A Transgenic Tri-Modality Reporter Mouse

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Yan, Xinrui; Ray, Pritha; Paulmurugan, Ramasamy; Tong, Ricky; Gong, Yongquan; Sathirachinda, Ataya; Wu, Joseph C.; Gambhir, Sanjiv S.

2013-01-01

Transgenic mouse with a stably integrated reporter gene(s) can be a valuable resource for obtaining uniformly labeled stem cells, tissues, and organs for various applications. We have generated a transgenic mouse model that ubiquitously expresses a tri-fusion reporter gene (fluc2-tdTomato-ttk) driven by a constitutive chicken β-actin promoter. This "Tri-Modality Reporter Mouse" system allows one to isolate most cells from this donor mouse and image them for bioluminescent (fluc2), fluorescent...

The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition.

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Eskandari-Sedighi, Ghazaleh; Daude, Nathalie; Gapeshina, Hristina; Sanders, David W; Kamali-Jamil, Razieh; Yang, Jing; Shi, Beipei; Wille, Holger; Ghetti, Bernardino; Diamond, Marc I; Janus, Christopher; Westaway, David

2017-10-04

MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes. Given heterogeneities observed in a transgenic (Tg) mouse line expressing low levels of human (2 N, 4R) P301L Tau, we backcrossed founder stocks of mice to C57BL/6Tac, 129/SvEvTac and FVB/NJ inbred backgrounds to discern the role of genetic versus environmental effects on disease-related phenotypes. Three inbred derivatives of a TgTau P301L founder line had similar quality and steady-state quantity of Tau production, accumulation of abnormally phosphorylated 64-68 kDa Tau species from 90 days of age onwards and neuronal loss in aged Tg mice. Variegation was not seen in the pattern of transgene expression and seeding properties in a fluorescence-based cellular assay indicated a single "strain" of misfolded Tau. However, in other regards, the aged Tg mice were heterogeneous; there was incomplete penetrance for Tau deposition despite maintained transgene expression in aged animals and, for animals with Tau deposits, distinctions were noted even within each subline. Three classes of rostral deposition in the cortex, hippocampus and striatum accounted for 75% of pathology-positive mice yet the mean ages of mice scored as class I, II or III were not significantly different and, hence, did not fit with a predictable progression from one class to another defined by chronological age. Two other patterns of Tau deposition designated as classes IV and V, occurred in caudal structures. Other pathology-positive Tg mice of similar age not falling within classes I-V presented with focal accumulations in additional caudal neuroanatomical areas including the locus coeruleus. Electron microscopy revealed that brains of Classes I, II and IV animals all exhibit straight filaments, but with coiled filaments and occasional twisted filaments apparent in Class I. Most strikingly, Class I, II and IV animals presented

Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate.

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Bondulich, Marie K; Guo, Tong; Meehan, Christopher; Manion, John; Rodriguez Martin, Teresa; Mitchell, Jacqueline C; Hortobagyi, Tibor; Yankova, Natalia; Stygelbout, Virginie; Brion, Jean-Pierre; Noble, Wendy; Hanger, Diane P

2016-08-01

Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies. © The Author (2016). Published by

Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate

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Bondulich, Marie K.; Guo, Tong; Meehan, Christopher; Manion, John; Rodriguez Martin, Teresa; Mitchell, Jacqueline C.; Hortobagyi, Tibor; Yankova, Natalia; Stygelbout, Virginie; Brion, Jean-Pierre; Noble, Wendy

2016-01-01

Abstract Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies. PMID:27297240

Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice.

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Chu, J; Li, J-G; Giannopoulos, P F; Blass, B E; Childers, W; Abou-Gharbia, M; Praticò, D

2015-11-01

The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.

Dexmedetomidine Increases Tau Phosphorylation Under Normothermic Conditions In Vivo and In Vitro

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Whittington, Robert A.; Virág, László; Gratuze, Maud; Petry, Franck R.; Noël, Anastasia; Poitras, Isabelle; Truchetti, Geoffrey; Marcouiller, François; Papon, Marie-Amélie; Khoury, Noura El; Wong, Kevin; Bretteville, Alexis; Morin, Françoise; Planel, Emmanuel

2015-01-01

There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have thus been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine, an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to non-transgenic mice, dexmedetomidine induced tau hyperphosphorylation persisting up to 6h in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor (α2-AR) antagonist, blocked dexmedetomidine-induced tau hyperphosphorylation. Furthermore, dexmedetomidine dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze, and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that dexmedetomidine: i) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-AR activation, ii) promotes tau aggregation in a mouse model of tauopathy, and iii) impacts spatial reference memory. PMID:26058840

Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy.

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Nash, Kevin R; Lee, Daniel C; Hunt, Jerry B; Morganti, Josh M; Selenica, Maj-Linda; Moran, Peter; Reid, Patrick; Brownlow, Milene; Guang-Yu Yang, Clement; Savalia, Miloni; Gemma, Carmelina; Bickford, Paula C; Gordon, Marcia N; Morgan, David

2013-06-01

Alzheimer's disease is characterized by amyloid plaques, neurofibrillary tangles, glial activation, and neurodegeneration. In mouse models, inflammatory activation of microglia accelerates tau pathology. The chemokine fractalkine serves as an endogenous neuronal modulator to quell microglial activation. Experiments with fractalkine receptor null mice suggest that fractalkine signaling diminishes tau pathology, but exacerbates amyloid pathology. Consistent with this outcome, we report here that soluble fractalkine overexpression using adeno-associated viral vectors significantly reduced tau pathology in the rTg4510 mouse model of tau deposition. Furthermore, this treatment reduced microglial activation and appeared to prevent neurodegeneration normally found in this model. However, in contrast to studies with fractalkine receptor null mice, parallel studies in an APP/PS1 model found no effect of increased fractalkine signaling on amyloid deposition. These data argue that agonism at fractalkine receptors might be an excellent target for therapeutic intervention in tauopathies, including those associated with amyloid deposition. Copyright © 2013 Elsevier Inc. All rights reserved.

Dietary Lycopene Supplementation Improves Cognitive Performances in Tau Transgenic Mice Expressing P301L Mutation via Inhibiting Oxidative Stress and Tau Hyperphosphorylation.

