in the wall of the narrow beampipe of 10.5 mm radius. (orig.)

  7. Camel Milk Triggers Apoptotic Signaling Pathways in Human Hepatoma HepG2 and Breast Cancer MCF7 Cell Lines through Transcriptional Mechanism

    Directory of Open Access Journals (Sweden)

    Hesham M. Korashy

    2012-01-01

    Full Text Available Few published studies have reported the use of crude camel milk in the treatment of stomach infections, tuberculosis and cancer. Yet, little research was conducted on the effect of camel milk on the apoptosis and oxidative stress associated with human cancer. The present study investigated the effect and the underlying mechanisms of camel milk on the proliferation of human cancer cells using an in vitro model of human hepatoma (HepG2 and human breast (MCF7 cancer cells. Our results showed that camel milk, but not bovine milk, significantly inhibited HepG2 and MCF7 cells proliferation through the activation of caspase-3 mRNA and activity levels, and the induction of death receptors in both cell lines. In addition, Camel milk enhanced the expression of oxidative stress markers, heme oxygenase-1 and reactive oxygen species production in both cells. Mechanistically, the increase in caspase-3 mRNA levels by camel milk was completely blocked by the transcriptional inhibitor, actinomycin D; implying that camel milk increased de novo RNA synthesis. Furthermore, Inhibition of the mitogen activated protein kinases differentially modulated the camel milk-induced caspase-3 mRNA levels. Taken together, camel milk inhibited HepG2 and MCF7 cells survival and proliferation through the activation of both the extrinsic and intrinsic apoptotic pathways.

  8. Increased mortality exposure within the family rather than individual mortality experiences triggers faster life-history strategies in historic human populations

    NARCIS (Netherlands)

    Störmer, Charlotte; Lummaa, Virpi

    2014-01-01

    impact of family versus individual-level effects of mortality exposure on two central life-history parameters, ages at first marriage and first birth, in three historical human populations (Germany, Finland, Canada). Mortality experience is measured as the confrontation with sibling deaths within

  9. Temporally resolved electrocardiogram-triggered diffusion-weighted imaging of the human kidney: correlation between intravoxel incoherent motion parameters and renal blood flow at different time points of the cardiac cycle.

    Science.gov (United States)

    Wittsack, Hans-Jörg; Lanzman, Rotem S; Quentin, Michael; Kuhlemann, Julia; Klasen, Janina; Pentang, Gael; Riegger, Caroline; Antoch, Gerald; Blondin, Dirk

    2012-04-01

    To evaluate the influence of pulsatile blood flow on apparent diffusion coefficients (ADC) and the fraction of pseudodiffusion (F(P)) in the human kidney. The kidneys of 6 healthy volunteers were examined by a 3-T magnetic resonance scanner. Electrocardiogram (ECG)-gated and respiratory-triggered diffusion-weighted imaging (DWI) and phase-contrast flow measurements were performed. Flow imaging of renal arteries was carried out to quantify the dependence of renal blood flow on the cardiac cycle. ECG-triggered DWI was acquired in the coronal plane with 16 b values in the range of 0 s/mm(2) and 750 s/mm(2) at the time of minimum (MIN) (20 milliseconds after R wave) and maximum renal blood flow (MAX) (197 ± 24 milliseconds after R wave). The diffusion coefficients were calculated using the monoexponential approach as well as the biexponential intravoxel incoherent motion model and correlated to phase-contrast flow measurements. Flow imaging showed pulsatile renal blood flow depending on the cardiac cycle. The mean flow velocity at MIN was 45 cm/s as compared with 61 cm/s at MAX. F(p) at MIN (0.29) was significantly lower than at MAX (0.40) (P = 0.001). Similarly, ADC(mono), derived from the monoexponential model, also showed a significant difference (P renal blood flow and F(p) (r = 0.85) as well as ADC(mono) (r = 0.67) was statistically significant. Temporally resolved ECG-gated DWI enables for the determination of the diffusion coefficients at different time points of the cardiac cycle. ADC(mono) and FP vary significantly among acquisitions at minimum (diastole) and maximum (systole) renal blood flow. Temporally resolved ECG-gated DWI might therefore serve as a novel technique for the assessment of pulsatility in the human kidney.

  10. Identification of new ovulation-related genes in humans by comparing the transcriptome of granulosa cells before and after ovulation triggering in the same controlled ovarian stimulation cycle

    DEFF Research Database (Denmark)

    Wissing, M L; Kristensen, S G; Andersen, C Y

    2014-01-01

    . Many new ovulation-related genes were revealed, such as CD24, ANKRD22, CLDN11 and FBXO32. FF estrogen, androstenedione and anti-Müllerian hormone decreased significantly while progesterone increased, accompanied by radical changes in the expression of steroidogenic genes (CYP17A, CYP19A, HSD11B1......, REASONS FOR CAUTION: The present dataset was generated from women under hormonal stimulation. However, comparison with a macaque natural cycle whole follicle ovulation dataset revealed major overlap, supporting the idea that the ovulation-related genes found in this study are relevant in the human natural...... cycle. WIDER IMPLICATIONS OF THE FINDINGS: These data will serve as a research resource for genes involved in human ovulation and final oocyte maturation. Ovulation-related genes might be good candidate biomarkers of follicle and oocyte health. Further, some of the ovulation-related genes may serve...

  11. Increased mortality exposure within the family rather than individual mortality experiences triggers faster life-history strategies in historic human populations.

    Science.gov (United States)

    Störmer, Charlotte; Lummaa, Virpi

    2014-01-01

    Life History Theory predicts that extrinsic mortality risk is one of the most important factors shaping (human) life histories. Evidence from contemporary populations suggests that individuals confronted with high mortality environments show characteristic traits of fast life-history strategies: they marry and reproduce earlier, have shorter birth intervals and invest less in their offspring. However, little is known of the impact of mortality experiences on the speed of life histories in historical human populations with generally higher mortality risk, and on male life histories in particular. Furthermore, it remains unknown whether individual-level mortality experiences within the family have a greater effect on life-history decisions or family membership explains life-history variation. In a comparative approach using event history analyses, we study the impact of family versus individual-level effects of mortality exposure on two central life-history parameters, ages at first marriage and first birth, in three historical human populations (Germany, Finland, Canada). Mortality experience is measured as the confrontation with sibling deaths within the natal family up to an individual's age of 15. Results show that the speed of life histories is not adjusted according to individual-level mortality experiences but is due to family-level effects. The general finding of lower ages at marriage/reproduction after exposure to higher mortality in the family holds for both females and males. This study provides evidence for the importance of the family environment for reproductive timing while individual-level mortality experiences seem to play only a minor role in reproductive life history decisions in humans.

  12. Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Yu-Ping Hsiao

    2015-01-01

    Full Text Available Malic acid (MA has been commonly used in cosmetic products, but the safety reports in skin are sparse. To investigate the biological effects of MA in human skin keratinocytes, we investigated the potential cytotoxicity and apoptotic effects of MA in human keratinocyte cell lines (HaCaT. The data showed that MA induced apoptosis based on the observations of DAPI staining, DNA fragmentation, and sub-G1 phase in HaCaT cells and normal human epidermal keratinocytes (NHEKs. Flow cytometric assays also showed that MA increased the production of mitochondrial superoxide (mito-SOX but decreased the mitochondrial membrane potential. Analysis of bioenergetics function with the XF 24 analyzer Seahorse extracellular flux analyzer demonstrated that oxygen consumption rate (OCR was significantly decreased whereas extracellular acidification rate (ECAR was increased in MA-treated keratinocytes. The occurrence of apoptosis was proved by the increased expressions of FasL, Fas, Bax, Bid, caspases-3, -8, -9, cytochrome c, and the declined expressions of Bcl-2, PARP. MA also induced endoplasmic reticulum stress associated protein expression such as GRP78, GADD153, and ATF6α. We demonstrated that MA had anti-proliferative effect in HaCaT cell through the inhibition of cell cycle progression at G0/G1, and the induction of programmed cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.

  13. The mechanisms of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease

    Science.gov (United States)

    Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanis...

  14. Validation of a quantitative cerebrospinal fluid alpha-synuclein assay in a European-wide interlaboratory study

    DEFF Research Database (Denmark)

    Kruse, N.; Persson, S.; Alcolea, D.

    2015-01-01

    (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when...... the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings...... assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program -Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits...

  15. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models.

    Science.gov (United States)

    Games, Dora; Valera, Elvira; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Patrick, Christina; Ubhi, Kiren; Nuber, Silke; Sacayon, Patricia; Zago, Wagner; Seubert, Peter; Barbour, Robin; Schenk, Dale; Masliah, Eliezer

    2014-07-09

    Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease. Copyright © 2014 the authors 0270-6474/14/349441-14$15.00/0.

  16. Structural variation of alpha-synuclein with temperature by a coarse-grained approach with knowledge-based interactions

    Directory of Open Access Journals (Sweden)

    Peter Mirau

    2015-09-01

    Full Text Available Despite enormous efforts, our understanding the structure and dynamics of α-synuclein (ASN, a disordered protein (that plays a key role in neurodegenerative disease is far from complete. In order to better understand sequence-structure-property relationships in α-SYNUCLEIN we have developed a coarse-grained model using knowledge-based residue-residue interactions and used it to study the structure of free ASN as a function of temperature (T with a large-scale Monte Carlo simulation. Snapshots of the simulation and contour contact maps show changes in structure formation due to self-assembly as a function of temperature. Variations in the residue mobility profiles reveal clear distinction among three segments along the protein sequence. The N-terminal (1-60 and C-terminal (96-140 regions contain the least mobile residues, which are separated by the higher mobility non-amyloid component (NAC (61-95. Our analysis of the intra-protein contact profile shows a higher frequency of residue aggregation (clumping in the N-terminal region relative to that in the C-terminal region, with little or no aggregation in the NAC region. The radius of gyration (Rg of ASN decays monotonically with decreasing the temperature, consistent with the finding of Allison et al. (JACS, 2009. Our analysis of the structure function provides an insight into the mass (N distribution of ASN, and the dimensionality (D of the structure as a function of temperature. We find that the globular structure with D ≈ 3 at low T, a random coil, D ≈ 2 at high T and in between (2 ≤ D ≤ 3 at the intermediate temperatures. The magnitudes of D are in agreement with experimental estimates (J. Biological Chem 2002.

  17. Late-stage alpha-synuclein accumulation in TNWT-61 mouse model of Parkinson's disease detected by diffusion kurtosis imaging

    Czech Academy of Sciences Publication Activity Database

    Khairnar, A.; Rudá-Kučerová, J.; Dražanová, Eva; Szabó, N.; Latta, P.; Arab, A.; Hutter-Paier, B.; Havas, D.; Windisch, M.; Šulcová, A.; Starčuk jr., Zenon; Király, A.; Rektorová, I.

    2016-01-01

    Roč. 136, č. 6 (2016), s. 1259-1269 ISSN 0022-3042 R&D Projects: GA MŠk(CZ) LO1212; GA MŠk ED0017/01/01 Institutional support: RVO:68081731 Keywords : diffusion kurtosis imaging * diffusion kurtosis imaging * Parkinson's disease * TBSS * TNWT-61 * transgenic mice Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 4.083, year: 2016

  18. Application of MALDI-TOF mass spectrometry for study on fibrillar and oligomeric aggregates of alpha-synuclein

    NARCIS (Netherlands)

    Severinovskaya, O. V.; Kovalska, V B; Losytskyy, M Yu; Cherepanov, V. V.; Subramaniam, V.; Yarmoluk, S M

    2014-01-01

    Aim. To study the α-synuclein (ASN) aggregates of different structural origin, namely amyloid fibrils and spherical oligomers, in comparison with a native protein. Methods. MALDI TOF mass spectrometry and atomic force microscopy (AFM). Results. The mass spectra of native and fibrillar ASN have

  19. 5-HT2A Receptor Binding in the Frontal Cortex of Parkinson's Disease Patients and Alpha-Synuclein Overexpressing Mice

    DEFF Research Database (Denmark)

    Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Brudek, Tomasz

    2016-01-01

    The receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD) is primarily a motor disorder, reports of impaired executive...

  20. Non-uniform self-assembly: On the anisotropic architecture of alpha-synuclein supra-fibrillar aggregates

    Czech Academy of Sciences Publication Activity Database

    Semerdzhiev, S. A.; Shvadchak, Volodymyr V.; Subramaniam, V.; Claessens, M. M. A. E.

    2017-01-01

    Roč. 7, Aug 9 (2017), č. článku 7699. ISSN 2045-2322 Institutional support: RVO:61388963 Keywords : liquid crystal spherulites * Parkinson's disease * Alzheimer's disease Subject RIV: BO - Biophysics OBOR OECD: Biophysics Impact factor: 4.259, year: 2016 https://www.nature.com/articles/s41598-017-06532-1

  1. Pressure effects on .alpha.-synuclein amyloid fibrils: an experimental investigation on their dissociation and reversible nature

    Czech Academy of Sciences Publication Activity Database

    Piccirilli, F.; Plotegher, N.; Spinozzi, F.; Bubacco, L.; Mariani, P.; Beltramini, M.; Tessari, I.; Militello, V.; Perucchi, A.; Amenitsch, H.; Baldassarri Jr., E.; Steinhart, Miloš; Lupi, S.; Ortore, M. G.

    2017-01-01

    Roč. 627, 1 August (2017), s. 46-55 ISSN 0003-9861 Institutional support: RVO:61389013 Keywords : amyloid * high-pressure * SAXS Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 3.165, year: 2016

  2. Structural Variation of Alpha-synuclein with Temperature by a Coarse-grained Approach with Knowledge-based Interactions (Postprint)

    Science.gov (United States)

    2015-07-01

    Alzheimer disease. ASN1,3 has been extensively studied as an intrinsically disordered (unstructured) protein with a monomeric conformation compa- rable to a...changes in these physical quantities occur by avoiding the low and high temperature extremes. Typical snapshots from the simulations as a function of...mobile as the residue-residue interactions become less impor- tant and the protein assumes a self- avoiding walk (SAW) or random coil conformation (vida

  3. Zinc triggers microglial activation.

    Science.gov (United States)

    Kauppinen, Tiina M; Higashi, Youichirou; Suh, Sang Won; Escartin, Carole; Nagasawa, Kazuki; Swanson, Raymond A

    2008-05-28

    Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, "ameboid" morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-kappaB (NF-kappaB) reporter gene showed a severalfold increase in NF-kappaB activity in response to 30 microm zinc. Cultured mouse microglia exposed to 15-30 microm zinc increased nitric oxide production, increased F4/80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-kappaB activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia-reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-kappaB. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.

  4. 6′-Hydroxy Justicidin B Triggers a Critical Imbalance in Ca2+ Homeostasis and Mitochondrion-Dependent Cell Death in Human Leukemia K562 Cells

    Directory of Open Access Journals (Sweden)

    Jiaoyang Luo

    2018-06-01

    Full Text Available Justicia procumbens (J. procumbens is a traditional Chinese herbal medicine which was used for the treatment of fever, pain, and cancer. A compound 6′-hydroxy justicidin B (HJB isolated from J. procumbens exhibits promising biological properties. However, the mechanism of action and the in vivo behavior of HJB remain to be elucidated. In this study, we investigated the mechanism of action of HJB on human leukemia K562 cells and its pharmacokinetic properties in rats. The results demonstrated that HJB significantly inhibited the proliferation of K562 cells and promoted apoptosis. Besides, HJB resulted in decreased mitochondrial membrane potential deltaPSIm, increased the level of the calcium homeostasis regulator protein TRPC6 and cytosolic calcium. The activity of caspase-8, caspase-9 and the expression of p53 were significantly increased after treatment with HJB. Additionally, HJB has rapid absorption rate and relative long elimination t1/2, indicating a longer residence time in vivo. The results indicate that HJB inhibited the proliferation of K562 cells and induced apoptosis by affecting the function of mitochondria and calcium homeostasis to activate the p53 signaling pathway. The pharmacokinetic study of HJB suggested it is absorbed well and has moderate metabolism in vivo. These results present HJB as a potential novel alternative to standard human leukemia therapies.

  5. Antigen Presenting Cells and Stromal Cells Trigger Human Natural Killer Lymphocytes to Autoreactivity: Evidence for the Involvement of Natural Cytotoxicity Receptors (NCR and NKG2D

    Directory of Open Access Journals (Sweden)

    Alessandro Poggi

    2006-01-01

    Full Text Available Human natural killer (NK lymphocytes should not damage autologous cells due to the engagement of inhibitory receptor superfamily (IRS members by HLA-I. Nevertheless, NK cells kill self cells expressing low levels or lacking HLA-I, as it may occur during viral infections (missing-self hypothesis. Herein, we show that human NK cells can be activated upon binding with self antigen presenting cells or stromal cells despite the expression of HLA-I. Indeed, NK cells can kill and produce pro-inflammatory and regulating cytokines as IFN-γ, TNF-α and IL10 during interaction with autologous dendritic cells or bone marrow stromal cells or skin fibroblasts. The killing of antigen presenting and stromal cells is dependent on LFA1/ICAM1 interaction. Further, the natural cytotoxicity receptors (NCR NKp30 and NKp46 are responsible for the delivery of lethal hit to DC, whereas NKG2D activating receptor, the ligand of the MHC-related molecule MIC-A and the UL16 binding protein, is involved in stromal cell killing. These findings indicate that different activating receptors are involved in cell to self cell interaction. Finally, NK cells can revert the veto effect of stromal cells on mixed lymphocyte reaction further supporting the idea that NK cells may alter the interaction between T lymphocytes and microenvironment leading to autoreactivity.

  6. Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE and 13-Hydroxyoctadecadienoic Acid (13-HODE in Human Cytotrophoblasts and Placental Cultures.

    Directory of Open Access Journals (Sweden)

    Kaoutar Leghmar

    Full Text Available Congenital infection by human cytomegalovirus (HCMV is a leading cause of congenital abnormalities of the central nervous system. Placenta infection by HCMV allows for viral spread to fetus and may result in intrauterine growth restriction, preeclampsia-like symptoms, or miscarriages. We previously reported that HCMV activates peroxisome proliferator-activated receptor gamma (PPARγ for its own replication in cytotrophoblasts. Here, we investigated the molecular bases of PPARγ activation in infected cytotrophoblasts.We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARγ activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARγ agonists are generated by PLA2 driven oxidization of linoleic and arachidonic acids. Therefore, using HPLC coupled with mass spectrometry, we disclosed that cellular and secreted levels of 13-hydroxyoctadecadienoic acid (13-HODE and 15-hydroxyeicosatetraenoic acid (15-HETE were significantly increased in and from HIPEC cytotrophoblasts at soon as 6 hours post infection. 13-HODE treatment of uninfected HIPEC recapitulated the effect of infection (PPARγ activation, migration impairment. We found that infection of histocultures of normal, first-term, human placental explants resulted in significantly increased levels of secreted 15-HETE and 13-HODE.Our findings reveal that 15-HETE and 13-HODE could be new pathogenic effectors of HCMV congenital infection They provide a new insight about the pathogenesis of congenital infection by HCMV.

  7. Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease.

    Science.gov (United States)

    Nixon, Briana; Fakioglu, Esra; Stefanidou, Martha; Wang, Yanhua; Dutta, Monica; Goldstein, Harris; Herold, Betsy C

    2014-02-15

    Epidemiological studies consistently demonstrate synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1). Higher HIV-1 loads are observed in coinfected individuals, and conversely, HIV-1 is associated with more-severe herpetic disease. A small animal model of coinfection would facilitate identification of the biological mechanisms underlying this synergy and provide the opportunity to evaluate interventions. Mice transgenic for HIV-1 provirus and human cyclin T1 under the control of a CD4 promoter (JR-CSF/hu-cycT1) were intravaginally infected with HSV-2 and evaluated for disease progression, HIV shedding, and mucosal immune responses. HSV-2 infection resulted in higher vaginal HIV loads and genital tissue expression of HIV RNA, compared with HSV-uninfected JR-CSF/hu-cycT1 mice. There was an increase in genital tract inflammatory cells, cytokines, chemokines, and interferons in response to HSV-2, although the kinetics of the response were delayed in HIV-transgenic, compared with control mice. Moreover, the JR-CSF/hu-cycT1 mice exhibited earlier and more-severe neurological disease. The latter was associated with downregulation of secretory leukocyte protease inhibitor expression in neuronal tissue, a molecule with antiinflammatory, antiviral, and neuroprotective properties. JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease.

  8. ATLAS Tau Trigger

    CERN Document Server

    Belanger-Champagne, C; Bosman, M; Brenner, R; Casado, MP; Czyczula, Z; Dam, M; Demers, S; Farrington, S; Igonkina, O; Kalinowski, A; Kanaya, N; Osuna, C; Pérez, E; Ptacek, E; Reinsch, A; Saavedra, A; Sopczak, A; Strom, D; Torrence, E; Tsuno, S; Vorwerk, V; Watson, A; Xella, S

    2008-01-01

    Moving to the high energy scale of the LHC, the identification of tau leptons will become a necessary and very powerful tool, allowing a discovery of physics beyond Standard Model. Many models, among them light SM Higgs and various SUSY models, predict an abundant production of taus with respect to other leptons. The reconstruction of hadronic tau decays, although a very challenging task in hadronic enviroments, allows to increase a signal efficiency by at least of factor 2, and provides an independent control sample to disantangle lepton tau decays from prompt electrons and muons. Thanks to the advanced calorimetry and tracking, the ATLAS experiment has developed tools to efficiently identify hadronic taus at the trigger level. In this presentation we will review the characteristics of taus and the methods to suppress low-multiplicity, low-energy jets contributions as well as we will address the tau trigger chain which provide a rejection rate of 10^5. We will further present plans for commissioning the ATLA...

  9. The D0 calorimeter trigger

    International Nuclear Information System (INIS)

    Guida, J.

    1992-12-01

    The D0 calorimeter trigger system consists of many levels to make physics motivated trigger decisions. The Level-1 trigger uses hardware techniques to reduce the trigger rate from ∼ 100kHz to 200Hz. It forms sums of electromagnetic and hadronic energy, globally and in towers, along with finding the missing transverse energy. A minimum energy is set on these energy sums to pass the event. The Level-2 trigger is a set of software filters, operating in a parallel-processing microvax farm which further reduces the trigger rate to a few Hertz. These filters will reject events which lack electron candidates, jet candidates, or missing transverse energy in the event. The performance of these triggers during the early running of the D0 detector will also be discussed

  10. Surgery for trigger finger.

    Science.gov (United States)

    Fiorini, Haroldo Junior; Tamaoki, Marcel Jun; Lenza, Mário; Gomes Dos Santos, Joao Baptista; Faloppa, Flávio; Belloti, Joao Carlos

    2018-02-20

    Trigger finger is a common clinical disorder, characterised by pain and catching as the patient flexes and extends digits because of disproportion between the diameter of flexor tendons and the A1 pulley. The treatment approach may include non-surgical or surgical treatments. Currently there is no consensus about the best surgical treatment approach (open, percutaneous or endoscopic approaches). To evaluate the effectiveness and safety of different methods of surgical treatment for trigger finger (open, percutaneous or endoscopic approaches) in adults at any stage of the disease. We searched CENTRAL, MEDLINE, Embase and LILACS up to August 2017. We included randomised or quasi-randomised controlled trials that assessed adults with trigger finger and compared any type of surgical treatment with each other or with any other non-surgical intervention. The major outcomes were the resolution of trigger finger, pain, hand function, participant-reported treatment success or satisfaction, recurrence of triggering, adverse events and neurovascular injury. Two review authors independently selected the trial reports, extracted the data and assessed the risk of bias. Measures of treatment effect for dichotomous outcomes calculated risk ratios (RRs), and mean differences (MDs) or standardised mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CIs). When possible, the data were pooled into meta-analysis using the random-effects model. GRADE was used to assess the quality of evidence for each outcome. Fourteen trials were included, totalling 1260 participants, with 1361 trigger fingers. The age of participants included in the studies ranged from 16 to 88 years; and the majority of participants were women (approximately 70%). The average duration of symptoms ranged from three to 15 months, and the follow-up after the procedure ranged from eight weeks to 23 months.The studies reported nine types of comparisons: open surgery versus steroid injections (two

  11. Long Non-Coding RNA MEG3 Downregulation Triggers Human Pulmonary Artery Smooth Muscle Cell Proliferation and Migration via the p53 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Zengxian Sun

    2017-08-01

    Full Text Available Background/Aims: Increasing evidence has demonstrated a significant role of long non-coding RNAs (lncRNAs in diverse biological processes, and many of which are likely to have functional roles in vascular remodeling. However, their functions in pulmonary arterial hypertension (PAH remain largely unknown. Pulmonary vascular remodeling is an important pathological feature of PAH, leading to increased vascular resistance and reduced compliance. Pulmonary artery smooth muscle cells (PASMCs dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of PASMCs function. Herein, we determined whether long noncoding RNA–maternally expressed gene 3 (MEG3 was involved in PAH-related vascular remodeling. Methods: The arterial wall thickness was examined by hematoxylin and eosin (H&E staining in distal pulmonary arteries (PAs isolated from lungs of healthy volunteers and PAH patients. The expression level of MEG3 was analyzed by qPCR. The effects of MEG3 on human PASMCs were assessed by cell counting Kit-8 assay, BrdU incorporation assay, flow cytometry, scratch-wound assay, immunofluorescence, and western blotting in human PASMCs. Results: We revealed that the expression of MEG3 was significantly downregulated in lung and PAs of patients with PAH. MEG3 knockdown affected PASMCs proliferation and migration in vitro. Moreover, inhibition of MEG3 regulated the cell cycle progression and made more smooth muscle cells from the G0/G1 phase to the G2/M+S phase and the process could stimulate the expression of PCNA, Cyclin A and Cyclin E. In addition, we found that the p53 pathway was involved in MEG3–induced smooth muscle cell proliferation. Conclusions: This study identified MEG3 as a critical regulator in PAH and demonstrated the potential of gene therapy and drug development for treating PAH.

  12. Luffa echinata Roxb. Induces Human Colon Cancer Cell (HT-29 Death by Triggering the Mitochondrial Apoptosis Pathway

    Directory of Open Access Journals (Sweden)

    Yan Yu

    2012-05-01

    Full Text Available The antiproliferative properties and cell death mechanism induced by the extract of the fruits of Luffa echinata Roxb. (LER were investigated. The methanolic extract of LER inhibited the proliferation of human colon cancer cells (HT-29 in both dose-dependent and time-dependent manners and caused a significant increase in the population of apoptotic cells. In addition, obvious shrinkage and destruction of the monolayer were observed in LER-treated cells, but not in untreated cells. Analysis of the cell cycle after treatment of HT-29 cells with various concentrations indicated that LER extracts inhibited the cellular proliferation of HT-29 cells via G2/M phase arrest of the cell cycle. The Reactive oxygen species (ROS level determination revealed that LER extracts induced apoptotic cell death via ROS generation. In addition, LER treatment led to a rapid drop in mitochondrial membrane potential (MMP as a decrease in fluorescence. The transcripts of several apoptosis-related genes were investigated by RT-PCR analysis. The caspase-3 transcripts of HT-29 cells significantly accumulated and the level of Bcl-XL mRNA was decreased after treatment with LER extract. Furthermore, the ratio of mitochondria-dependent apoptosis genes (Bax and Bcl-2 was sharply increased from 1.6 to 54.1. These experiments suggest that LER has anticancer properties via inducing the apoptosis in colon cancer cells, which provided the impetus for further studies on the therapeutic potential of LER against human colon carcinoma.

  13. The modulation of the motor resonance triggered by reach-to-grasp movements: No role of human physical similarity as conveyed by age.

    Science.gov (United States)

    Marino, Barbara F M; Ricciardelli, Paola

    2017-07-01

    The activation of the mirror-neuron circuit during the observation of motor acts is thought to be the basis of human capacity to read the intentions behind the behavior of others. Growing empirical evidence shows a different activation of the mirror-neuron resonance mechanism depending on how much the observer and the observed agent share their motor repertoires. Here, the possible modulatory effect of physical similarity between the observer and the agent was investigated in three studies. We used a visuo-motor priming task in which participants were asked to categorize manipulable and non-manipulable objects into natural or man-made kinds after having watched precision and power reach-to-grasp movements. Physical similarity was manipulated by presenting reach-to-grasp movements performed by the hands of actors of three different age ranges that are adults of the same age as the participants, children, and elderly. Faster responses were observed in trials where power grip movements were performed by the adults and precision grip movements were performed by the elderly (Main Study). This finding is not in keeping with the idea that physical similarity shapes the mirror-neuron resonance. Instead, it suggests an effect of the kinematic organization of the reach-to-grasp movements, which systematically changed with the actor age as revealed by a kinematic analysis. The differential effect played by adult and elderly actor primes was lost when static grasping hands (Control Study 1) and reach-to-grasp movements with uniform kinematic profiles (Control Study 2) were used. Therefore, we found preliminary evidence that mirror-neuron resonance is not shaped by physical similarity but by the kinematics of the observed action. This finding is novel as it suggests that human ability to read the intentions behind the behavior of others may benefit from a mere visual processing of spatiotemporal patterns.

  14. Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses.

    Science.gov (United States)

    Gronert, K; Martinsson-Niskanen, T; Ravasi, S; Chiang, N; Serhan, C N

    2001-01-01

    Aspirin-triggered lipoxin A(4) (ATL, 15-epi-LXA(4)) and leukotriene D(4) (LTD(4)) possess opposing vascular actions mediated via receptors distinct from the LXA(4) receptor (ALX) that is involved in leukocyte trafficking. Here, we identified these receptors by nucleotide sequencing and demonstrate that LTD(4) receptor (CysLT(1)) is induced in human vascular endothelia by interleukin-1beta. Recombinant CysLT(1) receptor gave stereospecific binding with both [(3)H]-LTD(4) and a novel labeled mimetic of ATL ([(3)H]-ATLa) that was displaced with LTD(4) and ATLa ( approximately IC(50) 0.2 to 0.9 nmol/L), but not with a bioinactive ATL isomer. The clinically used CysLT(1) receptor antagonist, Singulair, showed a lower rank order for competition with [(3)H]-ATLa (IC(50) approximately 8.3 nmol/L). In contrast, LTD(4) was an ineffective competitive ligand for recombinant ALX receptor with [(3)H]-ATLa, and ATLa did not compete for [(3)H]-LTB(4) binding with recombinant LTB(4) receptor. Endogenous murine CysLT(1) receptors also gave specific [(3)H]-ATLa binding that was displaced with essentially equal affinity by LTD(4) or ATLa. Systemic ATLa proved to be a potent inhibitor (>50%) of CysLT(1)-mediated vascular leakage in murine skin (200 microg/kg) in addition to its ability to block polymorphonuclear leukocyte recruitment to dorsal air pouch (4 microg/kg). These results indicate that ATL and LTD(4) bind and compete with equal affinity at CysLT(1), providing a molecular basis for aspirin-triggered LXs serving as a local damper of both vascular CysLT(1) signals as well as ALX receptor-regulated polymorphonuclear leukocyte traffic.

  15. Phorbol 12,13-dibutyrate-induced protein kinase C activation triggers sustained contracture in human myometrium in vitro.