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Yu, Lixia; Wang, Weiguang; Pang, Wei; Xiao, Zhonghai; Jiang, Yugang; Hong, Yan

2017-01-01

Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) and other tauopathies and participates in their development by promoting hyperphosphorylation of microtubule-associated protein tau. Lycopene, as an effective antioxidant, combined with vitamin E seemed to be additive against oxidative stress. The present study was undertaken to examine whether lycopene or lycopene/vitamin E could exert protective effects on memory deficit and oxidative stress in tau transgenic mice expressing P301L mutation. P301L transgenic mice were assigned to three groups: P301L group (P301L), P301L+lycopene (Lyc), and P301L+lycopene/vitamin E (Lyc+VE). Age-matched C57BL/6J mice as wild type controls (Con) were used in the present study. Spatial memory was assessed by radial arm while passive memories were evaluated by step-down and step-through tests. Levels of tau phosphorylation were detected by western blot. Oxidative stress biomarkers were measured in the serum using biochemical assay kits. Compared with the control group, P301L mice displayed significant spatial and passive memory impairments, elevated malondialdehyde (MDA) levels and decreased glutathione peroxidase (GSH-Px) activities in serum, and increased tau phosphorylation at Thr231/Ser235, Ser262, and Ser396 in brain. Supplementations of lycopene or lycopene/vitamin E could significantly ameliorate the memory deficits, observably decreased MDA concentrations and increased GSH-Px activities, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites. Our findings indicated that the combination of lycopene and vitamin E antioxidants acted in a synergistic fashion to bring significant effects against oxidative stress in tauopathies.

Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions.

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Franck R Petry

Full Text Available Aggregates of hyperphosphorylated tau protein are found in a group of diseases called tauopathies, which includes Alzheimer's disease. The causes and consequences of tau hyperphosphorylation are routinely investigated in laboratory animals. Mice are the models of choice as they are easily amenable to transgenic technology; consequently, their tau phosphorylation levels are frequently monitored by Western blotting using a panel of monoclonal/polyclonal anti-tau antibodies. Given that mouse secondary antibodies can recognize endogenous mouse immunoglobulins (Igs and the possible lack of specificity with some polyclonal antibodies, non-specific signals are commonly observed. Here, we characterized the profiles of commonly used anti-tau antibodies in four different mouse models: non-transgenic mice, tau knock-out (TKO mice, 3xTg-AD mice, and hypothermic mice, the latter a positive control for tau hyperphosphorylation. We identified 3 tau monoclonal antibody categories: type 1, characterized by high non-specificity (AT8, AT180, MC1, MC6, TG-3, type 2, demonstrating low non-specificity (AT270, CP13, CP27, Tau12, TG5, and type 3, with no non-specific signal (DA9, PHF-1, Tau1, Tau46. For polyclonal anti-tau antibodies, some displayed non-specificity (pS262, pS409 while others did not (pS199, pT205, pS396, pS404, pS422, A0024. With monoclonal antibodies, most of the interfering signal was due to endogenous Igs and could be eliminated by different techniques: i using secondary antibodies designed to bind only non-denatured Igs, ii preparation of a heat-stable fraction, iii clearing Igs from the homogenates, and iv using secondary antibodies that only bind the light chain of Igs. All of these techniques removed the non-specific signal; however, the first and the last methods were easier and more reliable. Overall, our study demonstrates a high risk of artefactual signal when performing Western blotting with routinely used anti-tau antibodies, and proposes

Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease.

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Jackson, Rosemary J; Rudinskiy, Nikita; Herrmann, Abigail G; Croft, Shaun; Kim, JeeSoo Monica; Petrova, Veselina; Ramos-Rodriguez, Juan Jose; Pitstick, Rose; Wegmann, Susanne; Garcia-Alloza, Monica; Carlson, George A; Hyman, Bradley T; Spires-Jones, Tara L

2016-12-01

Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss. © 2016 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice

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Mariana Vargas-Caballero

2017-04-01

Full Text Available Microtubule associated protein tau (MAPT is involved in the pathogenesis of Alzheimer's disease and many forms of frontotemporal dementia (FTD. We recently reported that Aβ-mediated inhibition of hippocampal long-term potentiation (LTP in mice requires tau. Here, we asked whether expression of human MAPT can restore Aβ-mediated inhibition on a mouse Tau−/− background and whether human tau with an FTD-causing mutation (N296H can interfere with Aβ-mediated inhibition of LTP. We used transgenic mouse lines each expressing the full human MAPT locus using bacterial artificial chromosome technology. These lines expressed all six human tau protein isoforms on a Tau−/− background. We found that the human wild-type MAPT H1 locus was able to restore Aβ42-mediated impairment of LTP. In contrast, Aβ42 did not reduce LTP in slices in two independently generated transgenic lines expressing tau protein with the mutation N296H associated with frontotemporal dementia (FTD. Basal phosphorylation of tau measured as the ratio of AT8/Tau5 immunoreactivity was significantly reduced in N296H mutant hippocampal slices. Our data show that human MAPT is able to restore Aβ42-mediated inhibition of LTP in Tau−/− mice. These results provide further evidence that tau protein is central to Aβ-induced LTP impairment and provide a valuable tool for further analysis of the links between Aβ, human tau and impairment of synaptic function.

Ebselen ameliorates β-amyloid pathology, tau pathology, and cognitive impairment in triple-transgenic Alzheimer's disease mice.

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Xie, Yongli; Tan, Yibin; Zheng, Youbiao; Du, Xiubo; Liu, Qiong

2017-08-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease which is clinically characterized by memory loss and cognitive decline caused by protein misfolding and aggregation. Imbalance between free radicals and the antioxidant system is a prominent and early feature in the neuropathology of AD. Selenium (Se), a vital trace element with excellent antioxidant potential, is preferentially retained in the brain in Se-limited conditions and has been reported to provide neuroprotection through resisting oxidative damage. In this paper, we studied for the first time the potential of Ebselen, a lipid-soluble selenium compound with GPx-like activity, in the treatment of cognitive dysfunction and neuropathology of triple-transgenic AD (3 × Tg-AD) mice, AD model cell, and primary culture. We demonstrated that Ebselen inhibited oxidative stress in both AD model cells and mouse brains with increasing GPx and SOD activities and meanwhile reduced p38 mitogen-activated protein kinases activities. By decreasing the expression of amyloid precursor protein and β-secretase, Ebselen reduced the levels of Aβ in AD neurons and mouse brains, especially the most toxic oligomeric form. Besides, mislocation of phosphorylated tau in neurons and phosphorylation levels of tau protein at Thr231, Ser396, and Ser404 residues were also inhibited by Ebselen, probably by its regulatory roles in glycogen synthase kinase 3β and protein phosphatase 2A activity. In addition, Ebselen mitigated the decrease of synaptic proteins including synaptophysin and postsynaptic density protein 95 in AD model cells and neurons. Consequently, the spatial learning and memory of 3 × Tg-AD mice were significantly improved upon Ebselen treatment. This study provides a potential novel therapeutic approach for the prevention of AD.

Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.

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Kirma, Nameer B; Tekmal, Rajeshwar R

2012-09-01

Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition.

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Baglietto-Vargas, David; Kitazawa, Masashi; Le, Elaine J; Estrada-Hernandez, Tatiana; Rodriguez-Ortiz, Carlos J; Medeiros, Rodrigo; Green, Kim N; LaFerla, Frank M

2014-02-01

Recent studies on tauopathy animal models suggest that the concomitant expression of the endogenous murine tau delays the pathological accumulation of human tau, and interferes with the disease progression. To elucidate the role of endogenous murine tau in a model with both plaques and tangles, we developed a novel transgenic mouse model by crossing 3xTg-AD with mtauKO mice (referred to as 3xTg-AD/mtauKO mice). Therefore, this new model allows us to determine the pathological consequences of the murine tau. Here, we show that 3xTg-AD/mtauKO mice have lower tau loads in both soluble and insoluble fractions, and lower tau hyperphosphorylation level in the soluble fraction relative to 3xTg-AD mice. In the 3xTg-AD model endogenous mouse tau is hyperphosphorylated and significantly co-aggregates with human tau. Despite the deletion of the endogenous tau gene in 3xTg-AD/mtauKO mice, cognitive dysfunction was equivalent to 3xTg-AD mice, as there was no additional impairment on a spatial memory task, and thus despite increased tau phosphorylation, accumulation and NFTs in 3xTg-AD mice no further effects on cognition are seen. These findings provide better understanding about the role of endogenous tau to Alzheimer's disease (AD) pathology and for developing new AD models. © 2013.

DOPA Decarboxylase Modulates Tau Toxicity.

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Kow, Rebecca L; Sikkema, Carl; Wheeler, Jeanna M; Wilkinson, Charles W; Kraemer, Brian C

2018-03-01

The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D 2 -family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. To better understand how loss of D 2 -family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D 2 receptors. We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D 2 -family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes. Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan. Published by Elsevier Inc.

Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model.

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Ricobaraza, Ana; Cuadrado-Tejedor, Mar; Pérez-Mediavilla, Alberto; Frechilla, Diana; Del Río, Joaquin; García-Osta, Ana

2009-06-01

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering beta-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3beta (GSK3beta). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

Selenomethionine Ameliorates Neuropathology in the Olfactory Bulb of a Triple Transgenic Mouse Model of Alzheimer’s Disease

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Zhong-Hao Zhang

2016-09-01

Full Text Available Olfactory dysfunction is an early and common symptom in Alzheimer′s disease (AD and is reported to be related to several pathologic changes, including the deposition of Aβ and hyperphosphorylated tau protein as well as synaptic impairment. Selenomethionine (Se-Met, the major form of selenium in animals and humans, may be a promising therapeutic option for AD as it decreases the deposition of Aβ and tau hyperphosphorylation in a triple transgenic mouse model of AD (3× Tg-AD. In this study, 4-month-old AD mice were treated with 6 µg/mL Se-Met in drinking water for 12 weeks and the effect of Se-Met on neuropathological deficits in olfactory bulb (OB of 3× Tg-AD mice was investigated. The administration of Se-Met effectively decreased the production and deposition of Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1-regulated amyloid precursor protein (APP processing and reduced the level of total tau and phosphorylated tau, which depended on depressing the activity and expression of glycogen synthase kinase-3β (GSK-3β and cyclin-dependent kinase 5 (CDK5. Meanwhile, Se-Met reduced glial activation, relieved neuroinflammation and attenuated neuronal cell death in the OB of AD mice. So Se-Met could improve pathologic changes of AD in the OB, which further demonstrated the potential therapeutic effect of Se-Met in AD.

Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

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Jackson George R

2011-06-01

Full Text Available Abstract Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I, and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

Novel marker for the onset of frontotemporal dementia: early increase in activity-dependent neuroprotective protein (ADNP in the face of Tau mutation.

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Yulie Schirer

Full Text Available Tauopathy, a major pathology in Alzheimer's disease, is also found in ~50% of frontotemporal dementias (FTDs. Tau transcript, a product of a single gene, undergoes alternative splicing to yield 6 protein species, each with either 3 or 4 microtubule binding repeat domains (tau 3R or 4R, associated with dynamic and stable microtubules, respectively. While the healthy human brain shows a 1/1 ratio of tau 3R/4R, this ratio may be dramatically changed in the FTD brain. We have previously discovered that activity-dependent neuroprotective protein (ADNP is essential for brain formation in the mouse, with ADNP+/- mice exhibiting tauopathy, age-driven neurodegeneration and behavioral deficits. Here, in transgenic mice overexpressing a mutated tau 4R species, in the cerebral cortex but not in the cerebellum, we showed significantly increased ADNP expression (~3-fold transcripts in the cerebral cortex of young transgenic mice (~disease onset, but not in the cerebellum, as compared to control littermates. The transgene-age-related increased ADNP expression paralleled augmented dynamic tau 3R transcript level compared to control littermates. Blocking mutated tau 4R transgene expression resulted in normalization of ADNP and tau 3R expression. ADNP was previously shown to be a member of the SWItch/Sucrose NonFermentable (SWI/SNF chromatin remodeling complex. Here, Brahma (Brm, a component of the SWI/SNF complex regulating alternative splicing, showed a similar developmental expression pattern to ADNP. Immunoprecipitations further suggested Brm-ADNP interaction coupled to ADNP - polypyrimidine tract-binding protein (PTB-associated splicing factor (PSF-binding, with PSF being a direct regulator of tau transcript splicing. It should be noted that although we have shown a correlation between levels of ADNP and tau isoform expression three months of age, we are not presenting evidence of a direct link between the two. Future research into ADNP/tau relations is

A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology

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Mar Matarin

2015-02-01

Full Text Available We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of “amyloid” transgenic mice (mutant human APP, PSEN1, or APP/PSEN1 and “TAU” transgenic mice (mutant human MAPT gene. Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.