    Science.gov (United States)

    Massenavette, Laurence; Paul, Wilène; Corriveau, Stéphanie; Pasquier, Jean-Charles; Rousseau, Éric

    2017-09-01

    Although physiologic transition from rhythmic contractions to uterine retraction postpartum remains a poorly understood process, it has been shown that the latter is essential in the prevention of hemorrhage and its negative consequences. To investigate the transition from oscillatory contractions to tonic contracture in human myometrium after delivery, a mechanism purported to facilitate postpartum hemostasis. Protein kinase C (PKC) plays a key regulatory role in human uterine contractions because it can prevent dephosphorylation of regulatory proteins and sensitize the contractile machinery to low Ca 2+ . Thus, activation of PKC by phorbol 12,13-dibutyrate (PDBu) may act as a strong uterotonic agent. Uterine biopsies were obtained from consenting women undergoing elective caesarian delivery at term without labor (N = 19). Isometric tension measurements were performed on uterine strips (n = 114). The amplitudes and area under the curve of phasic contractions and tonic responses were measured and compared. A total of 1 μM PDBu was added to the isolated organ baths, and maximal tension of the uterine contracture was determined in the absence and presence of either 1 μM of staurosporine, 100 nM nifedipine, or 10 μM cyclopiazonic acid to assess the role of PKC and calcium sensitivity on uterine contractility. On the addition of PDBu on either basal or oxytocin-induced activity, consistent contractures were obtained concomitant with complete inhibition of phasic contractions. After a 30-minute incubation period, the mean amplitude of the PDBu-induced tone represented 65.3% of the amplitude of spontaneous contraction. Staurosporine, a protein kinase inhibitor, induced a 91.9% inhibition of PDBu contractures, a process not affected by nifedipine or cyclopiazonic acid, thus indicating that this mechanism is largely Ca 2+ independent. Pharmacologic activation of PKC leads to a significant contracture of the myometrium. Together, these data suggest that the up

  16. Serum Amyloid A Production Is Triggered by Sleep Deprivation in Mice and Humans: Is That the Link between Sleep Loss and Associated Comorbidities?

    Science.gov (United States)

    de Oliveira, Edson M.; Visniauskas, Bruna; Tufik, Sergio; Andersen, Monica L.; Chagas, Jair R.; Campa, Ana

    2017-01-01

    Serum amyloid A (SAA) was recently associated with metabolic endotoxemia, obesity and insulin resistance. Concurrently, insufficient sleep adversely affects metabolic health and is an independent predisposing factor for obesity and insulin resistance. In this study we investigated whether sleep loss modulates SAA production. The serum SAA concentration increased in C57BL/6 mice subjected to sleep restriction (SR) for 15 days or to paradoxical sleep deprivation (PSD) for 72 h. Sleep restriction also induced the upregulation of Saa1.1/Saa2.1 mRNA levels in the liver and Saa3 mRNA levels in adipose tissue. SAA levels returned to the basal range after 24 h in paradoxical sleep rebound (PSR). Metabolic endotoxemia was also a finding in SR. Increased plasma levels of SAA were also observed in healthy human volunteers subjected to two nights of total sleep deprivation (Total SD), returning to basal levels after one night of recovery. The observed increase in SAA levels may be part of the initial biochemical alterations caused by sleep deprivation, with potential to drive deleterious conditions such as metabolic endotoxemia and weight gain. PMID:28335560

  17. Triggering at high luminosity: fake triggers from pile-up

    International Nuclear Information System (INIS)

    Johnson, R.

    1983-01-01

    Triggers based on a cut in transverse momentum (p/sub t/) have proved to be useful in high energy physics both because they indicte that a hard constituent scattering has occurred and because they can be made quickly enough to gate electronics. These triggers will continue to be useful at high luminosities if overlapping events do not cause an excessive number of fake triggers. In this paper, I determine if this is indeed a problem at high luminosity machines

  18. Nostalgia: content, triggers, functions.

    Science.gov (United States)

    Wildschut, Tim; Sedikides, Constantine; Arndt, Jamie; Routledge, Clay

    2006-11-01

    Seven methodologically diverse studies addressed 3 fundamental questions about nostalgia. Studies 1 and 2 examined the content of nostalgic experiences. Descriptions of nostalgic experiences typically featured the self as a protagonist in interactions with close others (e.g., friends) or in momentous events (e.g., weddings). Also, the descriptions contained more expressions of positive than negative affect and often depicted the redemption of negative life scenes by subsequent triumphs. Studies 3 and 4 examined triggers of nostalgia and revealed that nostalgia occurs in response to negative mood and the discrete affective state of loneliness. Studies 5, 6, and 7 investigated the functional utility of nostalgia and established that nostalgia bolsters social bonds, increases positive self-regard, and generates positive affect. These findings demarcate key landmarks in the hitherto uncharted research domain of nostalgia.

  19. Interleukin 2 (IL 2) up-regulates its own receptor on a subset of human unprimed peripheral blood lymphocytes and triggers their proliferation

    International Nuclear Information System (INIS)

    Harel-Bellan, A.; Bertoglio, J.; Quillet, A.; Marchiol, C.; Wakasugi, H.; Mishall, Z.; Fradelizi, D.

    1986-01-01

    Several reports indicate that human peripheral blood lymphoctyes (PBL) seeded in culture with purified or recombinant interleukin 2 (IL 2) immediately after separation from the blood display a substantial level of proliferation at day 5 or 6, even in the absence of any activating signal. The spontaneously IL 2 proliferating cells are large lymphocytes, and they co-purify on a Percoll gradient in the large granular lymphocytes (third (LGL) fraction) together with the natural killer (NK) activity. When LGL were separated into NKH1 (an NK-specific surface marker)-positive and NKH1-negative cells by fluorescence-activated cell sorting (FACS), proliferating cells were mainly found in the NKH1-negative fraction. On the contrary, when cells from Percoll fraction 3 were separated into OKT3-negative and positive cells, the majority of the proliferating cells was found in the OKT3-positive cells. These results indicate that spontaneously IL 2 proliferating (SIP) cells most probably belong to the T cell lineage, but are distinct from NK cells. Additional analysis of Il 2 receptor induced in culture with IL 2 was performed by [ 125 I]anti-TAC binding and by [ 3 H]Il 2 binding. Scatchard analysis of [ 3 H]IL 2 binding, in the range of concentrations leading to the detection of high-affinity binding sites, showed an affinity constant similar to that of conventional phytohemagglutinin blasts. The results indicate that SIP cells are preactivated cells circulating in the blood. They are large cells and represent a very small proportion of circulating lymphocytes (0.3%). They express a subliminar amount of IL 2 receptor. Cultivated in the presence of IL 2, IL 2 receptor expression is enhanced to a detectable level, and the SIP cells begin to proliferate. These SIP cells could be activated T cells in the course of a current immune response or memory T cells present in every normal individual

  20. Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells

    International Nuclear Information System (INIS)

    Chaudhari, Manjari; Jayaraj, R.; Bhaskar, A.S.B.; Lakshmana Rao, P.V.

    2009-01-01

    T-2 toxin is the most toxic trichothecene and both humans and animals suffer from several pathological conditions after consumption of foodstuffs contaminated with trichothecenes. We investigated the molecular mechanism of T-2 toxin induced cytotoxicity and cell death in HeLa cells. T-2 toxin at LC50 of 10 ng/ml caused time dependent increase in cytotoxicity as assessed by dye uptake, lactatedehydrogenase leakage and MTT assay. The toxin caused generation of reactive oxygen species as early as 30 min followed by significant depletion of glutathione levels and increased lipid peroxidation. The results indicate oxidative stress as underlying mechanism of cytotoxicity. Single stranded DNA damage after T-2 treatment was observed as early as 2 and 4 h by DNA diffusion assay. The cells exhibited apoptotic morphology like condensed chromatin and nuclear fragmentation after 4 h of treatment. Downstream of T-2 induced oxidative stress and DNA damage a time dependent increase in expression level of p53 protein was observed. The increase in Bax/Bcl2 ratio indicated shift in response, in favour of apoptotic process in T-2 toxin treated cells. Western blot analysis showed increase in levels of mitochondrial apoptogenic factors Bax, Bcl-2, cytochrome-c followed by activation of caspases-9, -3 and -7 leading to DNA fragmentation and apoptosis. In addition to caspase-dependent pathway, our results showed involvement of caspase-independent AIF pathway in T-2 induced apoptosis. Broad spectrum caspase inhibitor z-VAD-fmk could partially protect the cells from DNA damage but could not inhibit AIF induced oligonucleosomal DNA fragmentation beyond 4 h. Results of the study clearly show that oxidative stress is the underlying mechanism by which T-2 toxin causes DNA damage and apoptosis.

  1. Dyslipidemic Diet-Induced Monocyte “Priming” and Dysfunction in Non-Human Primates Is Triggered by Elevated Plasma Cholesterol and Accompanied by Altered Histone Acetylation

    Directory of Open Access Journals (Sweden)

    John D. Short

    2017-08-01

    Full Text Available Monocytes and the recruitment of monocyte-derived macrophages into sites of inflammation play a key role in atherogenesis and other chronic inflammatory diseases linked to cardiometabolic syndrome and obesity. Previous studies from our group have shown that metabolic stress promotes monocyte priming, i.e., enhanced adhesion and accelerated chemotaxis of monocytes in response to chemokines, both in vitro and in dyslipidemic LDLR−/− mice. We also showed that metabolic stress-induced monocyte dysfunction is, at least to a large extent caused by the S-glutathionylation, inactivation, and subsequent degradation of mitogen-activated protein kinase phosphatase 1. Here, we analyzed the effects of a Western-style, dyslipidemic diet (DD, which was composed of high levels of saturated fat, cholesterol, and simple sugars, on monocyte (dysfunction in non-human primates (NHPs. We found that similar to mice, a DD enhances monocyte chemotaxis in NHP within 4 weeks, occurring concordantly with the onset of hypercholesterolemia but prior to changes in triglycerides, blood glucose, monocytosis, or changes in monocyte subset composition. In addition, we identified transitory decreases in the acetylation of histone H3 at the lysine residues 18 and 23 in metabolically primed monocytes, and we found that monocyte priming was correlated with the acetylation of histone H3 at lysine 27 after an 8-week DD regimen. Our data show that metabolic stress promotes monocyte priming and hyper-chemotactic responses in NHP. The histone modifications accompanying monocyte priming in primates suggest a reprogramming of the epigenetic landscape, which may lead to dysregulated responses and functionalities in macrophages derived from primed monocytes that are recruited to sites of inflammation.

  2. The investigation of minoxidil-induced [Ca2+]i rises and non-Ca2+-triggered cell death in PC3 human prostate cancer cells.

    Science.gov (United States)

    Chen, I-Shu; Chou, Chiang-Ting; Liu, Yuan-Yuarn; Yu, Chia-Cheng; Liang, Wei-Zhe; Kuo, Chun-Chi; Shieh, Pochuen; Kuo, Daih-Huang; Chen, Fu-An; Jan, Chung-Ren

    2017-02-01

    Minoxidil is clinically used to prevent hair loss. However, its effect on Ca 2+ homeostasis in prostate cancer cells is unclear. This study explored the effect of minoxidil on cytosolic-free Ca 2+ levels ([Ca 2+ ] i ) and cell viability in PC3 human prostate cancer cells. Minoxidil at concentrations between 200 and 800 μM evoked [Ca 2+ ] i rises in a concentration-dependent manner. This Ca 2+ signal was inhibited by 60% by removal of extracellular Ca 2+ . Minoxidil-induced Ca 2+ influx was confirmed by Mn 2+ -induced quench of fura-2 fluorescence. Pre-treatment with the protein kinase C (PKC) inhibitor GF109203X, PKC activator phorbol 12-myristate 13 acetate (PMA), nifedipine and SKF96365 inhibited minoxidil-induced Ca 2+ signal in Ca 2+ containing medium by 60%. Treatment with the endoplasmic reticulum Ca 2+ pump inhibitor 2,5-ditert-butylhydroquinone (BHQ) in Ca 2+ -free medium abolished minoxidil-induced [Ca 2+ ] i rises. Conversely, treatment with minoxidil abolished BHQ-induced [Ca 2+ ] i rises. Inhibition of phospholipase C (PLC) with U73122 abolished minoxidil-evoked [Ca 2+ ] i rises. Overnight treatment with minoxidil killed cells at concentrations of 200-600 μM in a concentration-dependent fashion. Chelation of cytosolic Ca 2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not prevent minoxidil's cytotoxicity. Together, in PC3 cells, minoxidil induced [Ca 2+ ] i rises that involved Ca 2+ entry through PKC-regulated store-operated Ca 2+ channels and PLC-dependent Ca 2+ release from the endoplasmic reticulum. Minoxidil-induced cytotoxicity in a Ca 2+ -independent manner.

  3. Synthesis of interleukin 6 (interferon-β2/B cell stimulatory factor 2) in human fibroblasts is triggered by an increase in intracellular cyclic AMP

    International Nuclear Information System (INIS)

    Zhange, Y.; Lin, J.X.; Vilcek, J.

    1988-01-01

    Interleukin 6 (IL-6; also referred to as interferon-β 2 , 26-kDa protein, and B cell stimulatory factor 2) is a cytokine whose actions include a stimulation of immunoglobulin synthesis, enhancement of B cell growth, and modulation of acute phase protein synthesis by hepatocytes. Synthesis of IL-6 is stimulated by interleukin 1 (IL-1), tumor necrosis factor (TNF), or platelet-derived growth factor. The authors examined the role of the cyclic AMP (cAMP)-dependent signal transduction pathway in IL-6 gene expression. Several activators of adenylate cyclase, including prostaglandin E1, forskolin, and cholera toxin, as well as the phosphodiesterase inhibitor isobutylmethylxanthine and the cAMP analog dibutyryl cAMP, shared the ability to cause a dramatic and sustained increase in IL-6 mRNA levels in human FS-4 fibroblasts. Actinomycin D treatment abolished this enhancement. Treatments that increased intracellular cAMP also stimulated the secretion of the IL-6 protein in a biologically active form. Increased intracellular cAMP appears to enhance IL-6 gene expression by a protein kinase C-independent mechanism because down-regulation of protein kinase C by a chronic exposure of cells to a high dose of 12-O-tetradecanoylphorbol 13-acetate did not abolish the enhancement of IL-6 expression by treatments that increase cAMP. IL-1 and TNF too increased IL-6 mRNA levels by a protein kinase C-independent mechanism. The results suggest a role for the cAMP-dependent pathway(s) in IL-6 gene activation by TNF and IL-1

  4. Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles.

    Science.gov (United States)

    Esteves, Sandro C; Khastgir, Gautam; Shah, Jatin; Murdia, Kshitiz; Gupta, Shweta Mittal; Rao, Durga G; Dash, Soumyaroop; Ingale, Kundan; Patil, Milind; Moideen, Kunji; Thakor, Priti; Dewda, Pavitra

    2018-01-01

    Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of

  5. Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles

    Directory of Open Access Journals (Sweden)

    Sandro C. Esteves

    2018-04-01

    Full Text Available Progesterone elevation (PE during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii Is PE on the day of human chorionic gonadotropin (hCG associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI cycles outcomes in all patient subgroups? (iii Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the

  6. Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles

    Science.gov (United States)

    Esteves, Sandro C.; Khastgir, Gautam; Shah, Jatin; Murdia, Kshitiz; Gupta, Shweta Mittal; Rao, Durga G.; Dash, Soumyaroop; Ingale, Kundan; Patil, Milind; Moideen, Kunji; Thakor, Priti; Dewda, Pavitra

    2018-01-01

    Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle-stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of

  7. The ATLAS hadronic tau trigger

    CERN Document Server

    Black, C; The ATLAS collaboration

    2012-01-01

    With the high luminosities of proton-proton collisions achieved at the LHC, the strategies for triggering have become more important than ever for physics analysis. The naive inclusive single tau lepton triggers now suffer from severe rate limitations. To allow for a large program of physics analyses with taus, the development of topological triggers that combine tau signatures with other measured quantities in the event is required. These combined triggers open many opportunities to study new physics beyond the Standard Model and to search for the Standard Model Higgs. We present the status and performance of the hadronic tau trigger in ATLAS. We demonstrate that the ATLAS tau trigger ran remarkably well over 2011, and how the lessons learned from 2011 led to numerous improvements in the preparation of the 2012 run. These improvements include the introduction of tau selection criteria that are robust against varying pileup scenarios, and the implementation of multivariate selection techniques in the tau trig...

  8. The ATLAS hadronic tau trigger

    CERN Document Server

    Black, C; The ATLAS collaboration

    2012-01-01

    With the high luminosities of proton-proton collisions achieved at the LHC, the strategies for triggering have become more important than ever for physics analysis. The naïve inclusive single tau lepton triggers now suffer from severe rate limitations. To allow for a large program of physics analyses with taus, the development of topological triggers that combine tau signatures with other measured quantities in the event is required. These combined triggers open many opportunities to study new physics beyond the Standard Model and to search for the Standard Model Higgs. We present the status and performance of the hadronic tau trigger in ATLAS. We demonstrate that the ATLAS tau trigger ran remarkably well over 2011, and how the lessons learned from 2011 led to numerous improvements in the preparation of the 2012 run. These improvements include the introduction of tau selection criteria that are robust against varying pileup scenarios, and the implementation of multivariate selection techniques in the tau tri...

  9. The ATLAS hadronic tau trigger

    International Nuclear Information System (INIS)

    Shamim, Mansoora

    2012-01-01

    The extensive tau physics programs of the ATLAS experiment relies heavily on trigger to select hadronic decays of tau lepton. Such a trigger is implemented in ATLAS to efficiently collect signal events, while keeping the rate of multi-jet background within the allowed bandwidth. This contribution summarizes the performance of the ATLAS hadronic tau trigger system during 2011 data taking period and improvements implemented for the 2012 data collection.

  10. Flexible trigger menu implementation on the Global Trigger for the CMS Level-1 trigger upgrade

    Science.gov (United States)

    MATSUSHITA, Takashi; CMS Collaboration

    2017-10-01

    The CMS experiment at the Large Hadron Collider (LHC) has continued to explore physics at the high-energy frontier in 2016. The integrated luminosity delivered by the LHC in 2016 was 41 fb-1 with a peak luminosity of 1.5 × 1034 cm-2s-1 and peak mean pile-up of about 50, all exceeding the initial estimations for 2016. The CMS experiment has upgraded its hardware-based Level-1 trigger system to maintain its performance for new physics searches and precision measurements at high luminosities. The Global Trigger is the final step of the CMS Level-1 trigger and implements a trigger menu, a set of selection requirements applied to the final list of objects from calorimeter and muon triggers, for reducing the 40 MHz collision rate to 100 kHz. The Global Trigger has been upgraded with state-of-the-art FPGA processors on Advanced Mezzanine Cards with optical links running at 10 GHz in a MicroTCA crate. The powerful processing resources of the upgraded system enable implementation of more algorithms at a time than previously possible, allowing CMS to be more flexible in how it handles the available trigger bandwidth. Algorithms for a trigger menu, including topological requirements on multi-objects, can be realised in the Global Trigger using the newly developed trigger menu specification grammar. Analysis-like trigger algorithms can be represented in an intuitive manner and the algorithms are translated to corresponding VHDL code blocks to build a firmware. The grammar can be extended in future as the needs arise. The experience of implementing trigger menus on the upgraded Global Trigger system will be presented.

  11. Trigger and data acquisition

    CERN Multimedia

    CERN. Geneva; Gaspar, C

    2001-01-01

    Past LEP experiments generate data at 0.5 MByte/s from particle detectors with over a quarter of a million readout channels. The process of reading out the electronic channels, treating them, and storing the date produced by each collision for further analysis by the physicists is called "Data Acquisition". Not all beam crossings produce interesting physics "events", picking the interesting ones is the task of the "Trigger" system. In order to make sure that the data is collected in good conditions the experiment's operation has to be constantly verified. In all, at LEP experiments over 100 000 parameters were monitored, controlled, and synchronized by the "Monotoring and control" system. In the future, LHC experiments will produce as much data in a single day as a LEP detector did in a full year's running with a raw data rate of 10 - 100 MBytes/s and will have to cope with some 800 million proton-proton collisions a second of these collisions only one in 100 million million is interesting for new particle se...

  12. The TOTEM modular trigger system

    Energy Technology Data Exchange (ETDEWEB)

    Bagliesi, M.G., E-mail: mg.bagliesi@pi.infn.i [University of Siena and INFN Pisa (Italy); Berretti, M.; Cecchi, R.; Greco, V.; Lami, S.; Latino, G.; Oliveri, E.; Pedreschi, E.; Scribano, A.; Spinella, F.; Turini, N. [University of Siena and INFN Pisa (Italy)

    2010-05-21

    The TOTEM experiment will measure the total cross-section with the luminosity independent method and study elastic and diffractive scattering at the LHC. We are developing a modular trigger system, based on programmable logic, that will select meaningful events within 2.5{mu}s. The trigger algorithm is based on a tree structure in order to obtain information compression. The trigger primitive is generated directly on the readout chip, VFAT, that has a specific fast output that gives low resolution hits information. In two of the TOTEM detectors, Roman Pots and T2, a coincidence chip will perform track recognition directly on the detector readout boards, while for T1 the hits are transferred from the VFATs to the trigger hardware. Starting from more than 2000 bits delivered by the detector electronics, we extract, in a first step, six trigger patterns of 32 LVDS signals each; we build, then, on a dedicated board, a 1-bit (L1) trigger signal for the TOTEM experiment and 16 trigger bits to the CMS experiment global trigger system for future common data taking.

  13. The TOTEM modular trigger system

    International Nuclear Information System (INIS)

    Bagliesi, M.G.; Berretti, M.; Cecchi, R.; Greco, V.; Lami, S.; Latino, G.; Oliveri, E.; Pedreschi, E.; Scribano, A.; Spinella, F.; Turini, N.

    2010-01-01

    The TOTEM experiment will measure the total cross-section with the luminosity independent method and study elastic and diffractive scattering at the LHC. We are developing a modular trigger system, based on programmable logic, that will select meaningful events within 2.5μs. The trigger algorithm is based on a tree structure in order to obtain information compression. The trigger primitive is generated directly on the readout chip, VFAT, that has a specific fast output that gives low resolution hits information. In two of the TOTEM detectors, Roman Pots and T2, a coincidence chip will perform track recognition directly on the detector readout boards, while for T1 the hits are transferred from the VFATs to the trigger hardware. Starting from more than 2000 bits delivered by the detector electronics, we extract, in a first step, six trigger patterns of 32 LVDS signals each; we build, then, on a dedicated board, a 1-bit (L1) trigger signal for the TOTEM experiment and 16 trigger bits to the CMS experiment global trigger system for future common data taking.

  14. Upgrade trigger: Biannual performance update

    CERN Document Server

    Aaij, Roel; Couturier, Ben; Esen, Sevda; De Cian, Michel; De Vries, Jacco Andreas; Dziurda, Agnieszka; Fitzpatrick, Conor; Fontana, Marianna; Grillo, Lucia; Hasse, Christoph; Jones, Christopher Rob; Le Gac, Renaud; Matev, Rosen; Neufeld, Niko; Nikodem, Thomas; Polci, Francesco; Del Buono, Luigi; Quagliani, Renato; Schwemmer, Rainer; Seyfert, Paul; Stahl, Sascha; Szumlak, Tomasz; Vesterinen, Mika Anton; Wanczyk, Joanna; Williams, Mark Richard James; Yin, Hang; Zacharjasz, Emilia Anna

    2017-01-01

    This document presents the performance of the LHCb Upgrade trigger reconstruction sequence, incorporating changes to the underlying reconstruction algorithms and detector description since the Trigger and Online Upgrade TDR. An updated extrapolation is presented using the most recent example of an Event Filter Farm node.

  15. Minimum Bias Trigger in ATLAS

    International Nuclear Information System (INIS)

    Kwee, Regina

    2010-01-01

    Since the restart of the LHC in November 2009, ATLAS has collected inelastic pp collisions to perform first measurements on charged particle densities. These measurements will help to constrain various models describing phenomenologically soft parton interactions. Understanding the trigger efficiencies for different event types are therefore crucial to minimize any possible bias in the event selection. ATLAS uses two main minimum bias triggers, featuring complementary detector components and trigger levels. While a hardware based first trigger level situated in the forward regions with 2.2 < |η| < 3.8 has been proven to select pp-collisions very efficiently, the Inner Detector based minimum bias trigger uses a random seed on filled bunches and central tracking detectors for the event selection. Both triggers were essential for the analysis of kinematic spectra of charged particles. Their performance and trigger efficiency measurements as well as studies on possible bias sources will be presented. We also highlight the advantage of these triggers for particle correlation analyses. (author)

  16. DUMAND data acquisition with triggering

    International Nuclear Information System (INIS)

    Brenner, A.E.; Theriot, D.; March, R.H.

    1980-01-01

    A data acquisition scheme for the standard DUMAND array that includes a simple triggering scheme as a fundamental part of the system is presented. Although there are a number of not yet fully understood parameters, it is assumed that thresholds can be set in such a manner as to give rise to a triggered signal that is not so dominated by randoms that it gives a substantial decrease in the data acquisition rate over that which would be required by a nontriggered system. It is also assumed that the triggering logic is relatively simple and does not need major computational capabilities for a trigger logic decision. With these assumptions, it is possible to generate the trigger at the array and restrict the data transfer to shore. However, with a not unreasonable delay of 200 microseconds, it is even possible to transmit the information for the trigger to shore and perform all that logic on the shore. The critical point is to send the minimum amount of information necessary to construct the trigger such that one need not send all the possible information in all detectors of the array continuously to shore. 1 figure

  17. Triggered Release from Polymer Capsules

    Energy Technology Data Exchange (ETDEWEB)

    Esser-Kahn, Aaron P. [Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology and Dept. of Chemistry; Odom, Susan A. [Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology and Dept. of Chemistry; Sottos, Nancy R. [Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology and Dept. of Materials Science and Engineering; White, Scott R. [Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology and Dept. of Aerospace Engineering; Moore, Jeffrey S. [Univ. of Illinois, Urbana, IL (United States). Beckman Inst. for Advanced Science and Technology and Dept. of Chemistry

    2011-07-06

    Stimuli-responsive capsules are of interest in drug delivery, fragrance release, food preservation, and self-healing materials. Many methods are used to trigger the release of encapsulated contents. Here we highlight mechanisms for the controlled release of encapsulated cargo that utilize chemical reactions occurring in solid polymeric shell walls. Triggering mechanisms responsible for covalent bond cleavage that result in the release of capsule contents include chemical, biological, light, thermal, magnetic, and electrical stimuli. We present methods for encapsulation and release, triggering methods, and mechanisms and conclude with our opinions on interesting obstacles for chemically induced activation with relevance for controlled release.

  18. Levels of the epidermal growth factor-like peptide amphiregulin in follicular fluid reflect the mode of triggering ovulation: a comparison between gonadotrophin-releasing hormone agonist and urinary human chorionic gonadotrophin

    DEFF Research Database (Denmark)

    Al Humaidan, Peter Samir Heskjær; Westergaard, Lars Grabow; Mikkelsen, Anne Lis

    2011-01-01

    . INTERVENTION(S): Ovulation triggered with either urinary hCG or GnRH agonist (GnRH-a). Controls: 15 FF samples from small antral follicles (3-9 mm) and 12 FF samples from natural cycle. MAIN OUTCOME MEASURE(S): Follicular fluid concentration of AR, P(4), E(2), vascular endothelial growth factor, and inhibin B...... antral follicles only 5 out of 15 follicles contained measurable amounts of AR. When urinary hCG and GnRH-a triggering were compared, FF P(4) was significantly higher after urinary hCG triggering, whereas no difference was seen regarding E(2), vascular endothelial growth factor, and inhibin B. A total...... of 14% more metaphase II oocytes and 11% more transferable embryos were obtained after GnRH-a triggering. CONCLUSION(S): This study suggests that oocyte competence is linked to granulosa cell AR secretion....

  19. The CDF level-3 trigger

    International Nuclear Information System (INIS)

    Devlin, T.

    1993-01-01

    The Collider Detector at Fermilab (CDF) has been operating at the Tevatron and collecting data on proton-antiproton interactions with collision rates above 250,000 Hz. Three levels of filtering select events for data logging at a rate of about 4 Hz. The Level 3 trigger provides most of the capabilities of the offline production programs for event reconstruction and physics analysis. The type of physics triggers, application of cuts, and combinations of logical requirements for event selection are controlled at run time by a trigger table using a syntax fully integrated with the Level 1 and Level 2 hardware triggers. The level 3 software operates in 48 RISC/UNIX processors (over 1000 mips) served by four 20-MByte/sec data buses for input, output and control. The system architecture, debugging, code validation, error reporting, analysis capabilities and performance will be described

  20. Flexible trigger menu implementation on the Global Trigger for the CMS Level-1 trigger upgrade

    CERN Document Server

    Matsushita, Takashi

    2017-01-01

    The CMS experiment at the Large Hadron Collider (LHC) has continued to explore physics at the high-energy frontier in 2016. The integrated luminosity delivered by the LHC in 2016 was 41~fb$^{-1}$ with a peak luminosity of 1.5 $\\times$ 10$^{34}$ cm$^{-2}$s$^{-1}$ and peak mean pile-up of about 50, all exceeding the initial estimations for 2016. The CMS experiment has upgraded its hardware-based Level-1 trigger system to maintain its performance for new physics searches and precision measurements at high luminosities. The Global Trigger is the final step of the CMS \\mbox{Level-1} trigger and implements a trigger menu, a set of selection requirements applied to the final list of objects from calorimeter and muon triggers, for reducing the 40 MHz collision rate to 100 kHz. The Global Trigger has been upgraded with state-of-the-art FPGA processors on Advanced Mezzanine Cards with optical links running at 10 GHz in a MicroTCA crate. The powerful processing resources of the upgraded system enable implemen...

  1. Pharmaceutical Options for Triggering of Final Oocyte Maturation in ART

    Directory of Open Access Journals (Sweden)

    Juan Carlos Castillo

    2014-01-01

    Full Text Available Since the pioneering days of in vitro fertilization, hCG has been the gold standard to induce final follicular maturation. We herein reviewed different pharmaceutical options for triggering of final oocyte maturation in ART. The new upcoming agent seems to be GnRHa with its potential advantages over hCG trigger. GnRHa triggering elicits a surge of gonadotropins resembling the natural midcycle surge of gonadotropins, without the prolonged action of hCG, resulting in the retrieval of more mature oocytes and a significant reduction in or elimination of OHSS as compared to hCG triggering. The induction of final follicular maturation using GnRHa represents a paradigm shift in the ovulation triggering concept in ART and, thus, a way to develop a safer IVF procedure. Kisspeptins are key central regulators of the neuroendocrine mechanisms of human reproduction, who have been shown to effectively elicit an LH surge and to induce final oocyte maturation in IVF cycles. This new trigger concept may, therefore, offer a completely new, “natural” pharmacological option for ovulation induction. Whether kisspeptins will be the future agent to trigger ovulation remains to be further explored.