Liraglutide Improves Water Maze Learning and Memory Performance While Reduces Hyperphosphorylation of Tau and Neurofilaments in APP/PS1/Tau Triple Transgenic Mice.

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Chen, Shuyi; Sun, Jie; Zhao, Gang; Guo, Ai; Chen, Yanlin; Fu, Rongxia; Deng, Yanqiu

2017-08-01

The purpose of this study was to explore how liraglutide affects AD-like pathology and cognitive function in APP/PS1/Tau triple transgenic (3 × Tg) Alzheimer disease (AD) model mice. Male 3 × Tg mice and C57BL/6 J mice were treated for 8 weeks with liraglutide (300 μg/kg/day, subcutaneous injection) or saline. Levels of phosphorylated tau, neurofilaments (NFs), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in brain tissues were assessed with western blots. Fluoro-Jade-B labeling were applied to detect pathological changes. The Morris water maze (MWM) was used to assess the spatial learning and memory. Liraglutide decreased levels of hyperphosphorylated tau and NFs in 3 × Tg liraglutide-treated (Tg + LIR) mice, increased ERK phosphorylation, and decreased JNK phosphorylation. Liraglutide also decreased the number of degenerative neurons in the hippocampus and cortex of Tg + LIR mice, and shortened their escape latencies and increased their hidden platform crossings in the MWM task. Liraglutide did not significantly affect the animals' body weight (BW) or fasting blood glucose. Liraglutide can reduce hyperphosphorylation of tau and NFs and reduce neuronal degeneration, apparently through alterations in JNK and ERK signaling, which may be related to its positive effects on AD-like learning and memory impairment.

Nrl-Cre transgenic mouse mediates loxP recombination in developing rod photoreceptors.

Science.gov (United States)

Brightman, Diana S; Razafsky, David; Potter, Chloe; Hodzic, Didier; Chen, Shiming

2016-03-01

The developing mouse retina is a tractable model for studying neurogenesis and differentiation. Although transgenic Cre mouse lines exist to mediate conditional genetic manipulations in developing mouse retinas, none of them act specifically in early developing rods. For conditional genetic manipulations of developing retinas, a Nrl-Cre mouse line in which the Nrl promoter drives expression of Cre in rod precursors was created. The results showed that Nrl-Cre expression was specific to the retina where it drives rod-specific recombination with a temporal pattern similar to endogenous Nrl expression during retinal development. This Nrl-Cre transgene does not negatively impact retinal structure and function. Taken together, the data suggested that the Nrl-Cre mouse line was a valuable tool to drive Cre-mediated recombination specifically in developing rods. © 2016 Wiley Periodicals, Inc.

Genomic localization of the Z/EG transgene in the mouse genome.

Science.gov (United States)

Colombo, Sophie; Kumasaka, Mayuko; Lobe, Corrinne; Larue, Lionel

2010-02-01

The Z/EG transgenic mouse line, produced by Novak et al., displays tissue-specific EGFP expression after Cre-mediated recombination. The autofluorescence of EGFP allows the visualization of cells of interest displaying Cre recombination. The initial construct was designed such that cells without Cre recombination express the beta-galactosidase marker, facilitating counterselection. We used inverse PCR to identify the site of integration of the Z/EG transgene, to improve the efficiency of homozygous Z/EG mouse production. Recombined cells produced large amounts of EGFP protein, resulting in higher levels of fluorescence and therefore greater contrast with nonrecombined cells. We mapped the transgene to the G1 region of chromosome 5. This random insertion was found to have occurred 230-bp upstream from the start codon of the Rasa4 gene. The insertion of the Z/EG transgene in the C57BL/6 genetic background had no effect on Rasa4 expression. Homozygous Z/EG mice therefore had no obvious phenotype. (c) 2009 Wiley-Liss, Inc.

Autopsy and histological analysis of the transgenic mouse

NARCIS (Netherlands)

Gijbels, Marion J. J.; de Winther, Menno P. J.

2011-01-01

Over the past decades, transgenic and knock-out mouse models have become common use in research laboratories. Detailed phenotypic characterization of such models is essential for understanding basic mechanisms of normal physiology and disease. Hereto, pathological examination is a very helpful tool.

In Vivo Tau Imaging for a Diagnostic Platform of Tauopathy Using the rTg4510 Mouse Line

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Naruhiko Sahara

2017-12-01

Full Text Available Association of tau deposition with neurodegeneration in Alzheimer’s disease (AD and related tau-positive neurological disorders collectively referred to as tauopathies indicates contribution of tau aggregates to neurotoxicity. The discovery of tau gene mutations in FTDP-17-tau kindreds has provided unequivocal evidence that tau abnormalities alone can induce neurodegenerative disorders. Therefore, visualization of tau accumulation would offer a reliable, objective index to aid in the diagnosis of tauopathy and to assess the disease progression. Positron emission tomography (PET imaging of tau lesions is currently available using several tau PET ligands. Because most tau PET ligands have the property of an extrinsic fluorescent dye, these ligands are considered to be useful for both PET and fluorescence imaging. In addition, small-animal magnetic resonance imaging (MRI is available for both structural and functional imaging. Using these advanced imaging techniques, in vivo studies on a mouse model of tauopathy will provide significant insight into the translational research of neurodegenerative diseases. In this review, we will discuss the utilities of PET, MRI, and fluorescence imaging for evaluating the disease progression of tauopathy.