  2. Trigger processing using reconfigurable logic in the CMS calorimeter trigger

    Energy Technology Data Exchange (ETDEWEB)

    Brooke, J J; Cussans, D G; Heath, G P; Maddox, A J; Newbold, D M; Rabbetts, P D

    2001-04-01

    We present the design of the Global Calorimeter Trigger processor for the CMS detector at LHC. This is a fully pipelined processor system which collects data from all the CMS calorimeters and produces summary information used in forming the Level-1 trigger decision for each event. The design in based on the use of state-of-the-art reconfigurable logic devices (FPGAs) and fast data links. We present the results of device testing using a low-latency pipelined sort algorithm, which demonstrate that an FPGA can be used to perform processing previously foreseen to require custom ASICs. Our design approach results in a powerful, flexible and compact processor system.

  3. The DOe Silicon Track Trigger

    International Nuclear Information System (INIS)

    Steinbrueck, Georg

    2003-01-01

    We describe a trigger preprocessor to be used by the DOe experiment for selecting events with tracks from the decay of long-lived particles. This Level 2 impact parameter trigger utilizes information from the Silicon Microstrip Tracker to reconstruct tracks with improved spatial and momentum resolutions compared to those obtained by the Level 1 tracking trigger. It is constructed of VME boards with much of the logic existing in programmable processors. A common motherboard provides the I/O infrastructure and three different daughter boards perform the tasks of identifying the roads from the tracking trigger data, finding the clusters in the roads in the silicon detector, and fitting tracks to the clusters. This approach provides flexibility for the design, testing and maintenance phases of the project. The track parameters are provided to the trigger framework in 25 μs. The effective impact parameter resolution for high-momentum tracks is 35 μm, dominated by the size of the Tevatron beam

  4. Review Document: Full Software Trigger

    CERN Document Server

    Albrecht, J; Raven, G

    2014-01-01

    This document presents a trigger system for the upgraded LHCb detector, scheduled to begin operation in 2020. This document serves as input for the internal review towards the "DAQ, online and trigger TDR". The proposed trigger system is implemented entirely in software. In this document we show that track reconstruction of a similar quality to that available in the offline algorithms can be performed on the full inelastic $pp$-collision rate, without prior event selections implemented in custom hardware and without relying upon a partial event reconstruction. A track nding eciency of 98.8 % relative to oine can be achieved for tracks with $p_T >$ 500 MeV/$c$. The CPU time required for this reconstruction is about 40 % of the available budget. Proof-of-principle selections are presented which demonstrate that excellent performance is achievable using an inclusive beauty trigger, in addition to exclusive beauty and charm triggers. Finally, it is shown that exclusive beauty and charm selections that do not intr...

  5. Investigation of index finger triggering force using a cadaver experiment: Effects of trigger grip span, contact location, and internal tendon force.

    Science.gov (United States)

    Chang, Joonho; Freivalds, Andris; Sharkey, Neil A; Kong, Yong-Ku; Mike Kim, H; Sung, Kiseok; Kim, Dae-Min; Jung, Kihyo

    2017-11-01

    A cadaver study was conducted to investigate the effects of triggering conditions (trigger grip span, contact location, and internal tendon force) on index finger triggering force and the force efficiency of involved tendons. Eight right human cadaveric hands were employed, and a motion simulator was built to secure and control the specimens. Index finger triggering forces were investigated as a function of different internal tendon forces (flexor digitorum profundus + flexor digitorum superficialis = 40, 70, and 100 N), trigger grip spans (40, 50, and 60 mm), and contact locations between the index finger and a trigger. Triggering forces significantly increased when internal tendon forces increased from 40 to 100 N. Also, trigger grip spans and contact locations had significant effects on triggering forces; maximum triggering forces were found at a 50 mm span and the most proximal contact location. The results revealed that only 10-30% of internal tendon forces were converted to their external triggering forces. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. ATLAS FTK Fast Track Trigger

    CERN Document Server

    Iizawa, T; The ATLAS collaboration

    2014-01-01

    The Fast TracKer (FTK) will perform global track reconstruction after each Level-1 trigger accept signal to enable the software-based higher level trigger to have early access to tracking information. FTK is a dedicated processor based on a mixture of advanced technologies. Modern, powerful Field Programmable Gate Arrays (FPGAs) form an important part of the system architecture, and the large level of computing power required for pattern recognition is provided by incorporating standard-cell ASICs named Associative Memory (AM). Motivation and the architecture of the FTK system will be presented, and the status of hardware and simulation will be following.

  7. RPC Trigger Robustness: Status Report

    CERN Document Server

    Di Mattia, A; Nisati, A; Pastore, F; Vari, R; Veneziano, Stefano; Aielli, G; Camarri, P; Cardarelli, R; Di Ciaccio, A; Di Simone, A; Liberti, B; Santonico, R

    2002-01-01

    The present paper describes the Level-1 Barrel Muon Trigger performance as expected with the current configuration of the RPC detectors designed for the Barrel Muon Spectrometer of ATLAS. Results of a beam test performed at the X5-GIF facility at CERN are presented in order to show the trigger efficiency with different conditions of RPC detection efficiency and several background rates. Small (50$\\times$50 cm$^2$) RPC chambers with final Front-end electronics and splitter boards are used in the test, while the coincidence logic is applied off-line using a detailed simulation of the coincidence matrix.

  8. Fast processor for dilepton triggers

    International Nuclear Information System (INIS)

    Katsanevas, S.; Kostarakis, P.; Baltrusaitis, R.

    1983-01-01

    We describe a fast trigger processor, developed for and used in Fermilab experiment E-537, for selecting high-mass dimuon events produced by negative pions and anti-protons. The processor finds candidate tracks by matching hit information received from drift chambers and scintillation counters, and determines their momenta. Invariant masses are calculated for all possible pairs of tracks and an event is accepted if any invariant mass is greater than some preselectable minimum mass. The whole process, accomplished within 5 to 10 microseconds, achieves up to a ten-fold reduction in trigger rate

  9. DT Local Trigger performance in 2015

    CERN Document Server

    CMS Collaboration

    2015-01-01

    The Local Trigger system of the CMS Drift Tube chambers (DT) was checked applying similar methods as in the LHC Run 1 (2012). The main variables shown in this note are the trigger efficiency, the trigger quality and the fraction of trigger ghosts. The performance was found to be comparable or better than in Run 1.

  10. The Brainstem Pathologies of Parkinson's Disease and Dementia with Lewy Bodies

    NARCIS (Netherlands)

    Seidel, Kay; Mahlke, Josefine; Siswanto, Sonny; Krueger, Reijko; Heinsen, Helmut; Auburger, Georg; Bouzrou, Mohamed; Grinberg, Lea T.; Wicht, Helmut; Korf, Horst-Werner; den Dunnen, Wilfred; Rueb, Udo

    Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are among the human synucleinopathies, which show alpha-synuclein immunoreactive neuronal and/or glial aggregations and progressive neuronal loss in selected brain regions (eg, substantia nigra, ventral tegmental area, pedunculopontine

  11. The Trigger for Early Running

    CERN Document Server

    The ATLAS Collaboration

    2009-01-01

    The ATLAS trigger and data acquisition system is based on three levels of event selection designed to capture the physics of interest with high efficiency from an initial bunch crossing rate of 40 MHz. The selections in the three trigger levels must provide sufficient rejection to reduce the rate to 200 Hz, compatible with offline computing power and storage capacity. The LHC is expected to begin its operation with a peak luminosity of 10^31 with a relatively small number of bunches, but quickly ramp up to higher luminosities by increasing the number of bunches, and thus the overall interaction rate. Decisions must be taken every 25 ns during normal LHC operations at the design luminosity of 10^34, where the average bunch crossing will contain more than 20 interactions. Hence, trigger selections must be deployed that can adapt to the changing beam conditions while preserving the interesting physics and satisfying varying detector requirements. In this paper, we provide a menu of trigger selections that can be...

  12. The CDF Silicon Vertex Trigger

    International Nuclear Information System (INIS)

    Dell'Orso, Mauro

    2006-01-01

    Motivations, design, performance and ongoing upgrade of the CDF Silicon Vertex Trigger are presented. The system provides CDF with a powerful tool for online tracking with offline quality in order to enhance the reach on B-physics and large P t -physics coupled to b quarks

  13. Triggering of Suicidal Erythrocyte Death by Regorafenib

    Directory of Open Access Journals (Sweden)

    Jens Zierle

    2016-01-01

    Full Text Available Background/Aims: The multikinase inhibitor regorafenib is utilized for the treatment of malignancy. The substance is effective in part by triggering suicidal death or apoptosis of tumor cells. Side effects of regorafenib include anemia. At least in theory, regorafenib induced anemia could result from stimulated suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i, oxidative stress and ceramide. The present study explored, whether regorafenib induces eryptosis and, if so, whether it is effective up- and/or downstream of Ca2+. Methods: To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to regorafenib (≥ 0.5 µg/ml significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter (≥ 1.25 µg/ml, but did not significantly increase Fluo3-fluorescence, DCFDA fluorescence or ceramide abundance. The effect of regorafenib on annexin-V-binding and forward scatter was not significantly blunted by removal of extracellular Ca2+. Regorafenib (5 µg/ml significantly augmented the increase of annexin-V-binding, but significantly blunted the decrease of forward scatter following treatment with the Ca2+ ionophore ionomycin. Conclusions: Regorafenib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part downstream of Ca2+.

  14. Triggering of Suicidal Erythrocyte Death by Regorafenib.

    Science.gov (United States)

    Zierle, Jens; Bissinger, Rosi; Bouguerra, Ghada; Abbès, Salem; Lang, Florian

    2016-01-01

    The multikinase inhibitor regorafenib is utilized for the treatment of malignancy. The substance is effective in part by triggering suicidal death or apoptosis of tumor cells. Side effects of regorafenib include anemia. At least in theory, regorafenib induced anemia could result from stimulated suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether regorafenib induces eryptosis and, if so, whether it is effective up- and/or downstream of Ca2+. To this end, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. A 48 hours exposure of human erythrocytes to regorafenib (≥ 0.5 µg/ml) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter (≥ 1.25 µg/ml), but did not significantly increase Fluo3-fluorescence, DCFDA fluorescence or ceramide abundance. The effect of regorafenib on annexin-V-binding and forward scatter was not significantly blunted by removal of extracellular Ca2+. Regorafenib (5 µg/ml) significantly augmented the increase of annexin-V-binding, but significantly blunted the decrease of forward scatter following treatment with the Ca2+ ionophore ionomycin. Regorafenib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part downstream of Ca2+. © 2016 The Author(s) Published by S. Karger AG, Basel.

  15. Production of interleukin-1alpha by human endometrial stromal cells is triggered during menses and dysfunctional bleeding and is induced in culture by epithelial interleukin-1alpha released upon ovarian steroids withdrawal.

    Science.gov (United States)

    Pretto, Chrystel M; Gaide Chevronnay, Héloïse P; Cornet, Patricia B; Galant, Christine; Delvaux, Denis; Courtoy, Pierre J; Marbaix, Etienne; Henriet, Patrick

    2008-10-01

    Endometrial breakdown during menstruation and dysfunctional bleeding is triggered by the abrupt expression of matrix metalloproteinases (MMPs), including interstitial collagenase (MMP-1). The paracrine induction of MMP-1 in stromal cells via epithelium-derived IL-1alpha is repressed by ovarian steroids. However, the control by estradiol (E) and progesterone (P) of endometrial IL-1alpha expression and bioactivity remains unknown. Variations of endometrial IL-1alpha mRNA and protein along the menstrual cycle and during dysfunctional bleeding were determined using RT-PCR, in situ hybridization, and immunolabeling. The mechanism of EP control was analyzed using culture of explants, laser capture microdissection, and purified cells. Data were compared with expression changes of IL-1beta and IL-1 receptor antagonist. IL-1alpha is synthesized by epithelial cells throughout the cycle but E and/or P prevents its release. In contrast, endometrial stromal cells produce IL-1alpha only at menses and during irregular bleeding in areas of tissue breakdown. Stromal expression of IL-1alpha, like that of MMP-1, is repressed by P (alone or with E) but triggered by epithelium-derived IL-1alpha released upon EP withdrawal. Our experiments in cultured endometrium suggest that IL-1alpha released by epithelial cells triggers the production of IL-1alpha by stromal cells in a paracrine amplification loop to induce MMP-1 expression during menstruation and dysfunctional bleeding. All three steps of this amplification cascade are repressed by EP.

  16. GnRHa trigger for final oocyte maturation

    DEFF Research Database (Denmark)

    Humaidan, Peter; Alsbjerg, Birgit

    2014-01-01

    Since the introduction of the gonadotrophin-releasing hormone analogues (GnRHa) protocol, it has become possible to trigger final oocyte maturation with a bolus of GnRHa. This leads to a significant reduction or complete elimination of ovarian hyperstimulation syndrome compared with human chorion...

  17. Triggers in UA2 and UA1

    International Nuclear Information System (INIS)

    Dorenbosch, J.

    1985-01-01

    The UA2 and UA1 trigger systems are described as they will be used after the upgrade of the CERN SPPS. The luminosity of the collider will increase to 3x10 30 . The bunch spacing is 4 microseconds, comparable to the time available for a second level trigger at the SSC. The first level triggers are very powerful and deliver trigger rates of about 100 Hz. The UA1 second level trigger operates on the final digitizings with a combination of special and general purpose processors. At the highest trigger levels a small farm of processors performs the final reduction. (orig.)

  18. Muon Trigger for Mobile Phones

    Science.gov (United States)

    Borisyak, M.; Usvyatsov, M.; Mulhearn, M.; Shimmin, C.; Ustyuzhanin, A.

    2017-10-01

    The CRAYFIS experiment proposes to use privately owned mobile phones as a ground detector array for Ultra High Energy Cosmic Rays. Upon interacting with Earth’s atmosphere, these events produce extensive particle showers which can be detected by cameras on mobile phones. A typical shower contains minimally-ionizing particles such as muons. As these particles interact with CMOS image sensors, they may leave tracks of faintly-activated pixels that are sometimes hard to distinguish from random detector noise. Triggers that rely on the presence of very bright pixels within an image frame are not efficient in this case. We present a trigger algorithm based on Convolutional Neural Networks which selects images containing such tracks and are evaluated in a lazy manner: the response of each successive layer is computed only if activation of the current layer satisfies a continuation criterion. Usage of neural networks increases the sensitivity considerably comparable with image thresholding, while the lazy evaluation allows for execution of the trigger under the limited computational power of mobile phones.

  19. Stimulus conflict triggers behavioral avoidance.

    Science.gov (United States)

    Dignath, David; Eder, Andreas B

    2015-12-01

    According to a recent extension of the conflict-monitoring theory, conflict between two competing response tendencies is registered as an aversive event and triggers a motivation to avoid the source of conflict. In the present study, we tested this assumption. Over five experiments, we examined whether conflict is associated with an avoidance motivation and whether stimulus conflict or response conflict triggers an avoidance tendency. Participants first performed a color Stroop task. In a subsequent motivation test, participants responded to Stroop stimuli with approach- and avoidance-related lever movements. These results showed that Stroop-conflict stimuli increased the frequency of avoidance responses in a free-choice motivation test, and also increased the speed of avoidance relative to approach responses in a forced-choice test. High and low proportions of response conflict in the Stroop task had no effect on avoidance in the motivation test. Avoidance of conflict was, however, obtained even with new conflict stimuli that had not been presented before in a Stroop task, and when the Stroop task was replaced with an unrelated filler task. Taken together, these results suggest that stimulus conflict is sufficient to trigger avoidance.

  20. Industrial accidents triggered by lightning.

    Science.gov (United States)

    Renni, Elisabetta; Krausmann, Elisabeth; Cozzani, Valerio

    2010-12-15

    Natural disasters can cause major accidents in chemical facilities where they can lead to the release of hazardous materials which in turn can result in fires, explosions or toxic dispersion. Lightning strikes are the most frequent cause of major accidents triggered by natural events. In order to contribute towards the development of a quantitative approach for assessing lightning risk at industrial facilities, lightning-triggered accident case histories were retrieved from the major industrial accident databases and analysed to extract information on types of vulnerable equipment, failure dynamics and damage states, as well as on the final consequences of the event. The most vulnerable category of equipment is storage tanks. Lightning damage is incurred by immediate ignition, electrical and electronic systems failure or structural damage with subsequent release. Toxic releases and tank fires tend to be the most common scenarios associated with lightning strikes. Oil, diesel and gasoline are the substances most frequently released during lightning-triggered Natech accidents. Copyright © 2010 Elsevier B.V. All rights reserved.

  1. The UA1 trigger processor

    International Nuclear Information System (INIS)

    Grayer, G.H.

    1981-01-01

    Experiment UA1 is a large multi-purpose spectrometer at the CERN proton-antiproton collider, scheduled for late 1981. The principal trigger is formed on the basis of the energy deposition in calorimeters. A trigger decision taken in under 2.4 microseconds can avoid dead time losses due to the bunched nature of the beam. To achieve this we have built fast 8-bit charge to digital converters followed by two identical digital processors tailored to the experiment. The outputs of groups of the 2440 photomultipliers in the calorimeters are summed to form a total of 288 input channels to the ADCs. A look-up table in RAM is used to convert the digitised photomultiplier signals to energy in one processor, combinations of input channels, and also counts the number of clusters with electromagnetic or hadronic energy above pre-determined levels. Up to twelve combinations of these conditions, together with external information, may be combined in coincidence or in veto to form the final trigger. Provision has been made for testing using simulated data in an off-line mode, and sampling real data when on-line. (orig.)

  2. ATLAS Level-1 Topological Trigger

    CERN Document Server

    Zheng, Daniel; The ATLAS collaboration

    2018-01-01

    The ATLAS experiment has introduced and recently commissioned a completely new hardware sub-system of its first-level trigger: the topological processor (L1Topo). L1Topo consist of two AdvancedTCA blades mounting state-of-the-art FPGA processors, providing high input bandwidth (up to 4 Gb/s) and low latency data processing (200 ns). L1Topo is able to select collision events by applying kinematic and topological requirements on candidate objects (energy clusters, jets, and muons) measured by calorimeters and muon sub-detectors. Results from data recorded using the L1Topo trigger will be presented. These results demonstrate a significantly improved background event rejection, thus allowing for a rate reduction without efficiency loss. This improvement has been shown for several physics processes leading to low-pT leptons, including H->tau tau and J/Psi->mu mu. In addition to describing the L1Topo trigger system, we will discuss the use of an accurate L1Topo simulation as a powerful tool to validate and optimize...

  3. ATLAS FTK: Fast Track Trigger

    CERN Document Server

    Volpi, Guido; The ATLAS collaboration

    2015-01-01

    An overview of the ATLAS Fast Tracker processor is presented, reporting the design of the system, its expected performance, and the integration status. The next LHC runs, with a significant increase in instantaneous luminosity, will provide a big challenge to the trigger and data acquisition systems of all the experiments. An intensive use of the tracking information at the trigger level will be important to keep high efficiency in interesting events, despite the increase in multiple p-p collisions per bunch crossing (pile-up). In order to increase the use of tracks within the High Level Trigger (HLT), the ATLAS experiment planned the installation of an hardware processor dedicated to tracking: the Fast TracKer (FTK) processor. The FTK is designed to perform full scan track reconstruction at every Level-1 accept. To achieve this goal, the FTK uses a fully parallel architecture, with algorithms designed to exploit the computing power of custom VLSI chips, the Associative Memory, as well as modern FPGAs. The FT...

  4. Headache triggers in the US military.

    Science.gov (United States)

    Theeler, Brett J; Kenney, Kimbra; Prokhorenko, Olga A; Fideli, Ulgen S; Campbell, William; Erickson, Jay C

    2010-05-01

    Headaches can be triggered by a variety of factors. Military service members have a high prevalence of headache but the factors triggering headaches in military troops have not been identified. The objective of this study is to determine headache triggers in soldiers and military beneficiaries seeking specialty care for headaches. A total of 172 consecutive US Army soldiers and military dependents (civilians) evaluated at the headache clinics of 2 US Army Medical Centers completed a standardized questionnaire about their headache triggers. A total of 150 (87%) patients were active-duty military members and 22 (13%) patients were civilians. In total, 77% of subjects had migraine; 89% of patients reported at least one headache trigger with a mean of 8.3 triggers per patient. A wide variety of headache triggers was seen with the most common categories being environmental factors (74%), stress (67%), consumption-related factors (60%), and fatigue-related factors (57%). The types of headache triggers identified in active-duty service members were similar to those seen in civilians. Stress-related triggers were significantly more common in soldiers. There were no significant differences in trigger types between soldiers with and without a history of head trauma. Headaches in military service members are triggered mostly by the same factors as in civilians with stress being the most common trigger. Knowledge of headache triggers may be useful for developing strategies that reduce headache occurrence in the military.

  5. Embodied social robots trigger gaze following in real-time

    OpenAIRE

    Wiese, Eva; Weis, Patrick; Lofaro, Daniel

    2018-01-01

    In human-human interaction, we use information from gestures, facial expressions and gaze direction to make inferences about what interaction partners think, feel or intend to do next. Observing changes in gaze direction triggers shifts of attention to gazed-at locations and helps establish shared attention between gazer and observer - a prerequisite for more complex social skills like mentalizing, action understanding and joint action. The ability to follow others’ gaze develops early in lif...

  6. The Jefferson Lab Trigger Supervisor System

    International Nuclear Information System (INIS)

    Ed Jastrzembsi; David Abbott; Graham Heyes; R.W. MacLeod; Carl Timmer; Elliott Wolin

    2000-01-01

    We discuss the design and performance of a Trigger Supervisor System for use in nuclear physics experiments at Jefferson Lab. We also discuss the enhanced features of a new Trigger Supervisor Module now under construction

  7. The Jefferson Lab Trigger Supervisor System

    International Nuclear Information System (INIS)

    Jastrzembski, E.; Abbott, D.J.; Heyes, W.G.; MacLeod, R.W.; Timmer, C.; Wolin, E.

    1999-01-01

    The authors discuss the design and performance of a Trigger Supervisor System for use in nuclear physics experiments at Jefferson Lab. They also discuss the enhanced features of a new Trigger Supervisor Module now under construction

  8. The Trigger System of the CMS Experiment

    OpenAIRE

    Felcini, Marta

    2008-01-01

    We give an overview of the main features of the CMS trigger and data acquisition (DAQ) system. Then, we illustrate the strategies and trigger configurations (trigger tables) developed for the detector calibration and physics program of the CMS experiment, at start-up of LHC operations, as well as their possible evolution with increasing luminosity. Finally, we discuss the expected CPU time performance of the trigger algorithms and the CPU requirements for the event filter farm at start-up.

  9. Triggers for a high sensitivity charm experiment

    International Nuclear Information System (INIS)

    Christian, D.C.

    1994-07-01

    Any future charm experiment clearly should implement an E T trigger and a μ trigger. In order to reach the 10 8 reconstructed charm level for hadronic final states, a high quality vertex trigger will almost certainly also be necessary. The best hope for the development of an offline quality vertex trigger lies in further development of the ideas of data-driven processing pioneered by the Nevis/U. Mass. group

  10. First level trigger of the DIRAC experiment

    International Nuclear Information System (INIS)

    Afanas'ev, L.G.; Karpukhin, V.V.; Kulikov, A.V.; Gallas, M.

    2001-01-01

    The logic of the first level trigger of the DIRAC experiment at CERN is described. A parallel running of different trigger modes with tagging of events and optional independent prescaling is realized. A CAMAC-based trigger system is completely computer controlled

  11. The D OE software trigger

    International Nuclear Information System (INIS)

    Linnemann, J.T.; Michigan State Univ., East Lansing, MI

    1992-10-01

    In the D OE experiment, the software filter operates in a processor farm with each node processing a single event. Processing is data-driven: the filter does local processing to verify the candidates from the hardware trigger. The filter code consists of independent pieces called ''tools''; processing for a given hardware bit is a ''script'' invoking one or more ''tools'' sequentially. An offline simulator drives the same code with the same configuration files, running on real or simulated data. Online tests use farm nodes parasiting on the data stream. We discuss the performance of the system and how we attempt to verify its correctness

  12. Calorimeter triggers for hard collisions

    International Nuclear Information System (INIS)

    Landshoff, P.V.; Polkinghorne, J.C.

    1978-01-01

    We discuss the use of a forward calorimeter to trigger on hard hadron-hadron collisions. We give a derivation in the covariant parton model of the Ochs-Stodolsky scaling law for single-hard-scattering processes, and investigate the conditions when instead a multiple- scattering mechanism might dominate. With a proton beam, this mechanism results in six transverse jets, with a total average multiplicity about twice that seen in ordinary events. We estimate that its cross section is likely to be experimentally accessible at avalues of the beam energy in the region of 100 GeV/c

  13. Competition for trophies triggers male generosity.

    Directory of Open Access Journals (Sweden)

    Xiaofei Sophia Pan

    Full Text Available BACKGROUND: Cooperation is indispensable in human societies, and much progress has been made towards understanding human pro-social decisions. Formal incentives, such as punishment, are suggested as potential effective approaches despite the fact that punishment can crowd out intrinsic motives for cooperation and detrimentally impact efficiency. At the same time, evolutionary biologists have long recognized that cooperation, especially food sharing, is typically efficiently organized in groups living on wild foods, even absent formal economic incentives. Despite its evident importance, the source of this voluntary compliance remains largely uninformed. Drawing on costly signaling theory, and in light of the widely established competitive nature of males, we hypothesize that unique and displayable rewards (trophies out of competition may trigger male generosity in competitive social environments. PRINCIPAL FINDINGS: Here, we use a controlled laboratory experiment to show that cooperation is sustained in a generosity competition with trophy rewards, but breaks down in the same environment with equally valuable but non-unique and non-displayable rewards. Further, we find that males' competition for trophies is the driving force behind treatment differences. In contrast, it appears that female competitiveness is not modulated by trophy rewards. SIGNIFICANCE: Our results suggest new approaches to promoting cooperation in human groups that, unlike punishment mechanisms, do not sacrifice efficiency. This could have important implications in any domain where voluntary compliance matters--including relations between spouses, employers and employees, market transactions, and conformity to legal standards.

  14. Triggering for charm, beauty, and truth

    International Nuclear Information System (INIS)

    Appel, J.A.

    1982-02-01

    As the search for more and more rare processes accelerates, the need for more and more effective event triggers also accelerates. In the earliest experiments, a simple coincidence often sufficed not only as the event trigger, but as the complete record of an event of interest. In today's experiments, not only has the fast trigger become more sophisticated, but one or more additional level of trigger processing precedes writing event data to magnetic tape for later analysis. Further search experiments will certainly require further expansion in the number of trigger levels required to filter those rare events of particular interest

  15. The Database Driven ATLAS Trigger Configuration System

    CERN Document Server

    Martyniuk, Alex; The ATLAS collaboration

    2015-01-01

    This contribution describes the trigger selection configuration system of the ATLAS low- and high-level trigger (HLT) and the upgrades it received in preparation for LHC Run 2. The ATLAS trigger configuration system is responsible for applying the physics selection parameters for the online data taking at both trigger levels and the proper connection of the trigger lines across those levels. Here the low-level trigger consists of the already existing central trigger (CT) and the new Level-1 Topological trigger (L1Topo), which has been added for Run 2. In detail the tasks of the configuration system during the online data taking are Application of the selection criteria, e.g. energy cuts, minimum multiplicities, trigger object correlation, at the three trigger components L1Topo, CT, and HLT On-the-fly, e.g. rate-dependent, generation and application of prescale factors to the CT and HLT to adjust the trigger rates to the data taking conditions, such as falling luminosity or rate spikes in the detector readout ...

  16. Hadronic Triggers and trigger-object level analysis at ATLAS

    CERN Document Server

    Zaripovas, Donatas Ramilas; The ATLAS collaboration

    2017-01-01

    Hadronic signatures are critical to the high energy physics analysis program, and are broadly used for both Standard Model measurements and searches for new physics. These signatures include generic quark and gluon jets, as well as jets originating from b-quarks or the decay of massive particles (such as electroweak bosons or top quarks). Additionally missing transverse momentum from non-interacting particles provides an interesting probe in the search for new physics beyond the Standard Model. Developing trigger selections that target these events is a huge challenge at the LHC due to the enormous rates associated with these signatures. This challenge is exacerbated by the amount of pile-up activity, which continues to grow. In order to address these challenges, several new techniques have been developed during the past year in order to significantly improve the potential of the 2017 dataset and overcome the limiting factors to more deeply probing for new physics, such as storage and computing requirements f...

  17. Hadronic triggers and trigger object-level analysis at ATLAS

    CERN Document Server

    Zaripovas, Donatas Ramilas; The ATLAS collaboration

    2017-01-01

    Hadronic signatures are critical to the high energy physics analysis program at the Large Hadron Collider (LHC), and are broadly used for both Standard Model measurements and searches for new physics. These signatures include generic quark and gluon jets, as well as jets originating from b-quarks or the decay of massive particles (such as electroweak bosons or top quarks). Additionally missing transverse momentum from non-interacting particles provides an interesting probe in the search for new physics beyond the Standard Model. Developing trigger selections that target these events is a huge challenge at the LHC due to the enormous event rates associated with these signatures. This challenge is exacerbated by the amount of pile-up activity, which continues to grow. In order to address these challenges, several new techniques have been developed during the past year in order to significantly improve the potential of the 2017 dataset and overcome the limiting factors, such as storage and computing requirements...

  18. Wired and Wireless Camera Triggering with Arduino

    Science.gov (United States)

    Kauhanen, H.; Rönnholm, P.

    2017-10-01

    Synchronous triggering is an important task that allows simultaneous data capture from multiple cameras. Accurate synchronization enables 3D measurements of moving objects or from a moving platform. In this paper, we describe one wired and four wireless variations of Arduino-based low-cost remote trigger systems designed to provide a synchronous trigger signal for industrial cameras. Our wireless systems utilize 315 MHz or 434 MHz frequencies with noise filtering capacitors. In order to validate the synchronization accuracy, we developed a prototype of a rotating trigger detection system (named RoTriDeS). This system is suitable to detect the triggering accuracy of global shutter cameras. As a result, the wired system indicated an 8.91 μs mean triggering time difference between two cameras. Corresponding mean values for the four wireless triggering systems varied between 7.92 and 9.42 μs. Presented values include both camera-based and trigger-based desynchronization. Arduino-based triggering systems appeared to be feasible, and they have the potential to be extended to more complicated triggering systems.