In Vivo Monitoring of Pancreatic β-Cells in a Transgenic Mouse Model

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Steven J. Smith

2006-04-01

Full Text Available We generated a transgenic mouse model (RIP-luc for the in vivo monitoring of pancreatic islet mass and function in response to metabolic disease. Using the rat insulin promoter fused to firefly luciferase, and noninvasive technology to detect luciferase activity, we tracked changes in reporter signal during metabolic disease states and correlated the changes in luciferase signal with metabolic status of the mouse. Transgene expression was found to be specific to the pancreatic islets in this transgenic model. Basal transgene expression was tracked in male and female mice fed either a chow or a high-fat diet and in response to treatment with streptozotocin. Pancreatic bioluminescent signal increased in mice fed a high-fat diet compared with chow-fed animals. In a model of chemically induced diabetes, the bioluminescent signal decreased in accordance with the onset of diabetes and reduction of islet β-cell number. Preliminary studies using islets transplanted from this transgenic model suggest that in vivo image analysis can also be used to monitor transplanted islet viability and survival in the host. This transgenic model is a useful tool for in vivo studies of pancreatic β-cells and as a donor for islet transplantation studies.

Towards Transgenic Primates: What can we learn from mouse genetics?

Institute of Scientific and Technical Information of China (English)

KUANG Hui; WANG Phillip L.; TSIEN Joe Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the precUnical research and development of novel therapeutics for treating human diseases. Various powerful genetic tech-nologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.

Towards Transgenic Primates:What can we learn from mouse genetics?

Institute of Scientific and Technical Information of China (English)

WANG; Phillip; L.; TSIEN; Joe; Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans,monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases.Various powerful genetic tech-nologies initially developed for making mouse models are being explored for generating transgenic primate models.We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich ataxia.

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Sara Anjomani Virmouni

Full Text Available Friedreich ataxia (FRDA is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats, YG8R (90 and 190 GAA repeats and YG22R (190 GAA repeats.We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R.Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.

Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology.

Science.gov (United States)

Brownlow, Milene L; Benner, Leif; D'Agostino, Dominic; Gordon, Marcia N; Morgan, Dave

2013-01-01

Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.

Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology.

Directory of Open Access Journals (Sweden)

Milene L Brownlow

Full Text Available Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer's disease (AD patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs, widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition and Tg4510 (a model of tau deposition mice were offered either a ketogenic or a control (NIH-31 diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition.

PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo.

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Michiaki Okuda

Full Text Available In tauopathies, a neural microtubule-associated protein tau (MAPT is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.

Ketogenic Diet Improves Motor Performance but Not Cognition in Two Mouse Models of Alzheimer’s Pathology

Science.gov (United States)

Brownlow, Milene L.; Benner, Leif; D’Agostino, Dominic; Gordon, Marcia N.; Morgan, Dave

2013-01-01

Dietary manipulations are increasingly viewed as possible approaches to treating neurodegenerative diseases. Previous studies suggest that Alzheimer’s disease (AD) patients present an energy imbalance with brain hypometabolism and mitochondrial deficits. Ketogenic diets (KDs), widely investigated in the treatment and prevention of seizures, have been suggested to bypass metabolic deficits present in AD brain by providing ketone bodies as an alternative fuel to neurons. We investigated the effects of a ketogenic diet in two transgenic mouse lines. Five months old APP/PS1 (a model of amyloid deposition) and Tg4510 (a model of tau deposition) mice were offered either a ketogenic or a control (NIH-31) diet for 3 months. Body weight and food intake were monitored throughout the experiment, and blood was collected at 4 weeks and 4 months for ketone and glucose assessments. Both lines of transgenic mice weighed less than nontransgenic mice, yet, surprisingly, had elevated food intake. The ketogenic diet did not affect these differences in body weight or food consumption. Behavioral testing during the last two weeks of treatment found that mice offered KD performed significantly better on the rotarod compared to mice on the control diet independent of genotype. In the open field test, both transgenic mouse lines presented increased locomotor activity compared to nontransgenic, age-matched controls, and this effect was not influenced by KD. The radial arm water maze identified learning deficits in both transgenic lines with no significant differences between diets. Tissue measures of amyloid, tau, astroglial and microglial markers in transgenic lines showed no differences between animals fed the control or the ketogenic diet. These data suggest that ketogenic diets may play an important role in enhancing motor performance in mice, but have minimal impact on the phenotype of murine models of amyloid or tau deposition. PMID:24069439

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

National Research Council Canada - National Science Library

Brown, Susan

1999-01-01

... (HE) and familial amyotrophic lateral sclerosis (FALS), using transgenic mouse models. Studies in this first year employed C-14-2-deoxyglucose in vivo autoradiography and spectrophotometric metabolic enzyme assays...

R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease.

Science.gov (United States)

Carreras, Isabel; McKee, Ann C; Choi, Ji-Kyung; Aytan, Nurgul; Kowall, Neil W; Jenkins, Bruce G; Dedeoglu, Alpaslan

2013-12-06

We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function. © 2013 Published by Elsevier B.V.

Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD)-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD.

Science.gov (United States)

Verma, Megha; Beaulieu-Abdelahad, David; Ait-Ghezala, Ghania; Li, Rena; Crawford, Fiona; Mullan, Michael; Paris, Daniel

2015-01-01

Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe) of Alzheimer's disease (AD) which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD.

Chronic Anatabine Treatment Reduces Alzheimer's Disease (AD-Like Pathology and Improves Socio-Behavioral Deficits in a Transgenic Mouse Model of AD.

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Megha Verma

Full Text Available Anatabine is a minor tobacco alkaloid, which is also found in plants of the Solanaceae family and displays a chemical structure similarity with nicotine. We have shown previously that anatabine displays some anti-inflammatory properties and reduces microgliosis and tau phosphorylation in a pure mouse model of tauopathy. We therefore investigated the effects of a chronic oral treatment with anatabine in a transgenic mouse model (Tg PS1/APPswe of Alzheimer's disease (AD which displays pathological Aβ deposits, neuroinflammation and behavioral deficits. In the elevated plus maze, Tg PS1/APPswe mice exhibited hyperactivity and disinhibition compared to wild-type mice. Six and a half months of chronic oral anatabine treatment, suppressed hyperactivity and disinhibition in Tg PS1/APPswe mice compared to Tg PS1/APPswe receiving regular drinking water. Tg PS1/APPswe mice also elicited profound social interaction and social memory deficits, which were both alleviated by the anatabine treatment. We found that anatabine reduces the activation of STAT3 and NFκB in the vicinity of Aβ deposits in Tg PS1/APPswe mice resulting in a reduction of the expression of some of their target genes including Bace1, iNOS and Cox-2. In addition, a significant reduction in microgliosis and pathological deposition of Aβ was observed in the brain of Tg PS1/APPswe mice treated with anatabine. This is the first study to investigate the impact of chronic anatabine treatment on AD-like pathology and behavior in a transgenic mouse model of AD. Overall, our data show that anatabine reduces β-amyloidosis, neuroinflammation and alleviates some behavioral deficits in Tg PS1/APPswe, supporting further exploration of anatabine as a possible disease modifying agent for the treatment of AD.