  19. Triggers of oral lichen planus flares and the potential role of trigger avoidance in disease management.

    Science.gov (United States)

    Chen, Hannah X; Blasiak, Rachel; Kim, Edwin; Padilla, Ricardo; Culton, Donna A

    2017-09-01

    Many patients with oral lichen planus (OLP) report triggers of flares, some of which overlap with triggers of other oral diseases, including oral allergy syndrome and oral contact dermatitis. The purpose of this study was to evaluate the prevalence of commonly reported triggers of OLP flares, their overlap with triggers of other oral diseases, and the potential role of trigger avoidance as a management strategy. Questionnaire-based survey of 51 patients with biopsy-proven lichen planus with oral involvement seen in an academic dermatology specialty clinic and/or oral pathology clinic between June 2014 and June 2015. Of the participants, 94% identified at least one trigger of their OLP flares. Approximately half of the participants (51%) reported at least one trigger that overlapped with known triggers of oral allergy syndrome, and 63% identified at least one trigger that overlapped with known triggers of oral contact dermatitis. Emotional stress was the most commonly reported trigger (77%). Regarding avoidance, 79% of the study participants reported avoiding their known triggers in daily life. Of those who actively avoided triggers, 89% reported an improvement in symptoms and 70% reported a decrease in the frequency of flares. Trigger identification and avoidance can play a potentially effective role in the management of OLP. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Application of Vector Triggering Random Decrement

    DEFF Research Database (Denmark)

    Asmussen, J. C.; Ibrahim, S. R.; Brincker, Rune

    result is a Random Decrement function from each measurement. In traditional Random Decrement estimation the triggering condition is a scalar condition, which should only be fulfilled in a single measurement. In vector triggering Random Decrement the triggering condition is a vector condition......This paper deals with applications of the vector triggering Random Decrement technique. This technique is new and developed with the aim of minimizing estimation time and identification errors. The theory behind the technique is discussed in an accompanying paper. The results presented...... in this paper should be regarded as a further documentation of the technique. The key point in Random Decrement estimation is the formulation of a triggering condition. If the triggering condition is fulfilled a time segment from each measurement is picked out and averaged with previous time segments. The final...

  1. Application of Vector Triggering Random Decrement

    DEFF Research Database (Denmark)

    Asmussen, J. C.; Ibrahim, S. R.; Brincker, Rune

    1997-01-01

    result is a Random Decrement function from each measurement. In traditional Random Decrement estimation the triggering condition is a scalar condition, which should only be fulfilled in a single measurement. In vector triggering Random Decrement the triggering condition is a vector condition......This paper deals with applications of the vector triggering Random Decrement technique. This technique is new and developed with the aim of minimizing estimation time and identification errors. The theory behind the technique is discussed in an accompanying paper. The results presented...... in this paper should be regarded as a further documentation of the technique. The key point in Random Decrement estimation is the formulation of a triggering condition. If the triggering condition is fulfilled a time segment from each measurement is picked out and averaged with previous time segments. The final...

  2. Smart trigger logic for focal plane arrays

    Science.gov (United States)

    Levy, James E; Campbell, David V; Holmes, Michael L; Lovejoy, Robert; Wojciechowski, Kenneth; Kay, Randolph R; Cavanaugh, William S; Gurrieri, Thomas M

    2014-03-25

    An electronic device includes a memory configured to receive data representing light intensity values from pixels in a focal plane array and a processor that analyzes the received data to determine which light values correspond to triggered pixels, where the triggered pixels are those pixels that meet a predefined set of criteria, and determines, for each triggered pixel, a set of neighbor pixels for which light intensity values are to be stored. The electronic device also includes a buffer that temporarily stores light intensity values for at least one previously processed row of pixels, so that when a triggered pixel is identified in a current row, light intensity values for the neighbor pixels in the previously processed row and for the triggered pixel are persistently stored, as well as a data transmitter that transmits the persistently stored light intensity values for the triggered and neighbor pixels to a data receiver.

  3. The STAR Level-3 trigger system

    International Nuclear Information System (INIS)

    Adler, C.; Berger, J.; Demello, M.; Dietel, T.; Flierl, D.; Landgraf, J.; Lange, J.S.; LeVine, M.J.; Ljubicic, A.; Nelson, J.; Roehrich, D.; Stock, R.; Struck, C.; Yepes, P.

    2003-01-01

    The STAR Level-3 trigger issues a trigger decision upon a complete online reconstruction of Au+Au collisions at relativistic heavy ion collider energies. Central interactions are processed up to a rate of 50 s -1 including a simple analysis of physics observables. The setup of the processor farm and the event reconstruction as well as experiences and the proposed trigger algorithms are described

  4. Upgrade trigger & reconstruction strategy: 2017 milestone

    CERN Document Server

    Albrecht, Johannes; Campora Perez, Daniel Hugo; Cattaneo, Marco; Marco, Clemencic; Couturier, Ben; Dziurda, Agnieszka; Fitzpatrick, Conor; Fontana, Marianna; Grillo, Lucia; Hasse, Christoph; Hill, Donal; Jones, Christopher Rob; Lemaitre, Florian; Lupton, Olli; Matev, Rosen; Pearce, Alex; Polci, Francesco; Promberger, Laura; Ponce, Sebastien; Quagliani, Renato; Raven, Gerhard; Sciascia, Barbara; Schiller, Manuel Tobias; Stahl, Sascha; Szymanski, Maciej Pawel; Chefdeville, Maximilien

    2018-01-01

    The LHCb collaboration is currently preparing an update of the experiment to take data in Run 3 of the LHC. The dominant feature of this upgrade is a trigger-less readout of the full detector followed by a full software trigger. To make optimal use of the collected data, the events are reconstructed at the inelastic collision rate of 30 MHz. This document presents the baseline trigger and reconstruction strategy as of the end of 2017.

  5. A muon trigger for the MACRO apparatus

    International Nuclear Information System (INIS)

    Barbarito, E.; Bellotti, R.; Calicchio, M.; Castellano, M.; DeCataldo, G.; DeMarzo, C.; Erriquez, O.; Favuzzi, C.; Giglietto, N.; Liuzzi, R.; Spinelli, P.

    1991-01-01

    A trigger circuit based on EPROM components, able to manage up to 30 lines from independent counters, is described. The circuit has been designed and used in the MACRO apparatus at the Gran Sasso Laboratory for triggering on fast particles. The circuit works with standard TTL positive logic and is assembled in a double standard CAMAC module. It has a high triggering capacity and a high flexibility. (orig.)

  6. The ATLAS Level-1 Calorimeter Trigger

    International Nuclear Information System (INIS)

    Achenbach, R; Andrei, V; Adragna, P; Apostologlou, P; Barnett, B M; Brawn, I P; Davis, A O; Edwards, J P; Asman, B; Bohm, C; Ay, C; Bauss, B; Bendel, M; Dahlhoff, A; Eckweiler, S; Booth, J R A; Thomas, P Bright; Charlton, D G; Collins, N J; Curtis, C J

    2008-01-01

    The ATLAS Level-1 Calorimeter Trigger uses reduced-granularity information from all the ATLAS calorimeters to search for high transverse-energy electrons, photons, τ leptons and jets, as well as high missing and total transverse energy. The calorimeter trigger electronics has a fixed latency of about 1 μs, using programmable custom-built digital electronics. This paper describes the Calorimeter Trigger hardware, as installed in the ATLAS electronics cavern

  7. The ATLAS Level-1 Calorimeter Trigger

    Energy Technology Data Exchange (ETDEWEB)

    Achenbach, R; Andrei, V [Kirchhoff-Institut fuer Physik, University of Heidelberg, D-69120 Heidelberg (Germany); Adragna, P [Physics Department, Queen Mary, University of London, London E1 4NS (United Kingdom); Apostologlou, P; Barnett, B M; Brawn, I P; Davis, A O; Edwards, J P [STFC Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxon OX11 0QX (United Kingdom); Asman, B; Bohm, C [Fysikum, Stockholm University, SE-106 91 Stockholm (Sweden); Ay, C; Bauss, B; Bendel, M; Dahlhoff, A; Eckweiler, S [Institut fuer Physik, University of Mainz, D-55099 Mainz (Germany); Booth, J R A; Thomas, P Bright; Charlton, D G; Collins, N J; Curtis, C J [School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT (United Kingdom)], E-mail: e.eisenhandler@qmul.ac.uk (and others)

    2008-03-15

    The ATLAS Level-1 Calorimeter Trigger uses reduced-granularity information from all the ATLAS calorimeters to search for high transverse-energy electrons, photons, {tau} leptons and jets, as well as high missing and total transverse energy. The calorimeter trigger electronics has a fixed latency of about 1 {mu}s, using programmable custom-built digital electronics. This paper describes the Calorimeter Trigger hardware, as installed in the ATLAS electronics cavern.

  8. The ATLAS Trigger System Commissioning and Performance

    CERN Document Server

    Hamilton, A

    2010-01-01

    The ATLAS trigger has been used very successfully to collect collision data during 2009 and 2010 LHC running at centre of mass energies of 900 GeV, 2.36 TeV, and 7 TeV. This paper presents the ongoing work to commission the ATLAS trigger with proton collisions, including an overview of the performance of the trigger based on extensive online running. We describe how the trigger has evolved with increasing LHC luminosity and give a brief overview of plans for forthcoming LHC running.

  9. A Novel in situ Trigger Combination Method

    International Nuclear Information System (INIS)

    Buzatu, Adrian; Warburton, Andreas; Krumnack, Nils; Yao, Wei-Ming

    2012-01-01

    Searches for rare physics processes using particle detectors in high-luminosity colliding hadronic beam environments require the use of multi-level trigger systems to reject colossal background rates in real time. In analyses like the search for the Higgs boson, there is a need to maximize the signal acceptance by combining multiple different trigger chains when forming the offline data sample. In such statistically limited searches, datasets are often amassed over periods of several years, during which the trigger characteristics evolve and their performance can vary significantly. Reliable production cross-section measurements and upper limits must take into account a detailed understanding of the effective trigger inefficiency for every selected candidate event. We present as an example the complex situation of three trigger chains, based on missing energy and jet energy, to be combined in the context of the search for the Higgs (H) boson produced in association with a W boson at the Collider Detector at Fermilab (CDF). We briefly review the existing techniques for combining triggers, namely the inclusion, division, and exclusion methods. We introduce and describe a novel fourth in situ method whereby, for each candidate event, only the trigger chain with the highest a priori probability of selecting the event is considered. The in situ combination method has advantages of scalability to large numbers of differing trigger chains and of insensitivity to correlations between triggers. We compare the inclusion and in situ methods for signal event yields in the CDF WH search.

  10. The ATLAS Muon and Tau Trigger

    CERN Document Server

    Dell'Asta, L; The ATLAS collaboration

    2013-01-01

    [Muon] The ATLAS experiment at CERN's Large Hadron Collider (LHC) deploys a three-levels processing scheme for the trigger system. The level-1 muon trigger system gets its input from fast muon trigger detectors. Fast sector logic boards select muon candidates, which are passed via an interface board to the central trigger processor and then to the High Level Trigger (HLT). The muon HLT is purely software based and encompasses a level-2 (L2) trigger followed by an event filter (EF) for a staged trigger approach. It has access to the data of the precision muon detectors and other detector elements to refine the muon hypothesis. Trigger-specific algorithms were developed and are used for the L2 to increase processing speed for instance by making use of look-up tables and simpler algorithms, while the EF muon triggers mostly benefit from offline reconstruction software to obtain most precise determination of the track parameters. There are two algorithms with different approaches, namely inside-out and outside-in...

  11. Data analysis at Level-1 Trigger level

    CERN Document Server

    Wittmann, Johannes; Aradi, Gregor; Bergauer, Herbert; Jeitler, Manfred; Wulz, Claudia; Apanasevich, Leonard; Winer, Brian; Puigh, Darren Michael

    2017-01-01

    With ever increasing luminosity at the LHC, optimum online data selection is getting more and more important. While in the case of some experiments (LHCb and ALICE) this task is being completely transferred to computer farms, the others - ATLAS and CMS - will not be able to do this in the medium-term future for technological, detector-related reasons. Therefore, these experiments pursue the complementary approach of migrating more and more of the offline and High-Level Trigger intelligence into the trigger electronics. This paper illustrates how the Level-1 Trigger of the CMS experiment and in particular its concluding stage, the Global Trigger, take up this challenge.

  12. The Run-2 ATLAS Trigger System

    International Nuclear Information System (INIS)

    Martínez, A Ruiz

    2016-01-01

    The ATLAS trigger successfully collected collision data during the first run of the LHC between 2009-2013 at different centre-of-mass energies between 900 GeV and 8TeV. The trigger system consists of a hardware Level-1 and a software-based high level trigger (HLT) that reduces the event rate from the design bunch-crossing rate of 40 MHz to an average recording rate of a few hundred Hz. In Run-2, the LHC will operate at centre-of-mass energies of 13 and 14 TeV and higher luminosity, resulting in up to five times higher rates of processes of interest. A brief review of the ATLAS trigger system upgrades that were implemented between Run-1 and Run-2, allowing to cope with the increased trigger rates while maintaining or even improving the efficiency to select physics processes of interest, will be given. This includes changes to the Level-1 calorimeter and muon trigger systems, the introduction of a new Level-1 topological trigger module and the merging of the previously two-level HLT system into a single event processing farm. A few examples will be shown, such as the impressive performance improvements in the HLT trigger algorithms used to identify leptons, hadrons and global event quantities like missing transverse energy. Finally, the status of the commissioning of the trigger system and its performance during the 2015 run will be presented. (paper)

  13. Geometrical Acceptance Analysis for RPC PAC Trigger

    CERN Document Server

    Seo, Eunsung

    2010-01-01

    The CMS(Compact Muon Solenoid) is one of the four experiments that will analyze the collision results of the protons accelerated by the Large Hardron Collider(LHC) at CERN(Conseil Europen pour la Recherche Nuclaire). In case of the CMS experiment, the trigger system is divided into two stages : The Level-1 Trigger and High Level Trigger. The RPC(Resistive Plate Chamber) PAC(PAttern Comparator) Trigger system, which is a subject of this thesis, is a part of the Level-1 Muon Trigger System. Main task of the PAC Trigger is to identify muons, measures transverse momenta and select the best muon candidates for each proton bunch collision occurring every 25 ns. To calculate the value of PAC Trigger efficiency for triggerable muon, two terms of different efficiencies are needed ; acceptance efficiency and chamber efficiency. Main goal of the works described in this thesis is obtaining the acceptance efficiency of the PAC Trigger in each logical cone. Acceptance efficiency is a convolution of the chambers geometry an...

  14. Landslide triggering by rain infiltration

    Science.gov (United States)

    Iverson, Richard M.

    2000-01-01

    Landsliding in response to rainfall involves physical processes that operate on disparate timescales. Relationships between these timescales guide development of a mathematical model that uses reduced forms of Richards equation to evaluate effects of rainfall infiltration on landslide occurrence, timing, depth, and acceleration in diverse situations. The longest pertinent timescale is A/D0, where D0 is the maximum hydraulic diffusivity of the soil and A is the catchment area that potentially affects groundwater pressures at a prospective landslide slip surface location with areal coordinates x, y and depth H. Times greater than A/D0 are necessary for establishment of steady background water pressures that develop at (x, y, H) in response to rainfall averaged over periods that commonly range from days to many decades. These steady groundwater pressures influence the propensity for landsliding at (x, y, H), but they do not trigger slope failure. Failure results from rainfall over a typically shorter timescale H2/D0 associated with transient pore pressure transmission during and following storms. Commonly, this timescale ranges from minutes to months. The shortest timescale affecting landslide responses to rainfall is √(H/g), where g is the magnitude of gravitational acceleration. Postfailure landslide motion occurs on this timescale, which indicates that the thinnest landslides accelerate most quickly if all other factors are constant. Effects of hydrologic processes on landslide processes across these diverse timescales are encapsulated by a response function, R(t*) = √(t*/π) exp (-1/t*) - erfc (1/√t*), which depends only on normalized time, t*. Use of R(t*) in conjunction with topographic data, rainfall intensity and duration information, an infinite-slope failure criterion, and Newton's second law predicts the timing, depth, and acceleration of rainfall-triggered landslides. Data from contrasting landslides that exhibit rapid, shallow

  15. Specificity and kinetics of alpha-synuclein binding to model membranes determined with fluorescent excited state intramolecular proton transfer (ESIPT) probe.

    Science.gov (United States)

    Shvadchak, Volodymyr V; Falomir-Lockhart, Lisandro J; Yushchenko, Dmytro A; Jovin, Thomas M

    2011-04-15

    Parkinson disease is characterized cytopathologically by the deposition in the midbrain of aggregates composed primarily of the presynaptic neuronal protein α-synuclein (AS). Neurotoxicity is currently attributed to oligomeric microaggregates subjected to oxidative modification and promoting mitochondrial and proteasomal dysfunction. Unphysiological binding to membranes of these and other organelles is presumably involved. In this study, we performed a systematic determination of the influence of charge, phase, curvature, defects, and lipid unsaturation on AS binding to model membranes using a new sensitive solvatochromic fluorescent probe. The interaction of AS with vesicular membranes is fast and reversible. The protein dissociates from neutral membranes upon thermal transition to the liquid disordered phase and transfers to vesicles with higher affinity. The binding of AS to neutral and negatively charged membranes occurs by apparently different mechanisms. Interaction with neutral bilayers requires the presence of membrane defects; binding increases with membrane curvature and rigidity and decreases in the presence of cholesterol. The association with negatively charged membranes is much stronger and much less sensitive to membrane curvature, phase, and cholesterol content. The presence of unsaturated lipids increases binding in all cases. These findings provide insight into the relation between membrane physical properties and AS binding affinity and dynamics that presumably define protein localization in vivo and, thereby, the role of AS in the physiopathology of Parkinson disease.

  16. Reciprocal signals between microglia and neurons regulate alpha-synuclein secretion by exophagy through a neuronal cJU-N-Nterminal kinase-signaling axis

    DEFF Research Database (Denmark)

    Christensen, Dan Ploug; Ejlerskov, Patrick; Rasmussen, Izabela

    2016-01-01

    implicate stress kinases of the JNK family in the regulation of exophagy and release of alpha-SNC following endogenous or exogenous stimulation. In a wider scope, our results imply that microglia not only inflict bystander damage to neurons in late phases of inflammatory brain disease but may also be active...

  17. Double-stranded DNA Stimulates the Fibrillation of alpha-Synuclein in vitro and is Associated with the Mature Fibrils: An Electron Microscopy Study

    NARCIS (Netherlands)

    Cherny, Dmitry; Hoyer, Wolfgang; Subramaniam, Vinod; Jovin, Thomas M.

    2004-01-01

    Filamentous aggregates formed by α-synuclein are a prominent and presumably key etiological factor in Parkinson's and other neurodegenerative diseases characterized by motor disorders. Numerous studies have demonstrated that various environmental and intracellular factors affect the fibrillation

  18. Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

    Directory of Open Access Journals (Sweden)

    Luisel R Lemkau

    Full Text Available Parkinson's disease (PD is pathologically characterized by the presence of Lewy bodies (LBs in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS, a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.

  19. Nonlinear dynamical triggering of slow slip

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Paul A [Los Alamos National Laboratory; Knuth, Matthew W [WISCONSIN; Kaproth, Bryan M [PENN STATE; Carpenter, Brett [PENN STATE; Guyer, Robert A [Los Alamos National Laboratory; Le Bas, Pierre - Yves [Los Alamos National Laboratory; Daub, Eric G [Los Alamos National Laboratory; Marone, Chris [PENN STATE

    2010-12-10

    Among the most fascinating, recent discoveries in seismology have been the phenomena of triggered slip, including triggered earthquakes and triggered-tremor, as well as triggered slow, silent-slip during which no seismic energy is radiated. Because fault nucleation depths cannot be probed directly, the physical regimes in which these phenomena occur are poorly understood. Thus determining physical properties that control diverse types of triggered fault sliding and what frictional constitutive laws govern triggered faulting variability is challenging. We are characterizing the physical controls of triggered faulting with the goal of developing constitutive relations by conducting laboratory and numerical modeling experiments in sheared granular media at varying load conditions. In order to simulate granular fault zone gouge in the laboratory, glass beads are sheared in a double-direct configuration under constant normal stress, while subject to transient perturbation by acoustic waves. We find that triggered, slow, silent-slip occurs at very small confining loads ({approx}1-3 MPa) that are smaller than those where dynamic earthquake triggering takes place (4-7 MPa), and that triggered slow-slip is associated with bursts of LFE-like acoustic emission. Experimental evidence suggests that the nonlinear dynamical response of the gouge material induced by dynamic waves may be responsible for the triggered slip behavior: the slip-duration, stress-drop and along-strike slip displacement are proportional to the triggering wave amplitude. Further, we observe a shear-modulus decrease corresponding to dynamic-wave triggering relative to the shear modulus of stick-slips. Modulus decrease in response to dynamical wave amplitudes of roughly a microstrain and above is a hallmark of elastic nonlinear behavior. We believe that the dynamical waves increase the material non-affine elastic deformation during shearing, simultaneously leading to instability and slow-slip. The inferred

  20. The trigger supervisor: Managing triggering conditions in a high energy physics experiment

    International Nuclear Information System (INIS)

    Wadsworth, B.; Lanza, R.; LeVine, M.J.; Scheetz, R.A.; Videbaek, F.

    1987-01-01

    A trigger supervisor, implemented in VME-bus hardware, is described, which enables the host computer to dynamically control and monitor the trigger configuration for acquiring data from multiple detector partitions in a complex experiment

  1. Tools for Trigger Aware Analyses in ATLAS

    CERN Document Server

    Krasznahorkay, A; The ATLAS collaboration; Stelzer, J

    2010-01-01

    In order to search for rare processes, all four LHC experiments have to use advanced triggering methods for selecting and recording the events of interest. At the expected nominal LHC operating conditions only about 0.0005% of the collision events can be kept for physics analysis in ATLAS. Therefore the understanding and evaluation of the trigger performance is one of the most crucial parts of any physics analysis. ATLAS’s first level trigger is composed of custom-built hardware, while the second and third levels are implemented using regular PCs running reconstruction and selection algorithms. Because of this split, accessing the results of the trigger execution for the two stages is different. The complexity of the software trigger presents further difficulties in accessing the trigger data. To make the job of the physicists easier when evaluating the trigger performance, multiple general-use tools are provided by the ATLAS Trigger Analysis Tools group. The TrigDecisionTool, a general tool, is provided to...

  2. The Run-2 ATLAS Trigger System

    CERN Document Server

    Ruiz-Martinez, Aranzazu; The ATLAS collaboration

    2016-01-01

    The ATLAS trigger has been successfully collecting collision data during the first run of the LHC between 2009-2013 at a centre-of-mass energy between 900 GeV and 8 TeV. The trigger system consists of a hardware Level-1 (L1) and a software based high-level trigger (HLT) that reduces the event rate from the design bunch-crossing rate of 40 MHz to an average recording rate of a few hundred Hz. In Run-2, the LHC will operate at centre-of-mass energies of 13 and 14 TeV resulting in roughly five times higher trigger rates. We will briefly review the ATLAS trigger system upgrades that were implemented during the shutdown, allowing us to cope with the increased trigger rates while maintaining or even improving our efficiency to select relevant physics processes. This includes changes to the L1 calorimeter and muon trigger systems, the introduction of a new L1 topological trigger module and the merging of the previously two-level HLT system into a single event filter farm. At hand of a few examples, we will show the ...

  3. The Run-2 ATLAS Trigger System

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00222798; The ATLAS collaboration

    2016-01-01

    The ATLAS trigger successfully collected collision data during the first run of the LHC between 2009-2013 at different centre-of-mass energies between 900 GeV and 8 TeV. The trigger system consists of a hardware Level-1 and a software-based high level trigger (HLT) that reduces the event rate from the design bunch-crossing rate of 40 MHz to an average recording rate of a few hundred Hz. In Run-2, the LHC will operate at centre-of-mass energies of 13 and 14 TeV and higher luminosity, resulting in roughly five times higher trigger rates. A brief review of the ATLAS trigger system upgrades that were implemented between Run-1 and Run-2, allowing to cope with the increased trigger rates while maintaining or even improving the efficiency to select physics processes of interest, will be given. This includes changes to the Level-1 calorimeter and muon trigger systems, the introduction of a new Level-1 topological trigger module and the merging of the previously two-level HLT system into a single event filter farm. A ...

  4. Intelligent trigger processor for the crystal box

    International Nuclear Information System (INIS)

    Sanders, G.H.; Butler, H.S.; Cooper, M.D.

    1981-01-01

    A large solid angle modular NaI(Tl) detector with 432 phototubes and 88 trigger scintillators is being used to search simultaneously for three lepton flavor changing decays of muon. A beam of up to 10 6 muons stopping per second with a 6% duty factor would yield up to 1000 triggers per second from random triple coincidences. A reduction of the trigger rate to 10 Hz is required from a hardwired primary trigger processor described in this paper. Further reduction to < 1 Hz is achieved by a microprocessor based secondary trigger processor. The primary trigger hardware imposes voter coincidence logic, stringent timing requirements, and a non-adjacency requirement in the trigger scintillators defined by hardwired circuits. Sophisticated geometric requirements are imposed by a PROM-based matrix logic, and energy and vector-momentum cuts are imposed by a hardwired processor using LSI flash ADC's and digital arithmetic loci. The secondary trigger employs four satellite microprocessors to do a sparse data scan, multiplex the data acquisition channels and apply additional event filtering

  5. Trigger factors for familial hemiplegic migraine

    DEFF Research Database (Denmark)

    Hansen, Jakob Møller; Hauge, Anne Werner; Ashina, Messoud

    2011-01-01

    The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample.......The aim was to identify and describe migraine trigger factors in patients with familial hemiplegic migraine (FHM) from a population-based sample....

  6. The ATLAS Level-1 Topological Trigger Performance

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00371751; The ATLAS collaboration

    2016-01-01

    The LHC will collide protons in the ATLAS detector with increasing luminosity through 2016, placing stringent operational and physical requirements to the ATLAS trigger system in order to reduce the 40 MHz collision rate to a manageable event storage rate of 1 kHz, while not rejecting interesting physics events. The Level-1 trigger is the first rate-reducing step in the ATLAS trigger system with an output rate of 100 kHz and decision latency smaller than 2.5 μs. It consists of a calorimeter trigger, muon trigger and a central trigger processor. During the LHC shutdown after the Run 1 finished in 2013, the Level-1 trigger system was upgraded including hardware, firmware and software updates. In particular, new electronics modules were introduced in the real-time data processing path: the Topological Processor System (L1Topo). It consists of a single AdvancedCTA shelf equipped with two Level-1 topological processor blades. They receive real-time information from the Level-1 calorimeter and muon triggers, which...

  7. Do episodes of anger trigger myocardial infarction?

    DEFF Research Database (Denmark)

    Möller, J; Hallqvist, J; Diderichsen, Finn

    1999-01-01

    Our objectives were to study anger as a trigger of acute myocardial infarction (MI) and to explore potential effect modification by usual behavioral patterns related to hostility.......Our objectives were to study anger as a trigger of acute myocardial infarction (MI) and to explore potential effect modification by usual behavioral patterns related to hostility....

  8. Triggering soft bombs at the LHC

    Science.gov (United States)

    Knapen, Simon; Griso, Simone Pagan; Papucci, Michele; Robinson, Dean J.

    2017-08-01

    Very high multiplicity, spherically-symmetric distributions of soft particles, with p T ˜ few×100 MeV, may be a signature of strongly-coupled hidden valleys that exhibit long, efficient showering windows. With traditional triggers, such `soft bomb' events closely resemble pile-up and are therefore only recorded with minimum bias triggers at a very low efficiency. We demonstrate a proof-of-concept for a high-level triggering strategy that efficiently separates soft bombs from pile-up by searching for a `belt of fire': a high density band of hits on the innermost layer of the tracker. Seeding our proposed high-level trigger with existing jet, missing transverse energy or lepton hardware-level triggers, we show that net trigger efficiencies of order 10% are possible for bombs of mass several × 100 GeV. We also consider the special case that soft bombs are the result of an exotic decay of the 125 GeV Higgs. The fiducial rate for `Higgs bombs' triggered in this manner is marginally higher than the rate achievable by triggering directly on a hard muon from associated Higgs production.

  9. The LVL2 trigger goes online

    CERN Multimedia

    David Berge

    On Friday, the 9th of February, the ATLAS TDAQ community reached an important milestone. In a successful integration test, cosmic-ray muons were recorded with parts of the muon spectrometer, the central-trigger system and a second-level trigger algorithm. This was actually the first time that a full trigger slice all the way from the first-level trigger muon chambers up to event building after event selection by the second-level trigger ran online with cosmic rays. The ATLAS trigger and data acquisition system has a three-tier structure that is designed to cope with the enormous demands of proton-proton collisions at a bunch-crossing frequency of 40 MHz, with a typical event size of 1-2 MB. The online event selection has to reduce the incoming rate by a factor of roughly 200,000 to 200 Hz, a rate digestible by the archival-storage and offline-processing facilities. ATLAS has a mixed system: the first-level trigger (LVL1) is in hardware, while the other two consecutive levels, the second-level trigger (LVL2)...

  10. Reliability model analysis and primary experimental evaluation of laser triggered pulse trigger

    International Nuclear Information System (INIS)

    Chen Debiao; Yang Xinglin; Li Yuan; Li Jin

    2012-01-01

    High performance pulse trigger can enhance performance and stability of the PPS. It is necessary to evaluate the reliability of the LTGS pulse trigger, so we establish the reliability analysis model of this pulse trigger based on CARMES software, the reliability evaluation is accord with the statistical results. (authors)

  11. A general-purpose trigger processor system and its application to fast vertex trigger

    International Nuclear Information System (INIS)

    Hazumi, M.; Banas, E.; Natkaniec, Z.; Ostrowicz, W.

    1997-12-01

    A general-purpose hardware trigger system has been developed. The system comprises programmable trigger processors and pattern generator/samplers. The hardware design of the system is described. An application as a prototype of the very fast vertex trigger in an asymmetric B-factory at KEK is also explained. (author)

  12. The ATLAS Level-1 Trigger Timing Setup

    CERN Document Server

    Spiwoks, R; Ellis, Nick; Farthouat, P; Gällnö, P; Haller, J; Krasznahorkay, A; Maeno, T; Pauly, T; Pessoa-Lima, H; Resurreccion-Arcas, I; Schuler, G; De Seixas, J M; Torga-Teixeira, R; Wengler, T

    2005-01-01

    The ATLAS detector at CERN's LHC will be exposed to proton-proton collisions at a bunch-crossing rate of 40 MHz. In order to reduce the data rate, a three-level trigger system selects potentially interesting physics. The first trigger level is implemented in electronics and firmware. It aims at reducing the output rate to less than 100 kHz. The Central Trigger Processor combines information from the calorimeter and muon trigger processors and makes the final Level-1-Accept decision. It is a central element in the timing setup of the experiment. Three aspects are considered in this article: the timing setup with respect to the Level-1 trigger, with respect to the expriment, and with respect to the world.

  13. MR imaging findings of trigger thumb

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Eric Y.; Chen, Karen C.; Chung, Christine B. [VA San Diego Healthcare System, Radiology Service, San Diego, CA (United States); University of California, San Diego Medical Center, Department of Radiology, San Diego, CA (United States)

    2015-08-15

    Trigger finger (or trigger thumb), also known as sclerosing tenosynovitis, is a common clinical diagnosis that rarely presents for imaging. Because of this selection bias, many radiologists may not be familiar with the process. Furthermore, patients who do present for imaging frequently have misleading examination indications. To our knowledge, magnetic resonance (MR) imaging findings of trigger thumb have not been previously reported in the literature. In this article, we review the entity of trigger thumb, the anatomy involved, and associated imaging findings, which include flexor pollicis longus tendinosis with a distinct nodule, A1 pulley thickening, and tenosynovitis. In addition, in some cases, an abnormal Av pulley is apparent. In the rare cases of trigger finger that present for MR imaging, accurate diagnosis by the radiologist can allow initiation of treatment and avoid further unnecessary workup. (orig.)

  14. MR imaging findings of trigger thumb

    International Nuclear Information System (INIS)

    Chang, Eric Y.; Chen, Karen C.; Chung, Christine B.