Curcumin Decreases Hyperphosphorylation of Tau by Down-Regulating Caveolin-1/GSK-3β in N2a/APP695swe Cells and APP/PS1 Double Transgenic Alzheimer's Disease Mice.

Science.gov (United States)

Sun, Jieyun; Zhang, Xiong; Wang, Chen; Teng, Zhipeng; Li, Yu

2017-01-01

Caveolin-1, the marker protein of membranal caveolae, is not only involved in cholesterol regulation, but also participates in the cleavage of amyloid [Formula: see text]-protein precursor (APP) and the generation of [Formula: see text]-amyloid peptide. It has been reported to be tightly related with Tau. In our previous studies, curcumin has been confirmed to play a neuroprotective role in Alzheimer's disease (AD), but its effects on Caveolin-1, Tau and their correlation, and the mechanism is still unknown. As such, in the present study, N2a/WT cells, N2a/APP695swe cell and six-month-old APP/PS1 double transgenic mice were enrolled. After curcumin treatment, the expression of Caveolin-1, Tau and their relationship was detected, and the potential mechanisms were explored. The results showed that in the N2a/APP695swe cells, curcumin not only decreased the number of caveolae, but also made their membrane to be thinner; and curcumin could decreased the expression of phosphorylated Tau (P-Tau(ser404)/Tau) and Caveolin-1 ([Formula: see text]), but the expression of phosphorylated GSK-3[Formula: see text] (P-GSK-3[Formula: see text]/GSK-3[Formula: see text] was increased ([Formula: see text]). In APP/PS1 transgenic mice, the same results were observed. Taken together, our data suggest that curcumin may play an important role in AD via reducing Caveolin-1, inactivating GSK-3[Formula: see text] and inhibiting the abnormal excessive phosphorylation of Tau, which will provide a new theory for AD treatment with curcumin.

Development of a transgenic mouse model to study the immunogenicity of recombinant human insulin

NARCIS (Netherlands)

Torosantucci, Riccardo; Brinks, Vera; Kijanka, Grzegorz; Halim, Liem Andhyk; Sauerborn, Melody; Schellekens, Huub; Jiskoot, Wim

2014-01-01

Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin

Preparation and Observation of Fresh-frozen Sections of the Green Fluorescent Protein Transgenic Mouse Head

International Nuclear Information System (INIS)

Tada, Masahito; Shinohara, Yoshinori; Kato, Ichiro; Hiraga, Koichi; Aizawa, Tomoyasu; Demura, Makoto; Mori, Yoshihiro; Shinoda, Hiroyuki; Mizuguchi, Mineyuki; Kawano, Keiichi

2006-01-01

Hard tissue decalcification can cause variation in the constituent protein characteristics. This paper describes a method of preparating of frozen mouse head sections so as to clearly observe the nature of the constituent proteins. Frozen sections of various green fluorescent protein (GFP) transgenic mouse heads were prepared using the film method developed by Kawamoto and Shimizu. This method made specimen dissection without decalcification possible, wherein GFP was clearly observed in an undamaged state. Conversely, using the same method with decalcification made GFP observation in the transgenic mouse head difficult. This new method is suitable for observing GFP marked cells, enabling us to follow the transplanted GFP marked cells within frozen head sections

Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

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C. Dirk Keene

2016-06-01

Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer’s Disease Like Tau Aggregation

Directory of Open Access Journals (Sweden)

Monique Richter

2014-07-01

Full Text Available Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235 and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer’s disease (AD specific B cell epitopes with foreign (bacterial T cell epitopes induced fast immune responses with high IgG1 titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice

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Yan-Hui Zhang

2018-04-01

Full Text Available Alzheimer's disease (AD is the most common neurodegenerative disease and is characterized by neurofibrillary tangles (NFTs composed of Tau protein. α-Lipoic acid (LA has been found to stabilize the cognitive function of AD patients, and animal study findings have confirmed its anti-amyloidogenic properties. However, the underlying mechanisms remain unclear, especially with respect to the ability of LA to control Tau pathology and neuronal damage. Here, we found that LA supplementation effectively inhibited the hyperphosphorylation of Tau at several AD-related sites, accompanied by reduced cognitive decline in P301S Tau transgenic mice. Furthermore, we found that LA not only inhibited the activity of calpain1, which has been associated with tauopathy development and neurodegeneration via modulating the activity of several kinases, but also significantly decreased the calcium content of brain tissue in LA-treated mice. Next, we screened for various modes of neural cell death in the brain tissue of LA-treated mice. We found that caspase-dependent apoptosis was potently inhibited, whereas autophagy did not show significant changes after LA supplementation. Interestingly, Tau-induced iron overload, lipid peroxidation, and inflammation, which are involved in ferroptosis, were significantly blocked by LA administration. These results provide compelling evidence that LA plays a role in inhibiting Tau hyperphosphorylation and neuronal loss, including ferroptosis, through several pathways, suggesting that LA may be a potential therapy for tauopathies. Keywords: Tau, α-Lipoic acid, Oxidative stress, Ferroptosis, Alzheimer's disease

12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice.