    2015-01-01

    Trigger finger (or trigger thumb), also known as sclerosing tenosynovitis, is a common clinical diagnosis that rarely presents for imaging. Because of this selection bias, many radiologists may not be familiar with the process. Furthermore, patients who do present for imaging frequently have misleading examination indications. To our knowledge, magnetic resonance (MR) imaging findings of trigger thumb have not been previously reported in the literature. In this article, we review the entity of trigger thumb, the anatomy involved, and associated imaging findings, which include flexor pollicis longus tendinosis with a distinct nodule, A1 pulley thickening, and tenosynovitis. In addition, in some cases, an abnormal Av pulley is apparent. In the rare cases of trigger finger that present for MR imaging, accurate diagnosis by the radiologist can allow initiation of treatment and avoid further unnecessary workup. (orig.)

  15. Pulse triggering mechanism of air proportional counters

    International Nuclear Information System (INIS)

    Aoyama, T.; Mori, T.; Watanabe, T.

    1983-01-01

    This paper describes the pulse triggering mechanism of a cylindrical proportional counter filled with air at atmospheric pressure for the incidence of β-rays. Experimental results indicate that primary electrons created distantly from the anode wire by a β-ray are transformed into negative ions, which then detach electrons close to the anode wire and generate electron avalanches thus triggering pulses, while electrons created near the anode wire by a β-ray directly trigger a pulse. Since a negative ion pulse is triggered by a single electron detached from a negative ion, multiple pulses are generated by a large number of ions produced by the incidence of a single β-ray. It is therefore necessary not to count pulses triggered by negative ions but to count those by primary electrons alone when use is made of air proportional counters for the detection of β-rays. (orig.)

  16. Concept of the CMS Trigger Supervisor

    CERN Document Server

    Magrans de Abril, Ildefons; Varela, Joao

    2006-01-01

    The Trigger Supervisor is an online software system designed for the CMS experiment at CERN. Its purpose is to provide a framework to set up, test, operate and monitor the trigger components on one hand and to manage their interplay and the information exchange with the run control part of the data acquisition system on the other. The Trigger Supervisor is conceived to provide a simple and homogeneous client interface to the online software infrastructure of the trigger subsystems. This document specifies the functional and non-functional requirements, design and operational details, and the components that will be delivered in order to facilitate a smooth integration of the trigger software in the context of CMS.

  17. Alimentary triggers of hormone dependent breast cancers

    Directory of Open Access Journals (Sweden)

    T. Y. Lykholat

    2014-04-01

    Full Text Available Breast cancer (BC consistently holds the leading positions in the structure of morbidity and mortality of the female population. Food containing veterinary hormones is extremely dangerous to human health: estrogens are female sex hormones. Excessive level of estrogen in the body gives rise to diseases of varying severity: in women (especially of older age it may cause breast cancer. The paper investigates the processes of lipid peroxidation and the status of antioxidant protection system in rats of different ages exposed to exogenous estrogens. The purpose of the work is to study lipid peroxidation and antioxidative protection status in rats of different ages exposed to exogenous estrogens for determining the trigger mechanisms for tumor development. Experiments were conducted on female Wistar rats exposed to exogenous estrogen for 45 days. At the beginning of the experiment, age of experimental animals was 3 months in pubertal period and 6 months as mature ones. The control groups consisted of intact animals of appropriate age. To simulate the influence of exogenous estrogen, rats’ food was treated with the Sinestron drug at the rate of 2 mg per kg. The research materials were serum and liver of rats. Objects of the research were indicators of lipid peroxidation activity (content of TBA-active products and antioxidant protection system (reduced glutathione (RG level, glutathione transferase (GT, glutathione reductase (GR, glutathione peroxidase (GP, superoxide dismutase (SOD activity, and total antioxidative activity (AOA. Data obtained was treated with standard methods of estimation of variation series. Various degrees of peroxidation intensification depending on the age and organs were determined. Maximum excess of control indexes in the serum was observed and it indicated synthetic estrogen effect of on all major body systems. In prepubertal period females’ liver the reaction of prooxidant system and tension in the antioxidant

  18. Designing signal-enriched triggers for boosted jets.

    CERN Document Server

    Toumazou, Marina

    2017-01-01

    Triggers designed to favour the selection of hadronically decaying massive particles have been studied. Both triggers using solely ET and mass cuts (similar to new 2017 triggers) and triggers exploiting polarization information have been studied. The mass cut triggers show substantial gains in rate reduction, while the benefits of polarization triggers are less obvious. The final conclusion is that it is more useful to identify and trigger on generic boosted decays, irrespective of the polarization of the decaying particle

  19. The ATLAS Electron and Photon Trigger

    CERN Document Server

    Jones, Samuel David; The ATLAS collaboration

    2017-01-01

    Electron and photon triggers covering transverse energies from 5 GeV to several TeV are essential for signal selection in a wide variety of ATLAS physics analyses to study Standard Model processes and to search for new phenomena. Final states including leptons and photons had, for example, an important role in the discovery and measurement of the Higgs boson. Dedicated triggers are also used to collect data for calibration, efficiency and fake rate measurements. The ATLAS trigger system is divided in a hardware-based Level-1 trigger and a software-based high-level trigger, both of which were upgraded during the LHC shutdown in preparation for Run-2 operation. To cope with the increasing luminosity and more challenging pile-up conditions at a center-of-mass energy of 13 TeV, the trigger selections at each level are optimized to control the rates and keep efficiencies high. To achieve this goal multivariate analysis techniques are used. The ATLAS electron and photon triggers and their performance with Run 2 dat...

  20. The ATLAS Electron and Photon Trigger

    CERN Document Server

    Jones, Samuel David; The ATLAS collaboration

    2018-01-01

    Electron and photon triggers covering transverse energies from 5 GeV to several TeV are essential for signal selection in a wide variety of ATLAS physics analyses to study Standard Model processes and to search for new phenomena. Final states including leptons and photons had, for example, an important role in the discovery and measurement of the Higgs boson. Dedicated triggers are also used to collect data for calibration, efficiency and fake rate measurements. The ATLAS trigger system is divided in a hardware-based Level-1 trigger and a software-based high-level trigger, both of which were upgraded during the LHC shutdown in preparation for Run-2 operation. To cope with the increasing luminosity and more challenging pile-up conditions at a center-of-mass energy of 13 TeV, the trigger selections at each level are optimized to control the rates and keep efficiencies high. To achieve this goal multivariate analysis techniques are used. The ATLAS electron and photon triggers and their performance with Run 2 dat...

  1. Upgrade of the CMS Global Muon Trigger

    CERN Document Server

    Jeitler, Manfred; Rabady, Dinyar; Sakulin, Hannes; Stahl, Achim

    2015-01-01

    The increase in center-of-mass energy and luminosity for Run-II of the Large Hadron Collider poses new challenges for the trigger systems of the experiments. To keep triggering with a similar performance as in Run-I, the CMS muon trigger is currently being upgraded. The new algorithms will provide higher resolution, especially for the muon transverse momentum and will make use of isolation criteria that combine calorimeter with muon information already in the level-1 trigger. The demands of the new algorithms can only be met by upgrading the level-1 trigger system to new powerful FPGAs with high bandwidth I/O. The processing boards will be based on the new μTCA standard. We report on the planned algorithms for the upgraded Global Muon Trigger (μGMT) which sorts and removes duplicates from boundaries of the muon trigger sub-systems. Furthermore, it determines how isolated the muon candidates are based on calorimetric energy deposits. The μGMT will be implemented using a processing board that features a larg...

  2. Upgrade of the CMS Global Muon Trigger

    CERN Document Server

    Lingemann, Joschka; Sakulin, Hannes; Jeitler, Manfred; Stahl, Achim

    2015-01-01

    The increase in center-of-mass energy and luminosity for Run 2 of the Large Hadron Collider pose new challenges for the trigger systems of the experiments. To keep triggering with a similar performance as in Run 1, the CMS muon trigger is currently being upgraded. The new algorithms will provide higher resolution, especially for the muon transverse momentum and will make use of isolation criteria that combine calorimeter with muon information already in the level-1 trigger. The demands of the new algorithms can only be met by upgrading the level-1 trigger system to new powerful FPGAs with high bandwidth I/O. The processing boards will be based on the new microTCA standard. We report on the planned algorithms for the upgraded Global Muon Trigger (GMT) which combines information from the muon trigger sub-systems and assigns the isolation variable. The upgraded GMT will be implemented using a Master Processor 7 card, built by Imperial College, that features a large Xilinx Virtex 7 FPGA. Up to 72 optical links at...

  3. The ZEUS calorimeter first level trigger

    International Nuclear Information System (INIS)

    Smith, W.H.; Ali, I.; Behrens, B.; Fordham, C.; Foudas, C.; Goussiou, A.; Jaworski, M.; Kinnel, T.; Lackey, J.; Robl, P.; Silverstein, S.; Dawson, J.W.; Krakauer, D.A.; Talaga, R.L.; Schlereth, J.L.

    1994-10-01

    The design of the ZEUS Calorimeter First Level Trigger (CFLT) is presented. The CFLT utilizes a pipelined architecture to provide trigger data for a global first leel trigger decision 5 μsec after each beam crossing, occurring every 96 nsec. The charges from 13K phototubes are summed into 1792 trigger tower pulseheights which are digitized by flash ADC's. The digital values are linearized, stored and used for sums and pattern tests. Summary data is forwarded to the Global First Level Trigger for each crossing 2 μsec after the crossing occurred. The CFLT determines the total energy, the total transverse energy, the missing energy, and the energy and number of isolated electrons and muons. It also provides information on the electromagnetic and hadronic energy deposited in various regions of the calorimeter. The CFLT has kept the experimental trigger rate below ∼200 Hz at the highest luminosity experienced at HERA. Performance studies suggest that the CFLT will keep the trigger rate below 1 kHZ against a rate of proton-beam gas interactions on the order of the 100 kHz expected at design luminosity. (orig.)

  4. The D0 run II trigger system

    International Nuclear Information System (INIS)

    Schwienhorst, Reinhard; Michigan State U.

    2004-01-01

    The D0 detector at the Fermilab Tevatron was upgraded for Run II. This upgrade included improvements to the trigger system in order to be able to handle the increased Tevatron luminosity and higher bunch crossing rates compared to Run I. The D0 Run II trigger is a highly exible system to select events to be written to tape from an initial interaction rate of about 2.5 MHz. This is done in a three-tier pipelined, buffered system. The first tier (level 1) processes fast detector pick-off signals in a hardware/firmware based system to reduce the event rate to about 1. 5kHz. The second tier (level 2) uses information from level 1 and forms simple Physics objects to reduce the rate to about 850 Hz. The third tier (level 3) uses full detector readout and event reconstruction on a filter farm to reduce the rate to 20-30 Hz. The D0 trigger menu contains a wide variety of triggers. While the emphasis is on triggering on generic lepton and jet final states, there are also trigger terms for specific final state signatures. In this document we describe the D0 trigger system as it was implemented and is currently operating in Run II

  5. Conjugated Bilirubin Triggers Anemia by Inducing Erythrocyte Death

    Science.gov (United States)

    Lang, Elisabeth; Gatidis, Sergios; Freise, Noemi F; Bock, Hans; Kubitz, Ralf; Lauermann, Christian; Orth, Hans Martin; Klindt, Caroline; Schuier, Maximilian; Keitel, Verena; Reich, Maria; Liu, Guilai; Schmidt, Sebastian; Xu, Haifeng C; Qadri, Syed M; Herebian, Diran; Pandyra, Aleksandra A; Mayatepek, Ertan; Gulbins, Erich; Lang, Florian; Häussinger, Dieter; Lang, Karl S; Föller, Michael; Lang, Philipp A

    2015-01-01

    Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca2+ influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. Conclusion: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease. (Hepatology 2015;61:275–284) PMID:25065608

  6. ATLAS: triggers for B-physics

    International Nuclear Information System (INIS)

    George, Simon

    2000-01-01

    The LHC will produce bb-bar events at an unprecedented rate. The number of events recorded by ATLAS will be limited by the rate at which they can be stored offline and subsequently analysed. Despite the huge number of events, the small branching ratios mean that analysis of many of the most interesting channels for CP violation and other measurements will be limited by statistics. The challenge for the Trigger and Data Acquisition (DAQ) system is therefore to maximise the fraction of interesting B decays in the B-physics data stream. The ATLAS Trigger/DAQ system is split into three levels. The initial B-physics selection is made in the first-level trigger by an inclusive low-p T muon trigger (∼6 GeV). The second-level trigger strategy is based on identifying classes of final states by their partial reconstruction. The muon trigger is confirmed before proceeding to a track search. Electron/hadron separation is given by the transition radiation tracking detector and the Electromagnetic calorimeter. Muon identification is possible using the muon detectors and the hadronic calorimeter. From silicon strips, pixels and straw tracking, precise track reconstruction is used to make selections based on invariant mass, momentum and impact parameter. The ATLAS trigger group is currently engaged in algorithm development and performance optimisation for the B-physics trigger. This is closely coupled to the R and D programme for the higher-level triggers. Together the two programmes of work will optimise the hardware, architecture and algorithms to meet the challenging requirements. This paper describes the current status and progress of this work

  7. Trigger tracking for the LHCb upgrade

    CERN Multimedia

    Dungs, K

    2014-01-01

    This poster presents a trigger system for the upgraded LHCb detector, scheduled to begin operation in 2020. The proposed trigger system is implemented entirely in software. We show that track reconstruction of a similar quality to that available in the offline algorithms can be performed on the full inelastic pp-collision rate. A track finding efficiency of 98.8% relative to offline can be achieved for good trigger tracks. The CPU time required for this reconstruction is less than 60% of the available budget.

  8. The CMS Barrel Muon trigger upgrade

    International Nuclear Information System (INIS)

    Triossi, A.; Sphicas, P.; Bellato, M.; Montecassiano, F.; Ventura, S.; Ruiz, J.M. Cela; Bedoya, C. Fernandez; Tobar, A. Navarro; Fernandez, I. Redondo; Ferrero, D. Redondo; Sastre, J.; Ero, J.; Wulz, C.; Flouris, G.; Foudas, C.; Loukas, N.; Mallios, S.; Paradas, E.; Guiducci, L.; Masetti, G.

    2017-01-01

    The increase of luminosity expected by LHC during Phase1 will impose tighter constraints for rate reduction in order to maintain high efficiency in the CMS Level1 trigger system. The TwinMux system is the early layer of the muon barrel region that concentrates the information from different subdetectors: Drift Tubes, Resistive Plate Chambers and Outer Hadron Calorimeter. It arranges the slow optical trigger links from the detector chambers into faster links (10 Gbps) that are sent in multiple copies to the track finders. Results from collision runs, that confirm the satisfactory operation of the trigger system up to the output of the barrel track finder, will be shown.

  9. Event-triggered attitude control of spacecraft

    Science.gov (United States)

    Wu, Baolin; Shen, Qiang; Cao, Xibin

    2018-02-01

    The problem of spacecraft attitude stabilization control system with limited communication and external disturbances is investigated based on an event-triggered control scheme. In the proposed scheme, information of attitude and control torque only need to be transmitted at some discrete triggered times when a defined measurement error exceeds a state-dependent threshold. The proposed control scheme not only guarantees that spacecraft attitude control errors converge toward a small invariant set containing the origin, but also ensures that there is no accumulation of triggering instants. The performance of the proposed control scheme is demonstrated through numerical simulation.

  10. Electronic trigger for the ASP experiment

    International Nuclear Information System (INIS)

    Wilson, R.J.

    1985-11-01

    The Anomalous Single Photon (ASP) electronic trigger is described. The experiments is based on an electromagnetic calorimeter composed of arrays of lead glass blocks, read out with photo-multiplier tubes, surrounding the interaction point at the PEP storage ring. The primary requirement of the trigger system is to be sensitive to low energy (approx. =0.5 GeV and above) photons whilst discriminating against high backgrounds at PEP. Analogue summing of the PMT signals and a sequence of programmable digital look-up tables produces a ''dead-timeless'' trigger for the beam collision rate of 408 kHz. 6 refs., 6 figs

  11. The LHCb trigger in Run II

    CERN Document Server

    Michielin, Emanuele

    2016-01-01

    The LHCb trigger system has been upgraded to allow alignment, calibration and physics analysis to be performed in real time. An increased CPU capacity and improvements in the software have allowed lifetime unbiased selections of beauty and charm decays in the high level trigger. Thanks to offline quality event reconstruction already available online, physics analyses can be performed directly on this information and for the majority of charm physics selections a reduced event format can be written out. Beauty hadron decays are more efficiently triggered by re-optimised inclusive selections, and the HLT2 output event rate is increased by a factor of three.

  12. American cutaneous leishmaniasis triggered byelectrocoagulation

    Directory of Open Access Journals (Sweden)

    Sofia Sales Martins

    Full Text Available Abstract Cutaneous leishmaniasis is usually transmitted by infected phlebotomine sand fly bites that initiate local cutaneous lesions. Few reports in the literature describe other modes of transmission. We report a case of a previously healthy 59-year-old woman who underwent electrocoagulation to remove seborrheic keratosis confirmed by dermatoscopy. Three months later, a skin fragment tested positive for Leishmania culture; the parasite was identified as L. (V. braziliensis. Trauma may generate inflammatory cascades that favor Leishmania growth and lesion formation in previously infected patients. American cutaneous leishmaniasis is a dynamic disease with unclear pathophysiology because of continually changing environments, demographics, and human behaviors.

  13. The Trigger Processor and Trigger Processor Algorithms for the ATLAS New Small Wheel Upgrade

    CERN Document Server

    Lazovich, Tomo; The ATLAS collaboration

    2015-01-01

    The ATLAS New Small Wheel (NSW) is an upgrade to the ATLAS muon endcap detectors that will be installed during the next long shutdown of the LHC. Comprising both MicroMegas (MMs) and small-strip Thin Gap Chambers (sTGCs), this system will drastically improve the performance of the muon system in a high cavern background environment. The NSW trigger, in particular, will significantly reduce the rate of fake triggers coming from track segments in the endcap not originating from the interaction point. We will present an overview of the trigger, the proposed sTGC and MM trigger algorithms, and the hardware implementation of the trigger. In particular, we will discuss both the heart of the trigger, an ATCA system with FPGA-based trigger processors (using the same hardware platform for both MM and sTGC triggers), as well as the full trigger electronics chain, including dedicated cards for transmission of data via GBT optical links. Finally, we will detail the challenges of ensuring that the trigger electronics can ...

  14. Triggered creep as a possible mechanism for delayed dynamic triggering of tremor and earthquakes

    Science.gov (United States)

    Shelly, David R.; Peng, Zhigang; Hill, David P.; Aiken, Chastity

    2011-01-01

    The passage of radiating seismic waves generates transient stresses in the Earth's crust that can trigger slip on faults far away from the original earthquake source. The triggered fault slip is detectable in the form of earthquakes and seismic tremor. However, the significance of these triggered events remains controversial, in part because they often occur with some delay, long after the triggering stress has passed. Here we scrutinize the location and timing of tremor on the San Andreas fault between 2001 and 2010 in relation to distant earthquakes. We observe tremor on the San Andreas fault that is initiated by passing seismic waves, yet migrates along the fault at a much slower velocity than the radiating seismic waves. We suggest that the migrating tremor records triggered slow slip of the San Andreas fault as a propagating creep event. We find that the triggered tremor and fault creep can be initiated by distant earthquakes as small as magnitude 5.4 and can persist for several days after the seismic waves have passed. Our observations of prolonged tremor activity provide a clear example of the delayed dynamic triggering of seismic events. Fault creep has been shown to trigger earthquakes, and we therefore suggest that the dynamic triggering of prolonged fault creep could provide a mechanism for the delayed triggering of earthquakes. ?? 2011 Macmillan Publishers Limited. All rights reserved.

  15. The second level trigger system of FAST

    CERN Document Server

    Martínez,G; Berdugo, J; Casaus, J; Casella, V; De Laere, D; Deiters, K; Dick, P; Kirkby, J; Malgeri, L; Mañá, C; Marín, J; Pohl, M; Petitjean, C; Sánchez, E; Willmott, C

    2009-01-01

    The Fibre Active Scintillator Target (FAST) experiment is a novel imaging particle detector currently operating in a high-intensity π+ beam at the Paul Scherrer Institute (PSI), Villigen, Switzerland. The detector is designed to perform a high precision measurement of the μ+ lifetime, in order to determine the Fermi constant, Gf, to 1 ppm precision. A dedicated second level (LV2) hardware trigger system has been developed for the experiment. It performs an online analysis of the π/μ decay chain by identifying the stopping position of each beam particle and detecting the subsequent appearance of the muon. The LV2 trigger then records the muon stop pixel and selectively triggers the Time-to-Digital Converters (TDCs) in the vicinity. A detailed description of the trigger system is presented in this paper.

  16. The second level trigger system of FAST

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, G. [CIEMAT, Avenida Complutense 22, 28040 Madrid (Spain)], E-mail: gustavo.martinez@ciemat.es; Barcyzk, A. [CERN, CH-1211 Geneva 23 (Switzerland); Berdugo, J.; Casaus, J. [CIEMAT, Avenida Complutense 22, 28040 Madrid (Spain); Casella, C.; De Laere, S. [Universite de Geneve, 30 quai Ernest-Anserment, CH-1211 Geneva 4 (Switzerland); Deiters, K.; Dick, P. [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Kirkby, J.; Malgeri, L. [CERN, CH-1211 Geneva 23 (Switzerland); Mana, C.; Marin, J. [CIEMAT, Avenida Complutense 22, 28040 Madrid (Spain); Pohl, M. [Universite de Geneve, 30 quai Ernest-Anserment, CH-1211 Geneva 4 (Switzerland); Petitjean, C. [Paul Scherrer Institut, 5232 Villigen PSI (Switzerland); Sanchez, E.; Willmott, C. [CIEMAT, Avenida Complutense 22, 28040 Madrid (Spain)

    2009-10-11

    The Fibre Active Scintillator Target (FAST) experiment is a novel imaging particle detector currently operating in a high-intensity {pi}{sup +} beam at the Paul Scherrer Institute (PSI), Villigen, Switzerland. The detector is designed to perform a high precision measurement of the {mu}{sup +} lifetime, in order to determine the Fermi constant, G{sub f}, to 1 ppm precision. A dedicated second level (LV2) hardware trigger system has been developed for the experiment. It performs an online analysis of the {pi}/{mu} decay chain by identifying the stopping position of each beam particle and detecting the subsequent appearance of the muon. The LV2 trigger then records the muon stop pixel and selectively triggers the Time-to-Digital Converters (TDCs) in the vicinity. A detailed description of the trigger system is presented in this paper.

  17. SSC physics signatures and trigger requirements

    International Nuclear Information System (INIS)

    1985-01-01

    Strategies are considered for triggering on new physics processes on the environment of the SSC, where interaction rates will be very high and most new physics processes quite rare. The quantities available for use in the trigger at various levels are related to the signatures of possible new physics. Two examples were investigated in some detail using the ISAJET Monte Carlo program: Higgs decays to W pairs and a missing energy trigger applied to gluino pair production. In both of the examples studied in detail, it was found that workable strategies for reducing the trigger rate were obtainable which also produced acceptable efficiency for the processes of interest. In future work, it will be necessary to carry out such a program for the full spectrum of suggested new physics

  18. Graphics Processing Units for HEP trigger systems

    International Nuclear Information System (INIS)

    Ammendola, R.; Bauce, M.; Biagioni, A.; Chiozzi, S.; Cotta Ramusino, A.; Fantechi, R.; Fiorini, M.; Giagu, S.; Gianoli, A.; Lamanna, G.; Lonardo, A.; Messina, A.

    2016-01-01

    General-purpose computing on GPUs (Graphics Processing Units) is emerging as a new paradigm in several fields of science, although so far applications have been tailored to the specific strengths of such devices as accelerator in offline computation. With the steady reduction of GPU latencies, and the increase in link and memory throughput, the use of such devices for real-time applications in high-energy physics data acquisition and trigger systems is becoming ripe. We will discuss the use of online parallel computing on GPU for synchronous low level trigger, focusing on CERN NA62 experiment trigger system. The use of GPU in higher level trigger system is also briefly considered.

  19. Pulling the trigger on LHC electronics

    CERN Document Server

    CERN. Geneva

    2001-01-01

    The conditions at CERN's Large Hadron Collider pose severe challenges for the designers and builders of front-end, trigger and data acquisition electronics. A recent workshop reviewed the encouraging progress so far and discussed what remains to be done. The LHC experiments have addressed level one trigger systems with a variety of high-speed hardware. The CMS Calorimeter Level One Regional Trigger uses 160 MHz logic boards plugged into the front and back of a custom backplane, which provides point-to-point links between the cards. Much of the processing in this system is performed by five types of 160 MHz digital applications-specific integrated circuits designed using Vitesse submicron high-integration gallium arsenide gate array technology. The LHC experiments make extensive use of field programmable gate arrays (FPGAs). These offer programmable reconfigurable logic, which has the flexibility that trigger designers need to be able to alter algorithms so that they can follow the physics and detector perform...

  20. Boredom and Passion: Triggers of Habitual Entrepreneurship

    DEFF Research Database (Denmark)

    Müller, Sabine; Neergaard, Helle

    . The case based, the study identifies eight factors, which contribute to consecutive venture creation. The findings suggest that boredom and passion are necessary conditions triggering habitual entrepreneurship. Other important mechanisms included the joy of discovering and exploiting an opportunity...

  1. D0 triggering and data acquisition

    International Nuclear Information System (INIS)

    Gibbard, B.

    1992-10-01

    The trigger for D0 is a multi-tier system. Within the 3.5 μsec bunch crossing interval, custom electronics select interesting event candidates based on electromagnetic and hadronic energy deposits in the calorimeter and on indications of tracks in the muon system. Subsequent hardware decisions use refined calculations of electron and muon characteristics. The highest level trigger occurs in one element of a farm of microprocessors, where fully developed algorithms for electrons, muons, jets, or missing E t are executed. This highest level trigger also provides the assembly of the event into its final data structure. Performance of this trigger and data acquisition system in collider operation is described

  2. Triggering and data acquisition general considerations

    International Nuclear Information System (INIS)

    Butler, Joel N.

    2003-01-01

    We provide a general introduction to trigger and data acquisition systems in High Energy Physics. We emphasize the new possibilities and new approaches that have been made possible by developments in computer technology and networking

  3. Session summary: Electronics, triggering and data acquisition

    International Nuclear Information System (INIS)

    Rescia, S.

    1991-12-01

    The session focused on the requirements for calorimetry at the SSC/LHC. Results on new readout techniques, calibration, radiation hard electronics and semiconductor devices, analog and digital front and electronics, and trigger strategies are presented

  4. Trigger factors in migraine with aura

    DEFF Research Database (Denmark)

    Hauge, A W; Kirchmann, M; Olesen, J

    2010-01-01

    The aim of the present study was to identify trigger factors in migraine with aura (MA). A total of 629 MA patients representative of the Danish population were sent a questionnaire listing 16 trigger factors thought to be relevant as well as space for free text. Distinction was made between...... attacks with or without aura within each patient. The questionnaire was returned by 522 patients of whom 347 had current MA attacks. In total 80% with current attacks (278/347) indicated that at least one factor triggered their migraine, and 67% (187/278) in this group indicated that they were aware...... of at least one factor often or always giving rise to an attack of MA. Forty-one per cent (113/278) had co-occurring attacks of migraine without aura (MO). Stress (following stress), bright light, intense emotional influences, stress (during stress) and sleeping too much or too little were the trigger factors...

  5. The Aurora accelerator's triggered oil switch

    International Nuclear Information System (INIS)

    Weidenheimer, D.M.; Pereira, N.R.; Judy, D.C.; Stricklett, K.L.

    1993-01-01

    Achieving a radiation pulse with 15 ns risetime using all four of the Aurora accelerator's Blumlein pulse-forming lines demands synchronization of the Blumleins to within 10 ns (in addition to a 15 ns risetime for a single line). Timing of each Blumlein is controlled by a triggered 12 MV oil switch. A smaller-than-customary trigger electrode makes the switching time more reproducible. Time-resolved photography of the oil arcs suggests that triggering occurs simultaneously around the sharp edge of the trigger electrode, perhaps with small deviations that grow into the most prominent arcs characteristically seen in open-shutter photographs. However, many smaller arcs that are usually overlooked in open-shutter pictures may contribute to current conduction in a closed switch

  6. Graphics Processing Units for HEP trigger systems

    Energy Technology Data Exchange (ETDEWEB)

    Ammendola, R. [INFN Sezione di Roma “Tor Vergata”, Via della Ricerca Scientifica 1, 00133 Roma (Italy); Bauce, M. [INFN Sezione di Roma “La Sapienza”, P.le A. Moro 2, 00185 Roma (Italy); University of Rome “La Sapienza”, P.lee A.Moro 2, 00185 Roma (Italy); Biagioni, A. [INFN Sezione di Roma “La Sapienza”, P.le A. Moro 2, 00185 Roma (Italy); Chiozzi, S.; Cotta Ramusino, A. [INFN Sezione di Ferrara, Via Saragat 1, 44122 Ferrara (Italy); University of Ferrara, Via Saragat 1, 44122 Ferrara (Italy); Fantechi, R. [INFN Sezione di Pisa, Largo B. Pontecorvo 3, 56127 Pisa (Italy); CERN, Geneve (Switzerland); Fiorini, M. [INFN Sezione di Ferrara, Via Saragat 1, 44122 Ferrara (Italy); University of Ferrara, Via Saragat 1, 44122 Ferrara (Italy); Giagu, S. [INFN Sezione di Roma “La Sapienza”, P.le A. Moro 2, 00185 Roma (Italy); University of Rome “La Sapienza”, P.lee A.Moro 2, 00185 Roma (Italy); Gianoli, A. [INFN Sezione di Ferrara, Via Saragat 1, 44122 Ferrara (Italy); University of Ferrara, Via Saragat 1, 44122 Ferrara (Italy); Lamanna, G., E-mail: gianluca.lamanna@cern.ch [INFN Sezione di Pisa, Largo B. Pontecorvo 3, 56127 Pisa (Italy); INFN Laboratori Nazionali di Frascati, Via Enrico Fermi 40, 00044 Frascati (Roma) (Italy); Lonardo, A. [INFN Sezione di Roma “La Sapienza”, P.le A. Moro 2, 00185 Roma (Italy); Messina, A. [INFN Sezione di Roma “La Sapienza”, P.le A. Moro 2, 00185 Roma (Italy); University of Rome “La Sapienza”, P.lee A.Moro 2, 00185 Roma (Italy); and others

    2016-07-11

    General-purpose computing on GPUs (Graphics Processing Units) is emerging as a new paradigm in several fields of science, although so far applications have been tailored to the specific strengths of such devices as accelerator in offline computation. With the steady reduction of GPU latencies, and the increase in link and memory throughput, the use of such devices for real-time applications in high-energy physics data acquisition and trigger systems is becoming ripe. We will discuss the use of online parallel computing on GPU for synchronous low level trigger, focusing on CERN NA62 experiment trigger system. The use of GPU in higher level trigger system is also briefly considered.

  7. Trigger circuits for the PHENIX electromagnetic calorimeter

    International Nuclear Information System (INIS)

    Frank, S.S.; Britton, C.L. Jr.; Winterberg, A.L.; Young, G.R.

    1997-11-01

    Monolithic and discrete circuits have been developed to provide trigger signals for the PHENIX electromagnetic calorimeter detector. These trigger circuits are deadtimeless and create overlapping 4 by 4 energy sums, a cosmic muon trigger, and a 144 channel energy sum. The front end electronics of the PHENIX system sample the energy and timing channels at each bunch crossing (BC) but it is not known immediately if this data is of interest. The information from the trigger circuits is used to determine if the data collected is of interest and should be digitized and stored or discarded. This paper presents details of the design, issues affecting circuit performance, characterization of prototypes fabricated in 1.2 microm Orbit CMOS, and integration of the circuits into the EMCal electronics system

  8. New Fast Interaction Trigger for ALICE

    Energy Technology Data Exchange (ETDEWEB)

    Trzaska, Wladyslaw Henryk

    2017-02-11

    The LHC heavy-ion luminosity and collision rate from 2021 onwards will considerably exceed the design parameters of the present ALICE forward trigger detectors and the introduction of the Muon Forward Tracker (MFT) will significantly reduce the space available for the new trigger detectors. To comply with these conditions a new Fast Interaction Trigger (FIT) will be built. FIT will be the main forward trigger, luminometer, and interaction-time detector. It will also determine multiplicity, centrality, and reaction plane of heavy-ion collisions. FIT will consist of two arrays of Cherenkov quartz radiators with MCP-PMT sensors and of a plastic scintillator ring. By increasing the overall acceptance of FIT, the scintillator will improve centrality and event plane resolution. It will also add sensitivity for the detection of beam-gas events and provide some degree of redundancy. FIT is currently undergoing an intense R&D and prototyping period. It is scheduled for installation in ALICE during 2020.

  9. The new UA1 calorimeter trigger

    International Nuclear Information System (INIS)

    Eisenhandler, E.

    1988-01-01

    The new UA1 first-level calorimeter trigger processor is described, with emphasis on the fast two-dimensional electromagnetic cluster-finding that is its most novel feature. This processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. (author)

  10. The upgrade of the LHCb trigger system

    CERN Document Server

    INSPIRE-00259834; Fitzpatrick, C.; Gligorov, V.; Raven, G.

    2014-10-20

    The LHCb experiment will operate at a luminosity of $2\\times10^{33}$ cm$^{-2}$s$^{-1}$ during LHC Run 3. At this rate the present readout and hardware Level-0 trigger become a limitation, especially for fully hadronic final states. In order to maintain a high signal efficiency the upgraded LHCb detector will deploy two novel concepts: a triggerless readout and a full software trigger.

  11. EMIC triggered chorus emissions in Cluster data

    Science.gov (United States)

    Grison, B.; SantolíK, O.; Cornilleau-Wehrlin, N.; Masson, A.; Engebretson, M. J.; Pickett, J. S.; Omura, Y.; Robert, P.; Nomura, R.

    2013-03-01

    Electromagnetic ion cyclotron (EMIC) triggered chorus emissions have recently been a subject of several experimental, theoretical and simulation case studies, noting their similarities with whistler-mode chorus. We perform a survey of 8 years of Cluster data in order to increase the database of EMIC triggered emissions. The results of this is that EMIC triggered emissions have been unambiguously observed for only three different days. These three events are studied in detail. All cases have been observed at the plasmapause between 22 and 24 magnetic local time (MLT) and between - 15° and 15° magnetic latitude (λm). Triggered emissions are also observed for the first time below the local He+ gyrofrequency (fHe+). The number of events is too low to produce statistical results, nevertheless we point out a variety of common properties of those waves. The rising tones have a high level of coherence and the waves propagate away from the equatorial region. The propagation angle and degree of polarization are related to the distance from the equator, whereas the slope and the frequency extent vary from one event to the other. From the various spacecraft separations, we determine that the triggering process is a localized phenomenon in space and time. However, we are unable to determine the occurrence rates of these waves. Small frequency extent rising tones are more common than large ones. The newly reported EMIC triggered events are generally observed during periods of large AE index values and in time periods close to solar maximum.

  12. Progress on the Level-1 Calorimeter Trigger

    CERN Multimedia

    Eric Eisenhandler

    The Level-1 Calorimeter Trigger (L1Calo) has recently passed a number of major hurdles. The various electronic modules that make up the trigger are either in full production or are about to be, and preparations in the ATLAS pit are well advanced. L1Calo has three main subsystems. The PreProcessor converts analogue calorimeter signals to digital, associates the rather broad trigger pulses with the correct proton-proton bunch crossing, and does a final calibration in transverse energy before sending digital data streams to the two algorithmic trigger processors. The Cluster Processor identifies and counts electrons, photons and taus, and the Jet/Energy-sum Processor looks for jets and also sums missing and total transverse energy. Readout drivers allow the performance of the trigger to be monitored online and offline, and also send region-of-interest information to the Level-2 Trigger. The PreProcessor (Heidelberg) is the L1Calo subsystem with the largest number of electronic modules (124), and most of its fu...

  13. Triggered tremor sweet spots in Alaska

    Science.gov (United States)

    Gomberg, Joan; Prejean, Stephanie

    2013-01-01

    To better understand what controls fault slip along plate boundaries, we have exploited the abundance of seismic and geodetic data available from the richly varied tectonic environments composing Alaska. A search for tremor triggered by 11 large earthquakes throughout all of seismically monitored Alaska reveals two tremor “sweet spots”—regions where large-amplitude seismic waves repeatedly triggered tremor between 2006 and 2012. The two sweet spots locate in very different tectonic environments—one just trenchward and between the Aleutian islands of Unalaska and Akutan and the other in central mainland Alaska. The Unalaska/Akutan spot corroborates previous evidence that the region is ripe for tremor, perhaps because it is located where plate-interface frictional properties transition between stick-slip and stably sliding in both the dip direction and laterally. The mainland sweet spot coincides with a region of complex and uncertain plate interactions, and where no slow slip events or major crustal faults have been noted previously. Analyses showed that larger triggering wave amplitudes, and perhaps lower frequencies (tremor. However, neither the maximum amplitude in the time domain or in a particular frequency band, nor the geometric relationship of the wavefield to the tremor source faults alone ensures a high probability of triggering. Triggered tremor at the two sweet spots also does not occur during slow slip events visually detectable in GPS data, although slow slip below the detection threshold may have facilitated tremor triggering.

  14. Hierarchical trigger of the ALICE calorimeters

    CERN Document Server

    Muller, Hans; Novitzky, Norbert; Kral, Jiri; Rak, Jan; Schambach, Joachim; Wang, Ya-Ping; Wang, Dong; Zhou, Daicui

    2010-01-01

    The trigger of the ALICE electromagnetic calorimeters is implemented in 2 hierarchically connected layers of electronics. In the lower layer, level-0 algorithms search shower energy above threshold in locally confined Trigger Region Units (TRU). The top layer is implemented as a single, global trigger unit that receives the trigger data from all TRUs as input to the level-1 algorithm. This architecture was first developed for the PHOS high pT photon trigger before it was adopted by EMCal also for the jet trigger. TRU units digitize up to 112 analogue input signals from the Front End Electronics (FEE) and concentrate their digital stream in a single FPGA. A charge and time summing algorithm is combined with a peakfinder that suppresses spurious noise and is precise to single LHC bunches. With a peak-to-peak noise level of 150 MeV the linear dynamic range above threshold spans from MIP energies at 215 up to 50 GeV. Local level-0 decisions take less than 600 ns after LHC collisions, upon which all TRUs transfer ...

  15. Level-1 Calorimeter Trigger starts firing

    CERN Multimedia

    Stephen Hillier

    2007-01-01

    L1Calo is one of the major components of ATLAS First Level trigger, along with the Muon Trigger and Central Trigger Processor. It forms all of the first-level calorimeter-based triggers, including electron, jet, tau and missing ET. The final system consists of over 250 custom designed 9U VME boards, most containing a dense array of FPGAs or ASICs. It is subdivided into a PreProcessor, which digitises the incoming trigger signals from the Liquid Argon and Tile calorimeters, and two separate processor systems, which perform the physics algorithms. All of these are highly flexible, allowing the possibility to adapt to beam conditions and luminosity. All parts of the system are read out through Read-Out Drivers, which provide monitoring data and Region of Interest (RoI) information for the Level-2 trigger. Production of the modules is now essentially complete, and enough modules exist to populate the full scale system in USA15. Installation is proceeding rapidly - approximately 90% of the final modules are insta...

  16. The LHCb trigger and data acquisition system

    CERN Document Server

    Dufey, J P; Harris, F; Harvey, J; Jost, B; Mato, P; Müller, E

    2000-01-01

    The LHCb experiment is the most recently approved of the 4 experiments under construction at CERNs LHC accelerator. It is a special purpose experiment designed to precisely measure the CP violation parameters in the B-B system. Triggering poses special problems since the interesting events containing B-mesons are immersed in a large background of inelastic p-p reactions. We therefore decided to implement a 4 level triggering scheme. The LHCb Data Acquisition (DAQ) system will have to cope with an average trigger rate of ~40 kHz, after two levels of hardware triggers, and an average event size of ~100 kB. Thus an event-building network which can sustain an average bandwidth of 4 GB/s is required. A powerful software trigger farm will have to be installed to reduce the rate from the 40 kHz to ~100 Hz of events written to permanent storage. In this paper we outline the general architecture of the Trigger and DAQ system and the readout protocols we plan to implement. First results of simulations of the behavior o...

  17. Design studies for the Double Chooz trigger

    International Nuclear Information System (INIS)

    Cucoanes, Andi Sebastian

    2009-01-01

    The main characteristic of the neutrino mixing effect is assumed to be the coupling between the flavor and the mass eigenstates. Three mixing angles (θ 12 , θ 23 , θ 13 ) are describing the magnitude of this effect. Still unknown, θ 13 is considered very small, based on the measurement done by the CHOOZ experiment. A leading experiment will be Double Chooz, placed in the Ardennes region, on the same site as used by CHOOZ. The Double Chooz goal is the exploration of ∝80% from the currently allowed θ 13 region, by searching the disappearance of reactor antineutrinos. Double Chooz will use two similar detectors, located at different distances from the reactor cores: a near one at ∝150 m where no oscillations are expected and a far one at 1.05 km distance, close to the first minimum of the survival probability function. The measurement foresees a precise comparison of neutrino rates and spectra between both detectors. The detection mechanism is based on the inverse β-decay. The Double Chooz detectors have been designed to minimize the rate of random background. In a simplified view, two optically separated regions are considered. The target, filled with Gd-doped liquid scintillator, is the main antineutrino interaction volume. Surrounding the target, the inner veto region aims to tag the cosmogenic muon background which hits the detector. Both regions are viewed by photomultipliers. The Double Chooz trigger system has to be highly efficient for antineutrino events as well as for several types of background. The trigger analyzes discriminated signals from the central region and the inner veto photomultipliers. The trigger logic is fully programmable and can combine the input signals. The trigger conditions are based on the total energy released in event and on the PMT groups multiplicity. For redundancy, two independent trigger boards will be used for the central region, each of them receiving signals from half of the photomultipliers. A third trigger board

  18. Design studies for the Double Chooz trigger

    Energy Technology Data Exchange (ETDEWEB)

    Cucoanes, Andi Sebastian

    2009-07-24

    The main characteristic of the neutrino mixing effect is assumed to be the coupling between the flavor and the mass eigenstates. Three mixing angles ({theta}{sub 12}, {theta}{sub 23}, {theta}{sub 13}) are describing the magnitude of this effect. Still unknown, {theta}{sub 13} is considered very small, based on the measurement done by the CHOOZ experiment. A leading experiment will be Double Chooz, placed in the Ardennes region, on the same site as used by CHOOZ. The Double Chooz goal is the exploration of {proportional_to}80% from the currently allowed {theta}{sub 13} region, by searching the disappearance of reactor antineutrinos. Double Chooz will use two similar detectors, located at different distances from the reactor cores: a near one at {proportional_to}150 m where no oscillations are expected and a far one at 1.05 km distance, close to the first minimum of the survival probability function. The measurement foresees a precise comparison of neutrino rates and spectra between both detectors. The detection mechanism is based on the inverse {beta}-decay. The Double Chooz detectors have been designed to minimize the rate of random background. In a simplified view, two optically separated regions are considered. The target, filled with Gd-doped liquid scintillator, is the main antineutrino interaction volume. Surrounding the target, the inner veto region aims to tag the cosmogenic muon background which hits the detector. Both regions are viewed by photomultipliers. The Double Chooz trigger system has to be highly efficient for antineutrino events as well as for several types of background. The trigger analyzes discriminated signals from the central region and the inner veto photomultipliers. The trigger logic is fully programmable and can combine the input signals. The trigger conditions are based on the total energy released in event and on the PMT groups multiplicity. For redundancy, two independent trigger boards will be used for the central region, each of

  19. Tinnitus-provoking salicylate treatment triggers social impairments in mice.

    Science.gov (United States)

    Guitton, Matthieu J

    2009-09-01

    Tinnitus (perception of sound in silence) strongly affects the quality of life of sufferers. Tinnitus sufferers and their relatives frequently complain about major social impairments. However, it is not known whether this impairment directly results from the occurrence of tinnitus or is the indirect expression of a preexisting psychological vulnerability. Using the well-characterized animal model of salicylate-induced tinnitus, we investigate in mice whether the occurrence of tinnitus can trigger social impairments. Experiments were performed on 32 male Balb/C mice. Tinnitus was induced in mice using salicylate treatment. Social behavior was assessed in experimental and control animals using social interaction paradigm. Interaction time, number of social events, and number of nonsocial events were assessed in all animals. We demonstrate for the first time that treatment known to induce tinnitus triggers complex social impairments in mice. While salicylate-treated animals present a massive decrease in their overall social interactions compared to control untreated animals, they also display a paradoxal increase in the number of conspecific followings. Tinnitus can thus trigger a complex set of modifications of behavior, which will not only find their expression at the individual level, but also at the social level. Our results suggest that tinnitus can directly be a cause of psychosocial impairment in human and have strong implications for the clinical management of tinnitus sufferers.

  20. What triggers catch-up saccades during visual tracking?

    Science.gov (United States)

    de Brouwer, Sophie; Yuksel, Demet; Blohm, Gunnar; Missal, Marcus; Lefèvre, Philippe

    2002-03-01

    When tracking moving visual stimuli, primates orient their visual axis by combining two kinds of eye movements, smooth pursuit and saccades, that have very different dynamics. Yet, the mechanisms that govern the decision to switch from one type of eye movement to the other are still poorly understood, even though they could bring a significant contribution to the understanding of how the CNS combines different kinds of control strategies to achieve a common motor and sensory goal. In this study, we investigated the oculomotor responses to a large range of different combinations of position error and velocity error during visual tracking of moving stimuli in humans. We found that the oculomotor system uses a prediction of the time at which the eye trajectory will cross the target, defined as the "eye crossing time" (T(XE)). The eye crossing time, which depends on both position error and velocity error, is the criterion used to switch between smooth and saccadic pursuit, i.e., to trigger catch-up saccades. On average, for T(XE) between 40 and 180 ms, no saccade is triggered and target tracking remains purely smooth. Conversely, when T(XE) becomes smaller than 40 ms or larger than 180 ms, a saccade is triggered after a short latency (around 125 ms).

  1. Remotely Triggered Nano-Theranostics For Cancer Applications

    Science.gov (United States)

    Sneider, Alexandra; VanDyke, Derek; Paliwal, Shailee; Rai, Prakash

    2017-01-01

    Nanotechnology has enabled the development of smart theranostic platforms that can concurrently diagnose disease, start primary treatment, monitor response, and, if required, initiate secondary treatments. Recent in vivo experiments demonstrate the promise of using theranostics in the clinic. In this paper, we review the use of remotely triggered theranostic nanoparticles for cancer applications, focusing heavily on advances in the past five years. Remote triggering mechanisms covered include photodynamic, photothermal, phototriggered chemotherapeutic release, ultrasound, electro-thermal, magneto-thermal, X-ray, and radiofrequency therapies. Each section includes a brief overview of the triggering mechanism and summarizes the variety of nanoparticles employed in each method. Emphasis in each category is placed on nano-theranostics with in vivo success. Some of the nanotheranostic platforms highlighted include photoactivatable multi-inhibitor nanoliposomes, plasmonic nanobubbles, reduced graphene oxide-iron oxide nanoparticles, photoswitching nanoparticles, multispectral optoacoustic tomography using indocyanine green, low temperature sensitive liposomes, and receptor-targeted iron oxide nanoparticles loaded with gemcitabine. The studies reviewed here provide strong evidence that the field of nanotheranostics is rapidly evolving. Such nanoplatforms may soon enable unique advances in the clinical management of cancer. However, reproducibility in the synthesis procedures of such “smart” platforms that lend themselves to easy scale-up in their manufacturing, as well as the development of new and improved models of cancer that are more predictive of human responses, need to happen soon for this field to make a rapid clinical impact. PMID:28191450

  2. The n-hexane and chloroform fractions of Piper betle L. trigger different arms of immune responses in BALB/c mice and exhibit antifilarial activity against human lymphatic filarid Brugia malayi.

    Science.gov (United States)

    Singh, Meghna; Shakya, Shilpy; Soni, Vishal Kumar; Dangi, Anil; Kumar, Nikhil; Bhattacharya, Shailja-Misra

    2009-06-01

    Modulation of immune functions by using herbal plants and their products has become fundamental regime of therapeutic approach. Piper betle Linn. (Piperaceae) is a widely distributed plant in the tropical and subtropical regions of the world and has been attributed as traditional herbal remedy for many diseases. We have recently reported the antifilarial and antileishmanial efficacy in the leaf extract of Bangla Mahoba landrace of P. betle which is a female plant. The present report describes the in vivo immunomodulatory efficacy of the crude methanolic extract and its n-hexane, chloroform, n-butanol fractions of the female plant at various dose levels ranging between 0.3 and 500 mg/kg in BALB/c. Attempts were also made to observe antifilarial activity of the active extracts and correlate it with the antigen specific immune responses in another rodent Mastomys coucha infected with human lymphatic filarial parasite Brugia malayi. The crude methanol extract and n-hexane fraction were found to potentiate significant (p<0.001) enhancement of both humoral (plaque forming cells, hemagglutination titre) as well as cell-mediated (lymphoproliferation, macrophage activation, delayed type hypersensitivity) immune responses in mice. The flow cytometric analysis of splenocytes of treated mice indicated enhanced population of T-cells (CD4(+), CD8(+)) and B-cells (CD19(+)). The n-hexane fraction (3 mg/kg) was found to induce biased type 2 cytokine response as revealed by increased IL-4(+) and decreased IFN-gamma(+) T-cell population while the chloroform fraction (10 mg/kg) produced a predominant type 1 cytokines. Crude methanolic extract (100 mg/kg) demonstrated a mixed type 1 and type 2 cytokine responses thus suggesting a remarkable immunomodulatory property in this plant. The induction of differential T-helper cell immune response appears ideal to overcome immunosuppression as observed in case of lymphatic, filarial Brugia malayi infection which may also be extended to other

  3. Retrospective respiratory triggering renal perfusion MRI

    Energy Technology Data Exchange (ETDEWEB)

    Attenberger, Ulrike I.; Michaely, Henrik J.; Schoenberg, Stefan O. (Dept. of Clinical Radiology and Nuclear Medicine, Univ. Hospital Mannheim, Univ. of Heidelberg, Mannheim (Germany)), e-mail: ulrike.attenberger@medma.uni-heidelberg.de; Sourbron, Steven P. (Div. of Medical Physics, Univ. of Leeds, Leeds (United Kingdom)); Reiser, Maximilian F. (Dept. of Clinical Radiology, Univ. Hospitals Munich, Grosshadern, Ludwig-Maximilians-Univ., Munich (Germany))

    2010-12-15

    Background: Artifacts of respiratory motion are one of the well-known limitations of dynamic contrast-enhanced MRI (DCE-MRI) of the kidney. Purpose: To propose and evaluate a retrospective triggering approach to minimize the effect of respiratory motion in DCE-MRI of the kidney. Material and Methods: Nine consecutive patients underwent renal perfusion measurements. Data were acquired with a 2D saturation-recovery TurboFLASH sequence. In order to test the dependence of the results on size and location of the manually drawn triggering regions of interest (ROIs), three widely differing triggering regions were defined by one observer. Mean value, standard deviation, and variability of the renal function parameters plasma flow (FP), plasma volume (VP), plasma transit time (TP), tubular flow (FT), tubular volume (VT), and tubular transit time (TT) were calculated on a per-patient basis. Results: The results show that triggered data have adequate temporal resolution to measure blood flow. The overall average values of the function parameters were: 152.77 (FP), 15.18 (VP), 6,73 (TP), 18.50 (FT), 35.36 (VT), and 117.67 (TT). The variability (calculated in % SD from the mean value) for three different respiratory triggering regions defined on a per-patient basis was between 0.81% and 9.87% for FP, 1.45% and 8.19% for VP, 0% and 9.63% for TP, 2.15% and 12.23% for TF, 0.8% and 17.28% for VT, and 1.97% and 12.87% for TT. Conclusion: Triggering reduces the oscillations in the signal curves and produces sharper parametric maps. In contrast to numerically challenging approaches like registration and segmentation it can be applied in clinical routine, but a (semi)-automatic approach to select the triggering ROI is desirable to reduce user dependence.

  4. Aftershocks and triggering processes in rock fracture

    Science.gov (United States)

    Davidsen, J.; Kwiatek, G.; Goebel, T.; Stanchits, S. A.; Dresen, G.

    2017-12-01

    One of the hallmarks of our understanding of seismicity in nature is the importance of triggering processes, which makes the forecasting of seismic activity feasible. These triggering processes by which one earthquake induces (dynamic or static) stress changes leading to potentially multiple other earthquakes are at the core relaxation processes. A specic example of triggering are aftershocks following a large earthquake, which have been observed to follow certain empirical relationships such as the Omori-Utsu relation. Such an empirical relation should arise from the underlying microscopic dynamics of the involved physical processes but the exact connection remains to be established. Simple explanations have been proposed but their general applicability is unclear. Many explanations involve the picture of an earthquake as a purely frictional sliding event. Here, we present experimental evidence that these empirical relationships are not limited to frictional processes but also arise in fracture zone formation and are mostly related to compaction-type events. Our analysis is based on tri-axial compression experiments under constant displacement rate on sandstone and granite samples using spatially located acoustic emission events and their focal mechanisms. More importantly, we show that event-event triggering plays an important role in the presence of large-scale or macrocopic imperfections while such triggering is basically absent if no signicant imperfections are present. We also show that spatial localization and an increase in activity rates close to failure do not necessarily imply triggering behavior associated with aftershocks. Only if a macroscopic crack is formed and its propagation remains subcritical do we observe significant triggering.

  5. Energy parasites trigger oncogene mutation.

    Science.gov (United States)

    Pokorný, Jiří; Pokorný, Jan; Jandová, Anna; Kobilková, Jitka; Vrba, Jan; Vrba, Jan

    2016-10-01

    Cancer initialization can be explained as a result of parasitic virus energy consumption leading to randomized genome chemical bonding. Analysis of experimental data on cell-mediated immunity (CMI) containing about 12,000 cases of healthy humans, cancer patients and patients with precancerous cervical lesions disclosed that the specific cancer and the non-specific lactate dehydrogenase-elevating (LDH) virus antigen elicit similar responses. The specific antigen is effective only in cancer type of its origin but the non-specific antigen in all examined cancers. CMI results of CIN patients display both healthy and cancer state. The ribonucleic acid (RNA) of the LDH virus parasitizing on energy reduces the ratio of coherent/random oscillations. Decreased effect of coherent cellular electromagnetic field on bonding electrons in biological macromolecules leads to elevating probability of random genome reactions. Overlapping of wave functions in biological macromolecules depends on energy of the cellular electromagnetic field which supplies energy to bonding electrons for selective chemical bonds. CMI responses of cancer and LDH virus antigens in all examined healthy, precancerous and cancer cases point to energy mechanism in cancer initiation. Dependence of the rate of biochemical reactions on biological electromagnetic field explains yet unknown mechanism of genome mutation.

  6. Cascading hazards: Understanding triggering relations between wet tropical cyclones, landslides, and earthquakes

    Science.gov (United States)

    Wdowinski, S.; Peng, Z.; Ferrier, K.; Lin, C. H.; Hsu, Y. J.; Shyu, J. B. H.

    2017-12-01

    Earthquakes, landslides, and tropical cyclones are extreme hazards that pose significant threats to human life and property. Some of the couplings between these hazards are well known. For example, sudden, widespread landsliding can be triggered by large earthquakes and by extreme rainfall events like tropical cyclones. Recent studies have also shown that earthquakes can be triggered by erosional unloading over 100-year timescales. In a NASA supported project, titled "Cascading hazards: Understanding triggering relations between wet tropical cyclones, landslides, and earthquake", we study triggering relations between these hazard types. The project focuses on such triggering relations in Taiwan, which is subjected to very wet tropical storms, landslides, and earthquakes. One example for such triggering relations is the 2009 Morakot typhoon, which was the wettest recorded typhoon in Taiwan (2850 mm of rain in 100 hours). The typhoon caused widespread flooding and triggered more than 20,000 landslides, including the devastating Hsiaolin landslide. Six months later, the same area was hit by the 2010 M=6.4 Jiashian earthquake near Kaohsiung city, which added to the infrastructure damage induced by the typhoon and the landslides. Preliminary analysis of temporal relations between main-shock earthquakes and the six wettest typhoons in Taiwan's past 50 years reveals similar temporal relations between M≥5 events and wet typhoons. Future work in the project will include remote sensing analysis of landsliding, seismic and geodetic monitoring of landslides, detection of microseismicity and tremor activities, and mechanical modeling of crustal stress changes due to surface unloading.

  7. Rate Predictions and Trigger/DAQ Resource Monitoring in ATLAS

    CERN Document Server

    Schaefer, D M; The ATLAS collaboration

    2012-01-01

    Since starting in 2010, the Large Hadron Collider (LHC) has pro- duced collisions at an ever increasing rate. The ATLAS experiment successfully records the collision data with high eciency and excel- lent data quality. Events are selected using a three-level trigger system, where each level makes a more re ned selection. The level-1 trigger (L1) consists of a custom-designed hardware trigger which seeds two higher software based trigger levels. Over 300 triggers compose a trig- ger menu which selects physics signatures such as electrons, muons, particle jets, etc. Each trigger consumes computing resources of the ATLAS trigger system and oine storage. The LHC instantaneous luminosity conditions, desired physics goals of the collaboration, and the limits of the trigger infrastructure determine the composition of the ATLAS trigger menu. We describe a trigger monitoring frame- work for computing the costs of individual trigger algorithms such as data request rates and CPU consumption. This framework has been used...

  8. Upgrades of the ATLAS trigger system

    CERN Document Server

    AUTHOR|(INSPIRE)INSPIRE-00221618; The ATLAS collaboration

    2018-01-01

    In coming years the LHC is expected to undergo upgrades to increase both the energy of proton-proton collisions and the instantaneous luminosity. In order to cope with these more challenging LHC conditions, upgrades of the ATLAS trigger system will be required. This talk will focus on some of the key aspects of these upgrades. Firstly, the upgrade period between 2019-2021 will see an increase in instantaneous luminosity to $3\\times10^{34} \\rm{cm^{-2}s^{-1}}$. Upgrades to the Level 1 trigger system during this time will include improvements for both the muon and calorimeter triggers. These include the upgrade of the first-level Endcap Muon trigger, the calorimeter trigger electronics and the addition of new calorimeter feature extractor hardware, such as the Global Feature Extractor (gFEX). An overview will be given on the design and development status the aforementioned systems, along with the latest testing and validation results. \\\\ By 2026, the High Luminosity LHC will be able to deliver 14 TeV collisions ...

  9. Graphical processors for HEP trigger systems

    International Nuclear Information System (INIS)

    Ammendola, R.; Biagioni, A.; Chiozzi, S.; Cotta Ramusino, A.; Di Lorenzo, S.; Fantechi, R.; Fiorini, M.; Frezza, O.; Lamanna, G.; Lo Cicero, F.; Lonardo, A.; Martinelli, M.; Neri, I.; Paolucci, P.S.; Pastorelli, E.; Piandani, R.; Pontisso, L.; Rossetti, D.; Simula, F.; Sozzi, M.

    2017-01-01

    General-purpose computing on GPUs is emerging as a new paradigm in several fields of science, although so far applications have been tailored to employ GPUs as accelerators in offline computations. With the steady decrease of GPU latencies and the increase in link and memory throughputs, time is ripe for real-time applications using GPUs in high-energy physics data acquisition and trigger systems. We will discuss the use of online parallel computing on GPUs for synchronous low level trigger systems, focusing on tests performed on the trigger of the CERN NA62 experiment. Latencies of all components need analysing, networking being the most critical. To keep it under control, we envisioned NaNet, an FPGA-based PCIe Network Interface Card (NIC) enabling GPUDirect connection. Moreover, we discuss how specific trigger algorithms can be parallelised and thus benefit from a GPU implementation, in terms of increased execution speed. Such improvements are particularly relevant for the foreseen LHC luminosity upgrade where highly selective algorithms will be crucial to maintain sustainable trigger rates with very high pileup.

  10. CMS Triggers for the LHC Startup

    CERN Document Server

    Nhan Nguyen, Chi

    2009-01-01

    The LHC will collide proton beams at a bunch-crossing rate of 40 MHz. At the design luminosity of $10^{34}$ cm$^{-2}$s$^{-1}$ each crossing results in an average of about 20 inelastic pp events. The CMS trigger system is designed to reduce the input rate to about 100 Hz. This task is carried out in two steps, namely the Level-1 (L1) and the High-Level trigger (HLT). The L1 trigger is built of customized fast electronics and is designed to reduce the rate to 100 kHz. The HLT is implemented in a filter farm running on hundreds of CPUs and is designed to reduce the rate by another factor of ~1000. It combines the traditional L2 and L3 trigger components in a novel way and allows the coherent tuning of the HLT algorithms to accommodate multiple physics channels. We will discuss the strategies for optimizing triggers covering the experiment`s early physics program.

  11. The Fast Interaction Trigger Upgrade for ALICE

    CERN Document Server

    Garcia-Solis, Edmundo

    2016-01-01

    The ALICE Collaboration is preparing a major detector upgrade for the second LHC long shutdown (2019–20). The LHC heavy-ion luminosity and collision rate from 2021 onwards will considerably exceed the design parameters of the present ALICE forward trigger detectors. Furthermore, the introduction of a new Muon Forward Tracker (MFT) will significantly reduce the space available for the upgraded trigger detectors. To comply with these conditions a Fast Interaction Trigger (FIT) has been designed. FIT will be the primary forward trigger, luminosity, and collision time measurement detector. The FIT will be capable of triggering at an interaction rate of 50 kHz, with a time resolution better than 30 ps, with 99% efficiency. It will also determine multiplicity, centrality, and reaction plane. FIT will consist of two arrays of Cherenkov radiators with MCP-PMT sensors and of a single, large-size scintillator ring. The arrays will be placed on both sides of the interaction point (IP). Because of the presence of the h...