Science.gov (United States)

Di Meco, Antonio; Li, Jian-Guo; Blass, Benjamin E; Abou-Gharbia, Magid; Lauretti, Elisabetta; Praticò, Domenico

2017-01-15

The 12/15-lipoxygenase (12/15-LO) enzyme is upregulated in the brains of patients with Alzheimer's disease (AD), and its expression levels influence the onset of the AD-like phenotype in mouse models. However, whether targeting this pathway after the neuropathology and behavioral impairments have been established remains to be investigated. Triple transgenic (3xTg) mice received either PD146176-a selective and specific pharmacological inhibitor of 12/15-LO-or placebo starting at 12 months of age for 12 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. At the end of the study, mice in the control group showed a worsening of memory and learning abilities, whereas mice receiving PD146176 were undistinguishable from wild-type mice. The same group also had significantly lower amyloid beta levels and deposition, less tau neuropathology, increased synaptic integrity, and autophagy activation. Ex vivo and in vitro genetic and pharmacological studies found that the mechanism involved in these effects was the activation of neuronal autophagy. Our findings provide new insights into the disease-modifying action of 12/15-LO pharmacological inhibition and establish it as a viable therapeutic approach for patients with AD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

TL transgenic mouse strains

International Nuclear Information System (INIS)

Obata, Y.; Matsudaira, Y.; Hasegawa, H.; Tamaki, H.; Takahashi, T.; Morita, A.; Kasai, K.

1993-01-01

As a result of abnormal development of the thymus of these mice, TCR αβ lineage of the T cell differentiation is disturbed and cells belonging to the TCR γδ CD4 - CD8 - double negative (DN) lineage become preponderant. The γδ DN cells migrate into peripheral lymphoid organs and constitute nearly 50% of peripheral T cells. Immune function of the transgenic mice is severely impaired, indicating that the γδ cells are incapable of participating in these reactions. Molecular and serological analyses of T-cell lymphomas reveal that they belong to the γδ lineage. Tg.Tla a -3-1 mice should be useful in defining the role of TL in normal and abnormal T cell differentiation as well as in the development of T-cell lymphomas, and further they should facilitate studies on the differentiation and function of γδ T cells. We isolated T3 b -TL gene from B6 mice and constructed a chimeric gene in which T3 b -TL is driven by the promoter of H-2K b . With the chimeric gene, two transgenic mouse strains, Tg. Con.3-1 and -2 have been derived in C3H background. Both strains express TL antigen in various tissues including skin. The skin graft of transgenic mice on C3H and (B6 X C3H)F 1 mice were rejected. In the mice which rejected the grafts, CD8 + TCRαβ cytotoxic T cells (CTL) against TL antigens were recognized. The recognition of TL by CTL did not require the antigen presentation by H-2 molecules. The results indicated that TL antigen in the skin becomes a transplantation antigen and behaves like a typical allogeneic MHC class I antigen. The facts that (B6 X C3H)F 1 mice rejected the skin expressing T3 b -TL antigen and induced CTL that killed TL + lymphomas of B6 origin revealed that TL antigen encoded by T3 b -TL is recognized as non-self in B6 mice. Experiments are now extended to analyze immune responses to TL antigen expressed on autochthonous T cell lymphomas. (J.P.N.)

Disrupted hippocampal sharp‐wave ripple‐associated spike dynamics in a transgenic mouse model of dementia

Science.gov (United States)

Witton, Jonathan; Staniaszek, Lydia E.; Bartsch, Ullrich; Randall, Andrew D.; Jones, Matthew W.

2015-01-01

Key points High frequency (100–250 Hz) neuronal oscillations in the hippocampus, known as sharp‐wave ripples (SWRs), synchronise the firing behaviour of groups of neurons and play a key role in memory consolidation.Learning and memory are severely compromised in dementias such as Alzheimer's disease; however, the effects of dementia‐related pathology on SWRs are unknown.The frequency and temporal structure of SWRs was disrupted in a transgenic mouse model of tauopathy (one of the major hallmarks of several dementias).Excitatory pyramidal neurons were more likely to fire action potentials in a phase‐locked manner during SWRs in the mouse model of tauopathy; conversely, inhibitory interneurons were less likely to fire phase‐locked spikes during SWRs.These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may underlie the cognitive impairments in this model of dementia. Abstract Neurons within the CA1 region of the hippocampus are co‐activated during high frequency (100–250 Hz) sharp‐wave ripple (SWR) activity in a manner that probably drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice), which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7‐ to 8‐month‐old wild‐type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off‐line were significantly lower in amplitude and had an altered temporal

Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro.

Science.gov (United States)

Nobuhara, Chloe K; DeVos, Sarah L; Commins, Caitlin; Wegmann, Susanne; Moore, Benjamin D; Roe, Allyson D; Costantino, Isabel; Frosch, Matthew P; Pitstick, Rose; Carlson, George A; Hock, Christoph; Nitsch, Roger M; Montrasio, Fabio; Grimm, Jan; Cheung, Anne E; Dunah, Anthone W; Wittmann, Marion; Bussiere, Thierry; Weinreb, Paul H; Hyman, Bradley T; Takeda, Shuko

2017-06-01

The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal-specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Caloric restriction mimetic 2-deoxyglucose maintains cytoarchitecture and reduces tau phosphorylation in primary culture of mouse hippocampal pyramidal neurons.

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Bele, M S; Gajare, K A; Deshmukh, A A

2015-06-01

Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3β (GSK3β) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3β and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies. In a number of studies, caloric restriction mimetic 2-deoxyglucose (C6H12O5) was found to be beneficial in improving the brain functions. However, no reports are available on the effect of 2-deoxyglucose 2-DG on tau phosphorylation. In the present study, hippocampal pyramidal neurons from E17 mouse embryos were isolated and cultured on poly-L-lysine-coated coverslips. Neurons from the experimental group were treated with 10 mM 2-deoxyglucose. The treatment of 2-DG resulted in healthier neuronal morphology in terms of significantly lower number of cytoplasmic vacuoles, little or no membrane blebbings, maintained axon hillock and intact neurites. There were decreased immunofluorescence signals for GSK3β, pTau at Ser262, Cdk5 and pTau at Ser235 suggesting decreased tau phosphorylation, which was further confirmed by Western blotting. The results indicate the beneficial effects of 2-DG in controlling the tau phosphorylation and maintaining the healthy neuronal cytoarchitecture.

Connective Tissue Growth Factor Transgenic Mouse Develops Cardiac Hypertrophy, Lean Body Mass and Alopecia.