  12. Tools for Trigger Rate Monitoring at CMS

    CERN Document Server

    Smith, Geoffrey; Wightman, Andrew Steven

    2017-01-01

    In 2017, we expect the LHC to deliver an instantaneous luminosity of roughly $2.0 \\times 10^{34}$~cm$^{-2}$s$^{-1}$ to the Compact Muon Solenoid (CMS) experiment, with about 60 simultaneous proton-proton collisions (pileup) per event. In these challenging conditions, it is important to be able to intelligently monitor the rate at which data are being collected (the trigger rate). It is not enough to simply look at the trigger rate; it is equally important to compare the trigger rate with expectations. We present a set of software tools that have been developed to accomplish this. The tools include a real-time component - a script that monitors the rates of individual triggers during data-taking, and activates an alarm if rates deviate significantly from expectation. Fits are made to previously collected data and extrapolated to higher pileup. The behavior of triggers as a function of pileup is then monitored as data are collected - plots are automatically produced on an hourly basis and uploaded to a web area...

  13. Tracking at High Level Trigger in CMS

    CERN Document Server

    Tosi, Mia

    2016-01-01

    The trigger systems of the LHC detectors play a crucial role in determining the physics capabili- ties of the experiments. A reduction of several orders of magnitude of the event rate is needed to reach values compatible with detector readout, offline storage and analysis capability. The CMS experiment has been designed with a two-level trigger system: the Level-1 Trigger (L1T), implemented on custom-designed electronics, and the High Level Trigger (HLT), a stream- lined version of the CMS offline reconstruction software running on a computer farm. A software trigger system requires a trade-off between the complexity of the algorithms, the sustainable out- put rate, and the selection efficiency. With the computing power available during the 2012 data taking the maximum reconstruction time at HLT was about 200 ms per event, at the nominal L1T rate of 100 kHz. Track reconstruction algorithms are widely used in the HLT, for the reconstruction of the physics objects as well as in the identification of b-jets and ...

  14. The D-Zero Run II Trigger

    International Nuclear Information System (INIS)

    Blazey, G. C.

    1997-01-01

    The general purpose D0 collider detector, located at Fermi National Accelerator Laboratory, requires significantly enhanced data acquisition and triggering to operate in the high luminosity (L = 2 x 10 32 cm -2 s -1 ), high rate environment (7 MHz or 132 ns beam crossings) of the upgraded TeVatron proton anti-proton accelerator. This article describes the three major levels and frameworks of the new trigger. Information from the first trigger stage (L1) which includes scintillating, tracking and calorimeter detectors will provide a deadtimeless, 4.2 (micro)s trigger decision with an accept rate of 10 kHz. The second stage (L2), comprised of hardware engines associated with specific detectors and a single global processor will test for correlations between L1 triggers. L2 will have an accept rate of 1 kHz at a maximum deadtime of 5% and require a 100 (micro)s decision time. The third and final stage (L3) will reconstruct events in a farm of processors for a final instantaneous accept rate of 50 Hz

  15. DZERO Level 3 DAQ/Trigger Closeout

    CERN Multimedia

    CERN. Geneva

    2012-01-01

    The Tevatron Collider, located at the Fermi National Accelerator Laboratory, delivered its last 1.96 TeV proton-antiproton collisions on September 30th, 2011. The DZERO experiment continues to take cosmic data for final alignment for several more months . Since Run 2 started, in March 2001, all DZERO data has been collected by the DZERO Level 3 Trigger/DAQ System. The system is a modern, networked, commodity hardware trigger and data acquisition system based around a large central switch with about 60 front ends and 200 trigger computers. DZERO front end crates are VME based. Single Board Computer interfaces between detector data on VME and the network transport for the DAQ system. Event flow is controlled by the Routing Master which can steer events to clusters of farm nodes based on the low level trigger bits that fired. The farm nodes are multi-core commodity computer boxes, without special hardware, that run isolated software to make the final Level 3 trigger decision. Passed events are transferred to th...

  16. Graphical processors for HEP trigger systems

    Energy Technology Data Exchange (ETDEWEB)

    Ammendola, R. [INFN Sezione di Roma Tor Vergata, Via della Ricerca Scientifica, 1, 00133 Roma (Italy); Biagioni, A. [INFN Sezione di Roma, P.le Aldo Moro, 2, 00185 Roma (Italy); Chiozzi, S.; Cotta Ramusino, A. [INFN Sezione di Ferrara, Via Saragat, 1, 44122 Ferrara (Italy); Di Lorenzo, S. [INFN Sezione di Pisa, L. Bruno Pontecorvo, 3, 56127 Pisa (Italy); Università di Pisa, Lungarno Pacinotti 43, 56126 Pisa (Italy); Fantechi, R. [INFN Sezione di Pisa, L. Bruno Pontecorvo, 3, 56127 Pisa (Italy); Fiorini, M. [INFN Sezione di Ferrara, Via Saragat, 1, 44122 Ferrara (Italy); Università di Ferrara, Via Ludovico Ariosto 35, 44121 Ferrara (Italy); Frezza, O. [INFN Sezione di Roma, P.le Aldo Moro, 2, 00185 Roma (Italy); Lamanna, G. [INFN, Laboratori Nazionali di Frascati (Italy); Lo Cicero, F.; Lonardo, A.; Martinelli, M.; Neri, I.; Paolucci, P.S.; Pastorelli, E. [INFN Sezione di Roma, P.le Aldo Moro, 2, 00185 Roma (Italy); Piandani, R. [INFN Sezione di Pisa, L. Bruno Pontecorvo, 3, 56127 Pisa (Italy); Pontisso, L., E-mail: luca.pontisso@cern.ch [INFN Sezione di Pisa, L. Bruno Pontecorvo, 3, 56127 Pisa (Italy); Rossetti, D. [NVIDIA Corp., Santa Clara, CA (United States); Simula, F. [INFN Sezione di Roma, P.le Aldo Moro, 2, 00185 Roma (Italy); Sozzi, M. [INFN Sezione di Pisa, L. Bruno Pontecorvo, 3, 56127 Pisa (Italy); Università di Pisa, Lungarno Pacinotti 43, 56126 Pisa (Italy); and others

    2017-02-11

    General-purpose computing on GPUs is emerging as a new paradigm in several fields of science, although so far applications have been tailored to employ GPUs as accelerators in offline computations. With the steady decrease of GPU latencies and the increase in link and memory throughputs, time is ripe for real-time applications using GPUs in high-energy physics data acquisition and trigger systems. We will discuss the use of online parallel computing on GPUs for synchronous low level trigger systems, focusing on tests performed on the trigger of the CERN NA62 experiment. Latencies of all components need analysing, networking being the most critical. To keep it under control, we envisioned NaNet, an FPGA-based PCIe Network Interface Card (NIC) enabling GPUDirect connection. Moreover, we discuss how specific trigger algorithms can be parallelised and thus benefit from a GPU implementation, in terms of increased execution speed. Such improvements are particularly relevant for the foreseen LHC luminosity upgrade where highly selective algorithms will be crucial to maintain sustainable trigger rates with very high pileup.

  17. Validation of ATLAS L1 Topological Triggers

    CERN Document Server

    Praderio, Marco

    2017-01-01

    The Topological trigger (L1Topo) is a new component of the ATLAS L1 (Level-1) trigger. Its purpose is that of reducing the otherwise too high rate of data collection from the LHC by rejecting those events considered “uninteresting” (meaning that they have already been studied). This event rate reduction is achieved by applying topological requirements to the physical objects present in each event. It is very important to make sure that this trigger does not reject any “interesting” event. Therefore we need to verify its correct functioning. The goal of this summer student project is to study the response of two L1Topo algorithms (concerning ∆R and invariant mass). To do so I will compare the trigger decisions produced by the L1Topo hardware with the ones produced by the “official” L1Topo simulation. This way I will be able to identify events that could be incorrectly rejected. Simultaneously I will produce an emulation of these triggers that will help me understand the cause of disagreements bet...

  18. Online software trigger at PANDA/FAIR

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Donghee; Kliemt, Ralf; Nerling, Frank [Helmholtz-Institut Mainz (Germany); Denig, Achim [Institut fuer Kernphysik, Universitaet Mainz (Germany); Goetzen, Klaus; Peters, Klaus [GSI Helmholtzzentrum fuer Schwerionenforschung GmbH (Germany); Collaboration: PANDA-Collaboration

    2014-07-01

    The PANDA experiment at FAIR will employ a novel trigger-less read-out system. Since a conventional hardware trigger concept is not suitable for PANDA, a high level online event filter will be applied to perform fast event selection based on physics properties of the reconstructed events. A trigger-less data stream implies an event selection with track reconstruction and pattern recognition to be performed online, and thus analysing data under real time conditions at event rates of up to 40 MHz.The projected data rate reduction of about three orders of magnitude requires an effective background rejection, while retaining interesting signal events. Real time event selection in the environment of hadronic reactions is rather challenging and relies on sophisticated algorithms for the software trigger. The implementation and the performance of physics trigger algorithms presently studied with realistic Monte Carlo simulations is discussed. The impact of parameters such as momentum or mass resolution, PID probability, vertex reconstruction and a multivariate analysis using the TMVA package for event filtering is presented.

  19. The CMS trigger in Run 2

    CERN Document Server

    Tosi, Mia

    2018-01-01

    During its second period of operation (Run 2) which started in 2015, the LHC will reach a peak instantaneous luminosity of approximately 2$\\times 10^{34}$~cm$^{-2}s^{-1}$ with an average pile-up of about 55, far larger than the design value. Under these conditions, the online event selection is a very challenging task. In CMS, it is realised by a two-level trigger system: the Level-1 (L1) Trigger, implemented in custom-designed electronics, and the High Level Trigger (HLT), a streamlined version of the offline reconstruction software running on a computer farm.\\\\ In order to face this challenge, the L1 trigger has undergone a major upgrade compared to Run 1, whereby all electronic boards of the system have been replaced, allowing more sophisticated algorithms to be run online. Its last stage, the global trigger, is now able to perform complex selections and to compute high-level quantities, like invariant masses. Likewise, the algorithms that run in the HLT went through big improvements; in particular, new ap...

  20. The ZEUS calorimeter first level trigger

    Science.gov (United States)

    Silverstein, S.; Ali, I.; Behrens, B.; Foudas, C.; Fordham, C.; Goussiou, A.; Jaworski, M.; Lackey, J.; Reeder, D.; Robl, P.; Smith, W. H.; Vaiciulis, A.; Wodarczyk, M.; Dawson, J.; Krakauer, D.; Talaga, R.; Schlereth, J.; Zhang, H.

    1995-02-01

    An overview of the ZEUS calorimeter first level trigger is presented. The CFLT uses a pipelined architecture to accept and analyze calorimeter data for every 96 ns beam crossing interval. PMT signals are combined by analog electronics into electromagnetic and hadronic sums for 896 trigger towers. The analog sums are then digitized and analyzed. The CFLT determines the total, transverse, and missing transverse energy, identifies isolated electrons and muons, and sums energies in programmable subregions. Calculations are performed in 96 ns steps, and new data are accepted for every beam crossing. Trigger data are forwarded to the global first level trigger (GFLT) after 2 μs, allowing a GFLT accept to be issued 5 μs after the beam crossing which produced the event. Important features of the CFLT include a 12-bit effective dynamic range, extensive use of memory lookup tables for trigger calculations, fast pattern searches for isolated leptons, and low electronics noise. During the 1993 HERA run, the CFLT reduced a 50 kHz background rate to around 100 Hz.

  1. Towards RTOS support for mixed time-triggered and event-triggered task sets

    NARCIS (Netherlands)

    Heuvel, van den M.M.H.P.; Bril, R.J.; Lukkien, J.J.; Isovic, D.; Sankar Ramachandran, G.

    2012-01-01

    Many embedded systems have complex timing constraints and, at the same time, have flexibility requirements which prohibit offline planning of the entire system. To support a mixture of time-triggered and event-triggered tasks, some industrial systems deploy a real-time operating system (RTOS) with a

  2. Limited preemptive scheduling of mixed time-triggered and event-triggered tasks

    NARCIS (Netherlands)

    Heuvel, van den M.M.H.P.; Bril, R.J.; Zhang, X.; Abdullah, S.M.J.; Isovic, D.

    2013-01-01

    Many embedded systems have complex timing constraints and, at the same time, have flexibility requirements which prohibit offline planning of the entire system. To support a mixture of time-triggered and event-triggered tasks, some industrial systems deploy a table-driven dispatcher for

  3. Performance of the ATLAS Muon Trigger and Phase-1 Upgrade of Level-1 Endcap Muon Trigger

    CERN Document Server

    Mizukami, Atsushi; The ATLAS collaboration

    2017-01-01

    The ATLAS experiment utilises a trigger system to efficiently record interesting events. It consists of first-level and high-level triggers. The first-level trigger is implemented with custom-built hardware to reduce the event rate from 40 MHz to100 kHz. Then the software-based high-level triggers refine the trigger decisions reducing the output rate down to 1 kHz. Events with muons in the final state are an important signature for many physics topics at the LHC. An efficient trigger on muons and a detailed understanding of its performance are required. Trigger efficiencies are, for example, obtained from the muon decay of Z boson, with a Tag&Probe method, using proton-proton collision data collected in 2016 at a centre-of-mass energy of 13 TeV. The LHC is expected to increase its instantaneous luminosity to $3\\times10^{34} \\rm{cm^{-2}s^{-1}}$ after the phase-1 upgrade between 2018-2020. The upgrade of the ATLAS trigger system is mandatory to cope with this high-luminosity. In the phase-1 upgrade, new det...

  4. The BTeV trigger system

    International Nuclear Information System (INIS)

    Kaplan, D.M.

    2000-01-01

    BTeV is a dedicated beauty and charm experiment proposed for the Fermilab Tevatron. The broad physics program envisaged for BTeV requires a trigger that is efficient for a wide variety of heavy-quark decays, including those to all-hadronic final states. To achieve this, we plan to trigger on evidence of detached vertices at the very first trigger level, taking advantage of fast-readout pixel detectors to facilitate fast pattern recognition. Simulations show that 100-to-1 rejection of light-quark background events can be achieved at Level 1 using specialized trackfinding hardware, and that an additional factor of 10-100 in data reduction can be achieved using general purpose processor farms at Levels 2 and 3. This is adequate to allow data taking at luminosities in excess of 2x10 32 cm -2 s -1

  5. Use of GPUs in Trigger Systems

    Science.gov (United States)

    Lamanna, Gianluca

    In recent years the interest for using graphics processor (GPU) in general purpose high performance computing is constantly rising. In this paper we discuss the possible use of GPUs to construct a fast and effective real time trigger system, both in software and hardware levels. In particular, we study the integration of such a system in the NA62 trigger. The first application of GPUs for rings pattern recognition in the RICH will be presented. The results obtained show that there are not showstoppers in trigger systems with relatively low latency. Thanks to the use of off-the-shelf technology, in continous development for purposes related to video game and image processing market, the architecture described would be easily exported to other experiments, to build a versatile and fully customizable online selection.

  6. The ATLAS Electron and Photon Trigger

    CERN Document Server

    Jones, Samuel David; The ATLAS collaboration

    2018-01-01

    ATLAS electron and photon triggers covering transverse energies from 5 GeV to several TeV are essential to record signals for a wide variety of physics: from Standard Model processes to searches for new phenomena. To cope with ever-increasing luminosity and more challenging pile-up conditions at a centre-of-mass energy of 13 TeV, the trigger selections need to be optimized to control the rates and keep efficiencies high. The ATLAS electron and photon trigger performance in Run 2 will be presented, including both the role of the ATLAS calorimeter in electron and photon identification and details of new techniques developed to maintain high performance even in high pile-up conditions.

  7. Combining triggers in HEP data analysis

    International Nuclear Information System (INIS)

    Lendermann, Victor; Herbst, Michael; Krueger, Katja; Schultz-Coulon, Hans-Christian; Stamen, Rainer; Haller, Johannes

    2009-01-01

    Modern high-energy physics experiments collect data using dedicated complex multi-level trigger systems which perform an online selection of potentially interesting events. In general, this selection suffers from inefficiencies. A further loss of statistics occurs when the rate of accepted events is artificially scaled down in order to meet bandwidth constraints. An offline analysis of the recorded data must correct for the resulting losses in order to determine the original statistics of the analysed data sample. This is particularly challenging when data samples recorded by several triggers are combined. In this paper we present methods for the calculation of the offline corrections and study their statistical performance. Implications on building and operating trigger systems are discussed. (orig.)

  8. Combining triggers in HEP data analysis

    Energy Technology Data Exchange (ETDEWEB)

    Lendermann, Victor; Herbst, Michael; Krueger, Katja; Schultz-Coulon, Hans-Christian; Stamen, Rainer [Heidelberg Univ. (Germany). Kirchhoff-Institut fuer Physik; Haller, Johannes [Hamburg Univ. (Germany). Institut fuer Experimentalphysik

    2009-01-15

    Modern high-energy physics experiments collect data using dedicated complex multi-level trigger systems which perform an online selection of potentially interesting events. In general, this selection suffers from inefficiencies. A further loss of statistics occurs when the rate of accepted events is artificially scaled down in order to meet bandwidth constraints. An offline analysis of the recorded data must correct for the resulting losses in order to determine the original statistics of the analysed data sample. This is particularly challenging when data samples recorded by several triggers are combined. In this paper we present methods for the calculation of the offline corrections and study their statistical performance. Implications on building and operating trigger systems are discussed. (orig.)

  9. A new fast and programmable trigger logic

    International Nuclear Information System (INIS)

    Fucci, A.; Amendolia, S.R.; Bertolucci, E.; Bottigli, U.; Bradaschia, C.; Foa, L.; Giazotto, A.; Giorgi, M.; Givoletti, M.; Lucardesi, P.; Menzione, A.; Passuello, D.; Quaglia, M.; Ristori, L.; Rolandi, L.; Salvadori, P.; Scribano, A.; Stanga, R.; Stefanini, A.; Vincelli, M.L.

    1977-01-01

    The NA1 (FRAMM) experiment, under construction for the CERN-SPS North Area, deals with more than 1000 counter signals which have to be combined together in order to build sophisticated and highly selective triggers. These requirements have led to the development of a low cost, combinatorial, fast electronics which can replace, in an advantageous way the standard NIM electronics at the trigger level. The essential performances of the basic circuit are: 1) programmability of any desired logical expression; 2) trigger time independent of the chosen expression; 3) reduced cost and compactness due to the use of commercial RAMs, PROMs, and PLAs; 4) short delay, less than 20 ns, between input and output pulses. (Auth.)

  10. FTK: a Fast Track Trigger for ATLAS

    International Nuclear Information System (INIS)

    Anderson, J; Auerbach, B; Blair, R; Andreani, A; Andreazza, A; Citterio, M; Annovi, A; Beretta, M; Castegnaro, A; Atkinson, M; Cavaliere, V; Chang, P; Bevacqua, V; Crescioli, F; Blazey, G; Bogdan, M; Boveia, A; Canelli, F; Cheng, Y; Cervigni, F

    2012-01-01

    We describe the design and expected performance of a the Fast Tracker Trigger (FTK) system for the ATLAS detector at the Large Hadron Collider. The FTK is a highly parallel hardware system designed to operate at the Level 1 trigger output rate. It is designed to provide global tracks reconstructed in the inner detector with resolution comparable to the full offline reconstruction as input of the Level 2 trigger processing. The hardware system is based on associative memories for pattern recognition and fast FPGAs for track reconstruction. The FTK is expected to dramatically improve the performance of track based isolation and b-tagging with little to no dependencies of pile-up interactions.

  11. A self triggered intensified Ccd (Stic)

    International Nuclear Information System (INIS)

    Charon, Y.; Laniece, P.; Bendali, M.

    1990-01-01

    We are developing a new device based on the results reported previously of the successfull coincidence detection of β- particles with a high spatial resolution [1]. The novelty of the device consists in triggering an intensified CCD, i.e. a CCD coupled to an image intensifier (II), by an electrical signal collected from the II itself. This is a suitable procedure for detecting with high efficiency and high resolution low light rare events. The trigger pulse is obtained from the secondary electrons produced by multiplication in a double microchannel plate (MCP) and collected on the aluminized layer protecting the phosphor screen in the II. Triggering efficiencies up to 80% has been already achieved

  12. The UA1 upgrade calorimeter trigger processor

    International Nuclear Information System (INIS)

    Bains, M.; Charleton, D.; Ellis, N.; Garvey, J.; Gregory, J.; Jimack, M.P.; Jovanovic, P.; Kenyon, I.R.; Baird, S.A.; Campbell, D.; Cawthraw, M.; Coughlan, J.; Flynn, P.; Galagedera, S.; Grayer, G.; Halsall, R.; Shah, T.P.; Stephens, R.; Biddulph, P.; Eisenhandler, E.; Fensome, I.F.; Landon, M.; Robinson, D.; Oliver, J.; Sumorok, K.

    1990-01-01

    The increased luminosity of the improved CERN Collider and the more subtle signals of second-generation collider physics demand increasingly sophisticated triggering. We have built a new first-level trigger processor designed to use the excellent granularity of the UA1 upgrade calorimeter. This device is entirely digital and handles events in 1.5 μs, thus introducing no dead time. Its most novel feature is fast two-dimensional electromagnetic cluster-finding with the possibility of demanding an isolated shower of limited penetration. The processor allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. This hard-wired processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It was used extensively in the 1988 and 1989 runs of the CERN Collider. (orig.)

  13. The UA1 upgrade calorimeter trigger processor

    International Nuclear Information System (INIS)

    Bains, N.; Baird, S.A.; Biddulph, P.

    1990-01-01

    The increased luminosity of the improved CERN Collider and the more subtle signals of second-generation collider physics demand increasingly sophisticated triggering. We have built a new first-level trigger processor designed to use the excellent granularity of the UA1 upgrade calorimeter. This device is entirely digital and handles events in 1.5 μs, thus introducing no deadtime. Its most novel feature is fast two-dimensional electromagnetic cluster-finding with the possibility of demanding an isolated shower of limited penetration. The processor allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. This hard-wired processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It was used extensively in the 1988 and 1989 runs of the CERN Collider. (author)

  14. The double Chooz hardware trigger system

    Energy Technology Data Exchange (ETDEWEB)

    Cucoanes, Andi; Beissel, Franz; Reinhold, Bernd; Roth, Stefan; Stahl, Achim; Wiebusch, Christopher [RWTH Aachen (Germany)

    2008-07-01

    The double Chooz neutrino experiment aims to improve the present knowledge on {theta}{sub 13} mixing angle using two similar detectors placed at {proportional_to}280 m and respectively 1 km from the Chooz power plant reactor cores. The detectors measure the disappearance of reactor antineutrinos. The hardware trigger has to be very efficient for antineutrinos as well as for various types of background events. The triggering condition is based on discriminated PMT sum signals and the multiplicity of groups of PMTs. The talk gives an outlook to the double Chooz experiment and explains the requirements of the trigger system. The resulting concept and its performance is shown as well as first results from a prototype system.

  15. Self-triggering superconducting fault current limiter

    Science.gov (United States)

    Yuan, Xing [Albany, NY; Tekletsadik, Kasegn [Rexford, NY

    2008-10-21

    A modular and scaleable Matrix Fault Current Limiter (MFCL) that functions as a "variable impedance" device in an electric power network, using components made of superconducting and non-superconducting electrically conductive materials. The matrix fault current limiter comprises a fault current limiter module that includes a superconductor which is electrically coupled in parallel with a trigger coil, wherein the trigger coil is magnetically coupled to the superconductor. The current surge doing a fault within the electrical power network will cause the superconductor to transition to its resistive state and also generate a uniform magnetic field in the trigger coil and simultaneously limit the voltage developed across the superconductor. This results in fast and uniform quenching of the superconductors, significantly reduces the burnout risk associated with non-uniformity often existing within the volume of superconductor materials. The fault current limiter modules may be electrically coupled together to form various "n" (rows).times."m" (columns) matrix configurations.

  16. Dendrite Injury Triggers DLK-Independent Regeneration

    Directory of Open Access Journals (Sweden)

    Michelle C. Stone

    2014-01-01

    Full Text Available Axon injury triggers regeneration through activation of a conserved kinase cascade, which includes the dual leucine zipper kinase (DLK. Although dendrites are damaged during stroke, traumatic brain injury, and seizure, it is not known whether mature neurons monitor dendrite injury and initiate regeneration. We probed the response to dendrite damage using model Drosophila neurons. Two larval neuron types regrew dendrites in distinct ways after all dendrites were removed. Dendrite regeneration was also triggered by injury in adults. Next, we tested whether dendrite injury was initiated with the same machinery as axon injury. Surprisingly, DLK, JNK, and fos were dispensable for dendrite regeneration. Moreover, this MAP kinase pathway was not activated by injury to dendrites. Thus, neurons respond to dendrite damage and initiate regeneration without using the conserved DLK cascade that triggers axon regeneration.

  17. The ZEUS second level calorimeter trigger

    International Nuclear Information System (INIS)

    Jong, S.J. de.

    1990-01-01

    ZEUS is a detector for the HERA ep collider, consisting of several large components. The most important being the inner tracking detectors, which are positioned nearest to the interaction point, the calorimeter surrounding the inner tracking detectors and the muon detectors on the outside of the experimental setup. Each component will deliver a vast amount of information. In order to keep this information manageable, data is preprocessed and condensed per component and then combined to obtain the final global trigger result. The main subject of this thesis is the second level calorimeter trigger processor of the ZEUS detector. In order to be able to reject the unwanted events passing the first level, the topological event signature will have to be used at the second level. The most demanding task of the second level is the recognition of local energy depositions corresponding to isolated electrons and hadron jets. Also part of the work performed by the first level will be repeated with a higher level of accuracy. Additional information not available to the first level trigger will be processed and will be made available to the global second level trigger decision module. For the second level calorimeter trigger processor a special VME module, containing two transputers, has been developed. The second level calorimeter trigger algorithm described in this thesis was tested with simulated events, that were tracked through a computer simulation of the ZEUS detector. A part of this thesis is therefore devoted to the description of the various Monte Carlo models and the justification of the way in which they were used. (author). 132 refs.; 76 figs.; 18 tabs

  18. The ATLAS trigger: high-level trigger commissioning and operation during early data taking

    International Nuclear Information System (INIS)

    Goncalo, R

    2008-01-01

    The ATLAS experiment is one of the two general-purpose experiments due to start operation soon at the Large Hadron Collider (LHC). The LHC will collide protons at a centre of mass energy of 14 TeV, with a bunch-crossing rate of 40 MHz. The ATLAS three-level trigger will reduce this input rate to match the foreseen offline storage capability of 100-200 Hz. This paper gives an overview of the ATLAS High Level Trigger focusing on the system design and its innovative features. We then present the ATLAS trigger strategy for the initial phase of LHC exploitation. Finally, we report on the valuable experience acquired through in-situ commissioning of the system where simulated events were used to exercise the trigger chain. In particular we show critical quantities such as event processing times, measured in a large-scale HLT farm using a complex trigger menu

  19. Application of Fault Management Theory to the Quantitative Selection of a Launch Vehicle Abort Trigger Suite

    Science.gov (United States)

    Lo, Yunnhon; Johnson, Stephen B.; Breckenridge, Jonathan T.

    2014-01-01

    This paper describes the quantitative application of the theory of System Health Management and its operational subset, Fault Management, to the selection of Abort Triggers for a human-rated launch vehicle, the United States' National Aeronautics and Space Administration's (NASA) Space Launch System (SLS). The results demonstrate the efficacy of the theory to assess the effectiveness of candidate failure detection and response mechanisms to protect humans from time-critical and severe hazards. The quantitative method was successfully used on the SLS to aid selection of its suite of Abort Triggers.

  20. Doppler Ultrasound Triggering for Cardiovascular MRI at 3T in a Healthy Volunteer Study.

    Science.gov (United States)

    Kording, Fabian; Yamamura, Jin; Lund, Gunnar; Ueberle, Friedrich; Jung, Caroline; Adam, Gerhard; Schoennagel, Bjoern Philip

    2017-04-10

    Electrocardiogram (ECG) triggering for cardiac magnetic resonance (CMR) may be influenced by electromagnetic interferences with increasing magnetic field strength. The aim of this study was to evaluate the performance of Doppler ultrasound (DUS) as an alternative trigger technique for CMR in comparison to ECG and pulse oximetry (POX) at 3T and using different sequence types. Balanced turbo field echo two-dimensional (2D) short axis cine CMR and 2D phase-contrast angiography of the ascending aorta was performed in 11 healthy volunteers at 3T using ECG, DUS, and POX for cardiac triggering. DUS and POX triggering were compared to the reference standard of ECG in terms of trigger quality (trigger detection and temporal variability), image quality [endocardial blurring (EB)], and functional measurements [left ventricular (LV) volumetry and aortic blood flow velocimetry]. Trigger signal detection and temporal variability did not differ significantly between ECG/DUS (I = 0.6) and ECG/POX (P = 0.4). Averaged EB was similar for ECG, DUS, and POX (p ECG/DUS = 0.4, p ECG/POX = 0.9). Diastolic EB was significantly decreased for DUS in comparison to ECG (P = 0.02) and POX (P = 0.04). The LV function assessment and aortic blood flow were not significantly different. This study demonstrated the feasibility of DUS for gating human CMR at 3T. The magnetohydrodynamic effect did not significantly disturb ECG triggering in this small healthy volunteer study. DUS showed a significant improvement in diastolic EB but could not be identified as a superior trigger method. The potential benefit of DUS has to be evaluated in a larger clinical patient population.

  1. Self triggered single pulse beam position monitor

    International Nuclear Information System (INIS)

    Rothman, J.L.; Blum, E.B.

    1993-01-01

    A self triggered beam position monitor (BPM) has been developed for the NSLS injection system to provide single pulse orbit measurements in the booster synchrotron, linac, and transport lines. The BPM integrates the negative going portion of 3 nS wide bipolar pickup electrode signals. The gated, self triggering feature confines critical timing components to the front end, relaxing external timing specifications. The system features a low noise high speed FET sampler, a fiber optic gate for bunch and turn selection, and an inexpensive interface to a standard PC data acquisition system

  2. Run 2 ATLAS Trigger and Detector Performance

    CERN Document Server

    Solovyanov, Oleg; The ATLAS collaboration

    2018-01-01

    The 2nd LHC run has started in June 2015 with a proton-proton centre-of-mass collision energy of 13 TeV. During the years 2016 and 2017, LHC delivered an unprecedented amount of luminosity under the ever-increasing challenging conditions in terms of peak luminosity, pile-up and trigger rates. In this talk, the LHC running conditions and the improvements made to the ATLAS experiment in the course of Run 2 will be discussed, and the latest ATLAS detector and ATLAS trigger performance results from the Run 2 will be presented.

  3. Advances in tracking and trigger concepts

    International Nuclear Information System (INIS)

    Kisel, Ivan

    2014-01-01

    Increasing beam intensities and input data rates require to rethink the traditional approaches in trigger concepts. At the same time the advanced many-core computer architectures providing new dimensions in programming require to rework the standard methods or to develop new methods of track reconstruction in order to efficiently use parallelism of the computer hardware. As a results a new tendency appears to replace the standard (usually implemented in FPGA) hardware triggers by clusters of computers running software reconstruction and selection algorithms. In addition that makes possible unification of the offline and on-line data processing and analysis in one software package running on a heterogeneous computer farm

  4. The CMS High-Level Trigger

    International Nuclear Information System (INIS)

    Covarelli, R.

    2009-01-01

    At the startup of the LHC, the CMS data acquisition is expected to be able to sustain an event readout rate of up to 100 kHz from the Level-1 trigger. These events will be read into a large processor farm which will run the 'High-Level Trigger'(HLT) selection algorithms and will output a rate of about 150 Hz for permanent data storage. In this report HLT performances are shown for selections based on muons, electrons, photons, jets, missing transverse energy, τ leptons and b quarks: expected efficiencies, background rates and CPU time consumption are reported as well as relaxation criteria foreseen for a LHC startup instantaneous luminosity.

  5. The CMS High-Level Trigger

    CERN Document Server

    Covarelli, Roberto

    2009-01-01

    At the startup of the LHC, the CMS data acquisition is expected to be able to sustain an event readout rate of up to 100 kHz from the Level-1 trigger. These events will be read into a large processor farm which will run the "High-Level Trigger" (HLT) selection algorithms and will output a rate of about 150 Hz for permanent data storage. In this report HLT performances are shown for selections based on muons, electrons, photons, jets, missing transverse energy, tau leptons and b quarks: expected efficiencies, background rates and CPU time consumption are reported as well as relaxation criteria foreseen for a LHC startup instantaneous luminosity.

  6. The CMS High-Level Trigger

    Science.gov (United States)

    Covarelli, R.

    2009-12-01

    At the startup of the LHC, the CMS data acquisition is expected to be able to sustain an event readout rate of up to 100 kHz from the Level-1 trigger. These events will be read into a large processor farm which will run the "High-Level Trigger" (HLT) selection algorithms and will output a rate of about 150 Hz for permanent data storage. In this report HLT performances are shown for selections based on muons, electrons, photons, jets, missing transverse energy, τ leptons and b quarks: expected efficiencies, background rates and CPU time consumption are reported as well as relaxation criteria foreseen for a LHC startup instantaneous luminosity.

  7. Popular sweetner sucralose as a migraine trigger.

    Science.gov (United States)

    Patel, Rajendrakumar M; Sarma, Rakesh; Grimsley, Edwin

    2006-09-01

    Sucralose (trichlorogalactosucrose, or better known as Splenda) is an artificial sweetener from native sucrose that was approved by the FDA on April 1, 1998 (April Fool's Day). This observation of a potential causal relationship between sucralose and migraines may be important for physicians to remember this can be a possible trigger during dietary history taking. Identifying further triggers for migraine headaches, in this case sucralose, may help alleviate some of the cost burden (through expensive medical therapy or missed work opportunity) as well as provide relief to migraineurs.

  8. CMS Calorimeter Trigger Phase I upgrade

    International Nuclear Information System (INIS)

    Klabbers, P; Gorski, T; Bachtis, M; Dasu, S; Fobes, R; Grothe, M; Ross, I; Smith, W H; Compton, K; Farmahini-Farahani, A; Gregerson, A; Seemuth, D; Schulte, M

    2012-01-01

    We present a design for the Phase-1 upgrade of the Compact Muon Solenoid (CMS) calorimeter trigger system composed of FPGAs and Multi-GBit/sec links that adhere to the μTCA crate Telecom standard. The upgrade calorimeter trigger will implement algorithms that create collections of isolated and non-isolated electromagnetic objects, isolated and non-isolated tau objects and jet objects. The algorithms are organized in several steps with progressive data reduction. These include a particle cluster finder that reconstructs overlapping clusters of 2x2 calorimeter towers and applies electron identification, a cluster overlap filter, particle isolation determination, jet reconstruction, particle separation and sorting.

  9. Hardware trigger processor for the MDT system

    CERN Document Server

    AUTHOR|(SzGeCERN)757787; The ATLAS collaboration; Hazen, Eric; Butler, John; Black, Kevin; Gastler, Daniel Edward; Ntekas, Konstantinos; Taffard, Anyes; Martinez Outschoorn, Verena; Ishino, Masaya; Okumura, Yasuyuki

    2017-01-01

    We are developing a low-latency hardware trigger processor for the Monitored Drift Tube system in the Muon spectrometer. The processor will fit candidate Muon tracks in the drift tubes in real time, improving significantly the momentum resolution provided by the dedicated trigger chambers. We present a novel pure-FPGA implementation of a Legendre transform segment finder, an associative-memory alternative implementation, an ARM (Zynq) processor-based track fitter, and compact ATCA carrier board architecture. The ATCA architecture is designed to allow a modular, staged approach to deployment of the system and exploration of alternative technologies.

  10. A trigger simulation framework for the ALICE experiment

    International Nuclear Information System (INIS)

    Antinori, F; Carminati, F; Gheata, A; Gheata, M

    2011-01-01

    A realistic simulation of the trigger system in a complex HEP experiment is essential for performing detailed trigger efficiency studies. The ALICE trigger simulation is evolving towards a framework capable of replaying the full trigger chain starting from the input to the individual trigger processors and ending with the decision mechanisms of the ALICE central trigger processor. This paper describes the new ALICE trigger simulation framework that is being tested and deployed. The framework handles details like trigger levels, signal delays and busy signals, implementing the trigger logic via customizable trigger device objects managed by a robust scheduling mechanism. A big advantage is the high flexibility of the framework, which is able to mix together components described with very different levels of detail. The framework is being gradually integrated within the ALICE simulation and reconstruction frameworks.

  11. Towards a Level-1 Tracking Trigger for the ATLAS Experiment

    CERN Document Server

    De Santo, A; The ATLAS collaboration

    2016-01-01

    In preparation for the high-luminosity phase of the Large Hadron Collider, ATLAS is planning a trigger upgrade that will enable the experiment to use tracking information already at the first trigger level. This will provide enhanced background rejection power at trigger level while preserving much needed flexibility for the trigger system. The status and current plans for the new ATLAS Level-1 tracking trigger are presented.

  12. UA1 upgrade first-level calorimeter trigger processor

    International Nuclear Information System (INIS)

    Bains, N.; Charlton, D.; Ellis, N.; Garvey, J.; Gregory, J.; Jimack, M.P.; Jovanovic, P.; Kenyon, I.R.; Baird, S.A.; Campbell, D.; Cawthraw, M.; Coughlan, J.; Flynn, P.; Galagedera, S.; Grayer, G.; Halsall, R.; Shah, T.P.; Stephens, R.; Eisenhandler, E.; Fensome, I.; Landon, M.

    1989-01-01

    A new first-level trigger processor has been built for the UA1 experiment on the Cern SppS Collider. The processor exploits the fine granularity of the new UA1 uranium-TMP calorimeter to improve the selectivity of the trigger. The new electron trigger has improved hadron jet rejection, achieved by requiring low energy deposition around the electromagnetic cluster. A missing transverse energy trigger and a total energy trigger have also been implemented. (orig.)

  13. Prostate cancer may trigger paraneoplastic limbic encephalitis

    DEFF Research Database (Denmark)

    Jakobsen, Jakob Kristian; Zakharia, Elias Raja; Boysen, Anders Kindberg Fossø

    2013-01-01

    -Hu antibody test the patient was diagnosed with paraneoplastic limbic encephalitis related to prostate cancer. The patient died within 6 months. We review the literature on prostate cancer-related paraneoplastic limbic encephalitis. High-risk prostate cancer can trigger paraneoplastic limbic encephalitis...

  14. Entity models for trigger-reaction documents

    NARCIS (Netherlands)

    Khalid, M.A.; Marx, M.; Makkes, M.X.

    2008-01-01

    We define the notion of an entity model for a special kind of document popular on the web: an article followed by a list of reactions on that article, usually by many authors, usually inverse chronologically ordered. We call these documents trigger-reactions pairs. The entity model describes which

  15. Hard scattering and a diffractive trigger

    International Nuclear Information System (INIS)

    Berger, E.L.; Collins, J.C.; Soper, D.E.; Sterman, G.

    1986-02-01

    Conclusions concerning the properties of hard scattering in diffractively produced systems are summarized. One motivation for studying diffractive hard scattering is to investigate the interface between Regge theory and perturbative QCD. Another is to see whether diffractive triggering can result in an improvement in the signal-to-background ratio of measurements of production of very heavy quarks. 5 refs

  16. 2017 B-Physics trigger efficiencies

    CERN Document Server

    CMS Collaboration

    2018-01-01

    The performance of the trigger used to select B-Physics decay channels in CMS is presented for data collected in 2017, corresponding to an integrated luminosity of $9.8\\,\\mathrm{fb}^{-1}$ at $13\\,\\mathrm{TeV}$.

  17. Self-triggered coordination with ternary controllers

    NARCIS (Netherlands)

    De Persis, Claudio; Frasca, Paolo

    2012-01-01

    This paper regards coordination of networked systems with ternary controllers. We develop a hybrid coordination system which implements a self-triggered communication policy, based on polling the neighbors upon need. We prove that the proposed scheme ensures finite-time convergence to a neighborhood

  18. BTeV trigger/DAQ innovations

    International Nuclear Information System (INIS)

    Votava, Margaret

    2005-01-01

    The BTeV experiment was a collider based high energy physics (HEP) B-physics experiment proposed at Fermilab. It included a large-scale, high speed trigger/data acquisition (DAQ) system, reading data off the detector at 500 Gbytes/sec and writing to mass storage at 200 Mbytes/sec. The online design was considered to be highly credible in terms of technical feasibility, schedule and cost. This paper will give an overview of the overall trigger/DAQ architecture, highlight some of the challenges, and describe the BTeV approach to solving some of the technical challenges. At the time of termination in early 2005, the experiment had just passed its baseline review. Although not fully implemented, many of the architecture choices, design, and prototype work for the online system (both trigger and DAQ) were well on their way to completion. Other large, high-speed online systems may have interest in the some of the design choices and directions of BTeV, including (a) a commodity-based tracking trigger running asynchronously at full rate, (b) the hierarchical control and fault tolerance in a large real time environment, (c) a partitioning model that supports offline processing on the online farms during idle periods with plans for dynamic load balancing, and (d) an independent parallel highway architecture

  19. Event Reconstruction Algorithms for the ATLAS Trigger

    Energy Technology Data Exchange (ETDEWEB)

    Fonseca-Martin, T.; /CERN; Abolins, M.; /Michigan State U.; Adragna, P.; /Queen Mary, U. of London; Aleksandrov, E.; /Dubna, JINR; Aleksandrov, I.; /Dubna, JINR; Amorim, A.; /Lisbon, LIFEP; Anderson, K.; /Chicago U., EFI; Anduaga, X.; /La Plata U.; Aracena, I.; /SLAC; Asquith, L.; /University Coll. London; Avolio, G.; /CERN; Backlund, S.; /CERN; Badescu, E.; /Bucharest, IFIN-HH; Baines, J.; /Rutherford; Barria, P.; /Rome U. /INFN, Rome; Bartoldus, R.; /SLAC; Batreanu, S.; /Bucharest, IFIN-HH /CERN; Beck, H.P.; /Bern U.; Bee, C.; /Marseille, CPPM; Bell, P.; /Manchester U.; Bell, W.H.; /Glasgow U. /Pavia U. /INFN, Pavia /Regina U. /CERN /Annecy, LAPP /Paris, IN2P3 /Royal Holloway, U. of London /Napoli Seconda U. /INFN, Naples /Argonne /CERN /UC, Irvine /Barcelona, IFAE /Barcelona, Autonoma U. /CERN /Montreal U. /CERN /Glasgow U. /Michigan State U. /Bucharest, IFIN-HH /Napoli Seconda U. /INFN, Naples /New York U. /Barcelona, IFAE /Barcelona, Autonoma U. /Salento U. /INFN, Lecce /Pisa U. /INFN, Pisa /Bucharest, IFIN-HH /UC, Irvine /CERN /Glasgow U. /INFN, Genoa /Genoa U. /Lisbon, LIFEP /Napoli Seconda U. /INFN, Naples /UC, Irvine /Valencia U. /Rio de Janeiro Federal U. /University Coll. London /New York U.; /more authors..

    2011-11-09

    The ATLAS experiment under construction at CERN is due to begin operation at the end of 2007. The detector will record the results of proton-proton collisions at a center-of-mass energy of 14 TeV. The trigger is a three-tier system designed to identify in real-time potentially interesting events that are then saved for detailed offline analysis. The trigger system will select approximately 200 Hz of potentially interesting events out of the 40 MHz bunch-crossing rate (with 10{sup 9} interactions per second at the nominal luminosity). Algorithms used in the trigger system to identify different event features of interest will be described, as well as their expected performance in terms of selection efficiency, background rejection and computation time per event. The talk will concentrate on recent improvements and on performance studies, using a very detailed simulation of the ATLAS detector and electronics chain that emulates the raw data as it will appear at the input to the trigger system.

  20. Multiple output timing and trigger generator

    Energy Technology Data Exchange (ETDEWEB)

    Wheat, Robert M. [Los Alamos National Laboratory; Dale, Gregory E [Los Alamos National Laboratory

    2009-01-01

    In support of the development of a multiple stage pulse modulator at the Los Alamos National Laboratory, we have developed a first generation, multiple output timing and trigger generator. Exploiting Commercial Off The Shelf (COTS) Micro Controller Units (MCU's), the timing and trigger generator provides 32 independent outputs with a timing resolution of about 500 ns. The timing and trigger generator system is comprised of two MCU boards and a single PC. One of the MCU boards performs the functions of the timing and signal generation (the timing controller) while the second MCU board accepts commands from the PC and provides the timing instructions to the timing controller. The PC provides the user interface for adjusting the on and off timing for each of the output signals. This system provides 32 output or timing signals which can be pre-programmed to be in an on or off state for each of 64 time steps. The width or duration of each of the 64 time steps is programmable from 2 {micro}s to 2.5 ms with a minimum time resolution of 500 ns. The repetition rate of the programmed pulse train is only limited by the time duration of the programmed event. This paper describes the design and function of the timing and trigger generator system and software including test results and measurements.

  1. Performance of the CMS High Level Trigger

    CERN Document Server

    Perrotta, Andrea

    2015-01-01

    The CMS experiment has been designed with a 2-level trigger system. The first level is implemented using custom-designed electronics. The second level is the so-called High Level Trigger (HLT), a streamlined version of the CMS offline reconstruction software running on a computer farm. For Run II of the Large Hadron Collider, the increases in center-of-mass energy and luminosity will raise the event rate to a level challenging for the HLT algorithms. The increase in the number of interactions per bunch crossing, on average 25 in 2012, and expected to be around 40 in Run II, will be an additional complication. We present here the expected performance of the main triggers that will be used during the 2015 data taking campaign, paying particular attention to the new approaches that have been developed to cope with the challenges of the new run. This includes improvements in HLT electron and photon reconstruction as well as better performing muon triggers. We will also present the performance of the improved trac...

  2. ALICE Trigger and Event Selection QA

    CERN Multimedia

    CERN. Geneva

    2012-01-01

    I will present the last nine weeks of work on building a class that efficiently produces trending physics selection of various trigger classes for the purposes of quality assurance. This class is easily generalizable and will be used for live monitoring via a webpage.

  3. Triggering on electrons and photons with CMS

    Directory of Open Access Journals (Sweden)

    Zabi Alexandre

    2012-06-01

    Full Text Available Throughout the year 2011, the Large Hadron Collider (LHC has operated with an instantaneous luminosity that has risen continually to around 4 × 1033cm−2s−1. With this prodigious high-energy proton collisions rate, efficient triggering on electrons and photons has become a major challenge for the LHC experiments. The Compact Muon Solenoid (CMS experiment implements a sophisticated two-level online selection system that achieves a rejection factor of nearly 106. The first level (L1 is based on coarse information coming from the calorimeters and the muon detectors while the High-Level Trigger (HLT combines fine-grain information from all sub-detectors. In this intense hadronic environment, the L1 electron/photon trigger provides a powerful tool to select interesting events. It is based upon information from the Electromagnetic Calorimeter (ECAL, a high-resolution detector comprising 75848 lead tungstate (PbWO4 crystals in a “barrel” and two “endcaps”. The performance as well as the optimization of the electron/photon trigger are presented.

  4. Reflex epilepsy: triggers and management strategies

    Directory of Open Access Journals (Sweden)

    Okudan ZV

    2018-01-01

    Full Text Available Zeynep Vildan Okudan,1 Çiğdem Özkara2 1Department of Neurology, Bakirkoy Dr Sadi Konuk Education and Research Hospital, 2Department of Neurology and Clinical Neurophysiology, Cerrahpasa Faculty of Medicine, University of Istanbul, Istanbul, Turkey Abstract: Reflex epilepsies (REs are identified as epileptic seizures that are consistently induced by identifiable and objective-specific triggers, which may be an afferent stimulus or by the patient’s own activity. RE may have different subtypes depending on the stimulus characteristic. There are significant clinical and electrophysiologic differences between different RE types. Visual stimuli-sensitive or photosensitive epilepsies constitute a large proportion of the RE and are mainly related to genetic causes. Reflex epilepsies may present with focal or generalized seizures due to specific triggers, and sometimes seizures may occur spontaneously. The stimuli can be external (light flashes, hot water, internal (emotion, thinking, or both and should be distinguished from triggering precipitants, which most epileptic patients could report such as emotional stress, sleep deprivation, alcohol, and menstrual cycle. Different genetic and acquired factors may play a role in etiology of RE. This review will provide a current overview of the triggering factors and management of reflex seizures. Keywords: seizure, reflex epilepsy, photosensitivity, hot water, reading, thinking

  5. Does heavy physical exertion trigger myocardial infarction?

    DEFF Research Database (Denmark)

    Hallqvist, J; Möller, J; Ahlbom, A

    2000-01-01

    To study possible triggering of first events of acute myocardial infarction by heavy physical exertion, the authors conducted a case-crossover analysis (1993-1994) within a population-based case-referent study in Stockholm County, Sweden (the Stockholm Heart Epidemiology Program). Interviews were...

  6. The CMS Barrel Muon Trigger Upgrade

    CERN Document Server

    Triossi, Andrea

    2017-01-01

    ABSTRACT: The increase of luminosity expected by LHC during Phase 1 will impose several constrains for rate reduction while maintaining high efficiency in the CMS Level 1 trigger system. The TwinMux system is the early layer of the muon barrel region that concentrates the information from different subdetectors DT, RPC and HO. It arranges and fan-out the slow optical trigger links from the detector chambers into faster links (10 Gbps) that are sent to the track finders. Results, from collision runs, that confirm the satisfactory operation of the trigger system up to the output of the barrel track finder, will be shown. SUMMARY: In view of the increase of luminosity during phase 1 upgrade of LHC, the muon trigger chain of the Compact Muon Solenoid (CMS) experiment underwent considerable improvements. The muon detector was designed for preserving the complementarity and redundancy of three separate muon detection systems, Cathode Strip Chambers (CSC), Drift Tubes (DT) and Resistive Plate Chambers (RPC), until ...

  7. Trigger factors and mechanisms in migraine

    NARCIS (Netherlands)

    Schoonman, Geurt Gerhard

    2008-01-01

    Migraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and photophobia. It is a paroxysmal disorder for which several several trigger factors have been identified by

  8. BTeV detached vertex trigger

    International Nuclear Information System (INIS)

    Gottschalk, E.E.

    2001-01-01

    BTeV is a collider experiment that has been approved to run in the Tevatron at Fermilab. The experiment will conduct precision studies of CP violation using a forward-geometry detector. The detector will be optimized for high-rate detection of beauty and charm particles produced in collisions between protons and anti-protons. BTeV will trigger on beauty and charm events by taking advantage of the main difference between these heavy quark events and more typical hadronic events - the presence of detached beauty and charm decay vertices. The first stage of the BTeV trigger will receive data from a pixel vertex detector at a rate of 100 gb s -1 , reconstruct tracks and vertices for every beam crossing, reject 99% of beam crossings that do not produce beauty or charm particles, and trigger on beauty events with high efficiency. An overview of the trigger design and its influence on the design of the pixel vertex detector is presented

  9. Event reconstruction algorithms for the ATLAS trigger

    Energy Technology Data Exchange (ETDEWEB)

    F-Martin, T; Avolio, G; Backlund, S [European Laboratory for Particle Physics (CERN), Geneva (Switzerland); Abolins, M [Michigan State University, Department of Physics and Astronomy, East Lansing, Michigan (United States); Adragna, P [Department of Physics, Queen Mary and Westfield College, University of London, London (United Kingdom); Aleksandrov, E; Aleksandrov, I [Joint Institute for Nuclear Research, Dubna (Russian Federation); Amorim, A [Laboratorio de Instrumentacao e Fisica Experimental, Lisboa (Portugal); Anderson, K [University of Chicago, Enrico Fermi Institute, Chicago, Illinois (United States); Anduaga, X [National University of La Plata, La Plata (United States); Aracena, I; Bartoldus, R [Stanford Linear Accelerator Center (SLAC), Stanford (United States); Asquith, L [Department of Physics and Astronomy, University College London, London (United Kingdom); Badescu, E [National Institute for Physics and Nuclear Engineering, Institute of Atomic Physics, Bucharest (Romania); Baines, J [Rutherford Appleton Laboratory, Chilton, Didcot (United Kingdom); Beck, H P [Laboratory for High Energy Physics, University of Bern, Bern (Switzerland); Bee, C [Centre de Physique des Particules de Marseille, IN2P3-CNRS, Marseille (France); Bell, P [Department of Physics and Astronomy, University of Manchester, Manchester (United Kingdom); Barria, P; Batreanu, S [and others

    2008-07-01

    The ATLAS experiment under construction at CERN is due to begin operation at the end of 2007. The detector will record the results of proton-proton collisions at a center-of-mass energy of 14 TeV. The trigger is a three-tier system designed to identify in real-time potentially interesting events that are then saved for detailed offline analysis. The trigger system will select approximately 200 Hz of potentially interesting events out of the 40 MHz bunch-crossing rate (with 10{sup 9} interactions per second at the nominal luminosity). Algorithms used in the trigger system to identify different event features of interest will be described, as well as their expected performance in terms of selection efficiency, background rejection and computation time per event. The talk will concentrate on recent improvements and on performance studies, using a very detailed simulation of the ATLAS detector and electronics chain that emulates the raw data as it will appear at the input to the trigger system.

  10. Event reconstruction algorithms for the ATLAS trigger

    International Nuclear Information System (INIS)

    F-Martin, T; Avolio, G; Backlund, S; Abolins, M; Adragna, P; Aleksandrov, E; Aleksandrov, I; Amorim, A; Anderson, K; Anduaga, X; Aracena, I; Bartoldus, R; Asquith, L; Badescu, E; Baines, J; Beck, H P; Bee, C; Bell, P; Barria, P; Batreanu, S

    2008-01-01

    The ATLAS experiment under construction at CERN is due to begin operation at the end of 2007. The detector will record the results of proton-proton collisions at a center-of-mass energy of 14 TeV. The trigger is a three-tier system designed to identify in real-time potentially interesting events that are then saved for detailed offline analysis. The trigger system will select approximately 200 Hz of potentially interesting events out of the 40 MHz bunch-crossing rate (with 10 9 interactions per second at the nominal luminosity). Algorithms used in the trigger system to identify different event features of interest will be described, as well as their expected performance in terms of selection efficiency, background rejection and computation time per event. The talk will concentrate on recent improvements and on performance studies, using a very detailed simulation of the ATLAS detector and electronics chain that emulates the raw data as it will appear at the input to the trigger system

  11. The ATLAS online High Level Trigger framework experience reusing offline software components in the ATLAS trigger

    CERN Document Server

    Wiedenmann, W

    2009-01-01

    Event selection in the Atlas High Level Trigger is accomplished to a large extent by reusing software components and event selection algorithms developed and tested in an offline environment. Many of these offline software modules are not specifically designed to run in a heavily multi-threaded online data flow environment. The Atlas High Level Trigger (HLT) framework based on the Gaudi and Atlas Athena frameworks, forms the interface layer, which allows the execution of the HLT selection and monitoring code within the online run control and data flow software. While such an approach provides a unified environment for trigger event selection across all of Atlas, it also poses strict requirements on the reused software components in terms of performance, memory usage and stability. Experience of running the HLT selection software in the different environments and especially on large multi-node trigger farms has been gained in several commissioning periods using preloaded Monte Carlo events, in data taking peri...

  12. Triggering of Erythrocyte Cell Membrane Scrambling by Emodin

    Directory of Open Access Journals (Sweden)

    Morena Mischitelli

    2016-11-01

    Full Text Available Background/Aims: The natural anthraquinone derivative emodin (1,3,8-trihydroxy-6-methylanthraquinone is a component of several Chinese medicinal herbal preparations utilized for more than 2000 years. The substance has been used against diverse disorders including malignancy, inflammation and microbial infection. The substance is effective in part by triggering suicidal death or apoptosis. Similar to apoptosis of nucleated cells erythrocytes may enter suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in the triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i, oxidative stress and ceramide. The present study aimed to test, whether emodin induces eryptosis and, if so, to elucidate underlying cellular mechanisms. Methods: Phosphatidylserine abundance at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Results: Exposure of human erythrocytes for 48 hours to emodin (≥ 10 µM significantly increased the percentage of annexin-V-binding cells, and at higher concentrations (≥ 50 µM significantly increased forward scatter. Emodin significantly increased Fluo3-fluorescence (≥ 10 µM, DCFDA fluorescence (75 µM and ceramide abundance (75 µM. The effect of emodin on annexin-V-binding was significantly blunted but not abolished by removal of extracellular Ca2+. Conclusions: Emodin triggers phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to stimulation of Ca2+ entry and paralleled by oxidative stress and ceramide appearance at the erythroctye surface.

  13. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles

    NARCIS (Netherlands)

    Youssef, Mohamed A. F. M.; van der Veen, Fulco; Al-Inany, Hesham G.; Griesinger, Georg; Mochtar, Monique H.; Aboulfoutouh, Ismail; Khattab, Sherif M.; van Wely, Madelon

    2011-01-01

    Background Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is

  14. The ATLAS High Level Trigger Steering Framework and the Trigger 
Configuration System.

    CERN Document Server

    Pérez Cavalcanti, Tiago; The ATLAS collaboration

    2011-01-01

    The ATLAS High Level Trigger Steering Framework and the Trigger 
Configuration System.
 
The ATLAS detector system installed in the Large Hadron Collider (LHC) 
at CERN is designed to study proton-proton and nucleus-nucleus 
collisions with a maximum center of mass energy of 14 TeV at a bunch 
collision rate of 40MHz.  In March 2010 the four LHC experiments saw 
the first proton-proton collisions at 7 TeV. Still within the year a 
collision rate of nearly 10 MHz is expected. At ATLAS, events of 
potential interest for ATLAS physics are selected by a three-level 
trigger system, with a final recording rate of about 200 Hz. The first 
level (L1) is implemented in custom hardware; the two levels of 
the high level trigger (HLT) are software triggers, running on large 
farms of standard computers and network devices. 

Within the ATLAS physics program more than 500 trigger signatures are 
defined. The HLT tests each signature on each L1-accepted event; the 
test outcome is recor...

  15. Machine learning techniques for razor triggers

    CERN Document Server

    Kolosova, Marina

    2015-01-01

    My project was focused on the development of a neural network which can predict if an event passes or not a razor trigger. Using synthetic data containing jets and missing transverse energy we built and trained a razor network by supervised learning. We accomplished a ∼ 91% agreement between the output of the neural network and the target while the other 10% was due to the noise of the neural network. We could apply such networks during the L1 trigger using neuromorhic hardware. Neuromorphic chips are electronic systems that function in a way similar to an actual brain, they are faster than GPUs or CPUs, but they can only be used with spiking neural networks.

  16. Exogenously triggered response inhibition in developmental stuttering.

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. The ALICE Central Trigger Processor (CTP) upgrade

    International Nuclear Information System (INIS)

    Krivda, M.; Alexandre, D.; Barnby, L.S.; Evans, D.; Jones, P.G.; Jusko, A.; Lietava, R.; Baillie, O. Villalobos; Pospíšil, J.

    2016-01-01

    The ALICE Central Trigger Processor (CTP) at the CERN LHC has been upgraded for LHC Run 2, to improve the Transition Radiation Detector (TRD) data-taking efficiency and to improve the physics performance of ALICE. There is a new additional CTP interaction record sent using a new second Detector Data Link (DDL), a 2 GB DDR3 memory and an extension of functionality for classes. The CTP switch has been incorporated directly onto the new LM0 board. A design proposal for an ALICE CTP upgrade for LHC Run 3 is also presented. Part of the development is a low latency high bandwidth interface whose purpose is to minimize an overall trigger latency

  18. CDF tau triggers, analysis and other developments

    International Nuclear Information System (INIS)

    J. R. Smith

    2003-01-01

    This note is a write-up of contribution made by the author to the HCP2002 conference. It has two principal subjects. The first subject concerns the CDF τ triggers, τ-cone algorithms and τ physics analysis. τ physics is going to be very important in Run II because τ's can extend SUSY searches at large tan β in particular, τ's will help in the searches for (tilde χ) 1 ± (tilde χ) 2 0 , MSSM Higgs and other non Standard Model (SM) processes. Also, τ events are important for various Standard Model processes including Precision Electroweak, t(bar t), and SM Higgs searches. τ triggers are installed and operating at CDF. The second subject of this contribution to the HCP2002 conference concerns the algorithms of backwards differentiation abstracted from their usual setting inside of Automatic Differentiation software packages. Backwards differentiation (reverse-mode differentiation) provides a useful means for optimizing many kinds of problems

  19. Particle combinations in the LHCb Upgrade trigger

    CERN Document Server

    Zhao, Fanyi

    2017-01-01

    The LHCb experiment will be upgraded during long shutdown II (2018-2020) to process inelastic proton-proton collisions at 30MHz in a software application and run at a higher instantaneous luminosity of $2\\times 10^{33}cm^{−2}s^{−1}$. Each of these collisions will contain substantially more proton-proton interactions and charged particles. It is important to identify the decay vertices of heavy-flavour hadrons produced by the primary proton-proton interaction in an efficient, CPU-performant manner. In this project, I will learn about the LHCb trigger and experimental programme and investigate alternative models for reconstructing these vertices, which may scale more efficiently to the upgraded trigger conditions than the current model.

  20. The ATLAS Trigger Simulation with Legacy Software

    CERN Document Server

    Bernius, Catrin; The ATLAS collaboration

    2017-01-01

    Physics analyses at the LHC which search for rare physics processes or measure Standard Model parameters with high precision require accurate simulations of the detector response and the event selection processes. The accurate simulation of the trigger response is crucial for determination of overall selection efficiencies and signal sensitivities. For the generation and the reconstruction of simulated event data, generally the most recent software releases are used to ensure the best agreement between simulated data and real data. For the simulation of the trigger selection process, however, the same software release with which real data were taken should be ideally used. This requires potentially running with software dating many years back, the so-called legacy software. Therefore having a strategy for running legacy software in a modern environment becomes essential when data simulated for past years start to present a sizeable fraction of the total. The requirements and possibilities for such a simulatio...