Science.gov (United States)

Nuglozeh, Edem

2017-07-01

Connective Tissue Growth Factor (CTGF/CCN2) is one of the six members of cysteine-rich, heparin-binding proteins, secreted as modular protein and recognised to play a major function in cell processes such as adhesion, migration, proliferation and differentiation as well as chondrogenesis, skeletogenesis, angiogenesis and wound healing. The capacity of CTGF to interact with different growth factors lends an important role during early and late development, especially in the anterior region of the embryo. CTGF Knockout (KO) mice have several craniofacial defects and bone miss shaped due to an impairment of the vascular system development during chondrogenesis. The aim of the study was to establish an association between multiple modular functions of CTGF and the phenotype and cardiovascular functions in transgenic mouse. Bicistronic cassette was constructed using pIRES expressing vector (Clontech, Palo Alto, CA). The construct harbours mouse cDNA in tandem with LacZ cDNA as a reporter gene under the control of Cytomegalovirus (CMV) promoter. The plasmid was linearised with NotI restriction enzyme, and 50 ng of linearised plasmid was injected into mouse pronucleus for the chimaera production. Immunohistochemical methods were used to assess the colocalisation renin and CTGF as well as morphology and rheology of the cardiovascular system. The chimeric mice were backcrossed against the wild-type C57BL/6 to generate hemizygous (F1) mouse. Most of the offsprings died as a result of respiratory distress and those that survived have low CTGF gene copy number, approximately 40 molecules per mouse genome. The copy number assessment on the dead pups showed 5×10 3 molecules per mouse genome explaining the threshold of the gene in terms of toxicity. Interestingly, the result of this cross showed 85% of the progenies to be positive deviating from Mendelian first law. All F2 progenies died excluding the possibility of establishing the CTGF transgenic mouse line, situation that

Increased tau phosphorylation and beta amyloid in the hipocampus of mouse pups by early life lead exposure.

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Li, N; Yu, Z L; Wang, L; Zheng, Y T; Jia, J X; Wang, Q; Zhu, M J; Liu, X L; Xia, X; Li, W J

2010-06-01

The aim of this study was to investigate the effects of maternal lead exposure on the learning and memory ability and expression of tau protein phosphorylation (P-tau) and beta amyloid protein (Abeta) in hippocampus of mice offspring. Pb exposure initiated from beginning of gestation to weaning. Pb acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups. On the 21 th of postnatal day, the learning and memory ability of the mouse pups was tested by Water Maze test and the Pb levels in blood and hippocampus of the offspring were also determined. The expression of P-tau and Abeta in hippocampus was measured by immunohistochemistry and Western blotting. The Pb levels in blood and hippocampus of all exposure groups were significantly higher than that of the control group ( P < 0.05). In Water Maze test, the performances of 0.5% and 1% groups were worse than that of the control group ( P < 0.05). The expression of P-tau and Abeta was increased in Pb exposed groups than that of the control group ( P < 0.05). Tau hyper-phosphorylation and Abeta increase in the hippocampus of pups may contribute to the impairment of learning and memory associated with maternal Pb exposure.

Generation and Characterization of a Transgenic Mouse Carrying a Functional Human β-Globin Gene with the IVSI-6 Thalassemia Mutation

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Giulia Breveglieri

2015-01-01

Full Text Available Mouse models that carry mutations causing thalassemia represent a suitable tool to test in vivo new mutation-specific therapeutic approaches. Transgenic mice carrying the β-globin IVSI-6 mutation (the most frequent in Middle-Eastern regions and recurrent in Italy and Greece are, at present, not available. We report the production and characterization of a transgenic mouse line (TG-β-IVSI-6 carrying the IVSI-6 thalassemia point mutation within the human β-globin gene. In the TG-β-IVSI-6 mouse (a the transgenic integration region is located in mouse chromosome 7; (b the expression of the transgene is tissue specific; (c as expected, normally spliced human β-globin mRNA is produced, giving rise to β-globin production and formation of a human-mouse tetrameric chimeric hemoglobin αmu-globin2/βhu-globin2 and, more importantly, (d the aberrant β-globin-IVSI-6 RNAs are present in blood cells. The TG-β-IVSI-6 mouse reproduces the molecular features of IVSI-6 β-thalassemia and might be used as an in vivo model to characterize the effects of antisense oligodeoxynucleotides targeting the cryptic sites responsible for the generation of aberrantly spliced β-globin RNA sequences, caused by the IVSI-6 mutation. These experiments are expected to be crucial for the development of a personalized therapy for β-thalassemia.

Generation and Characterization of a Transgenic Mouse Carrying a Functional Human β-Globin Gene with the IVSI-6 Thalassemia Mutation

Science.gov (United States)

Mancini, Irene; Lampronti, Ilaria; Salvatori, Francesca; Fabbri, Enrica; Zuccato, Cristina; Cosenza, Lucia C.; Montagner, Giulia; Borgatti, Monica; Altruda, Fiorella; Fagoonee, Sharmila; Carandina, Gianni; Aiello, Vincenzo; Breda, Laura; Rivella, Stefano; Gambari, Roberto

2015-01-01

Mouse models that carry mutations causing thalassemia represent a suitable tool to test in vivo new mutation-specific therapeutic approaches. Transgenic mice carrying the β-globin IVSI-6 mutation (the most frequent in Middle-Eastern regions and recurrent in Italy and Greece) are, at present, not available. We report the production and characterization of a transgenic mouse line (TG-β-IVSI-6) carrying the IVSI-6 thalassemia point mutation within the human β-globin gene. In the TG-β-IVSI-6 mouse (a) the transgenic integration region is located in mouse chromosome 7; (b) the expression of the transgene is tissue specific; (c) as expected, normally spliced human β-globin mRNA is produced, giving rise to β-globin production and formation of a human-mouse tetrameric chimeric hemoglobin mu α-globin2/hu β-globin2 and, more importantly, (d) the aberrant β-globin-IVSI-6 RNAs are present in blood cells. The TG-β-IVSI-6 mouse reproduces the molecular features of IVSI-6 β-thalassemia and might be used as an in vivo model to characterize the effects of antisense oligodeoxynucleotides targeting the cryptic sites responsible for the generation of aberrantly spliced β-globin RNA sequences, caused by the IVSI-6 mutation. These experiments are expected to be crucial for the development of a personalized therapy for β-thalassemia. PMID:26097845

Transgenic mouse - Methods and protocols, 2nd edition

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Carlo Alberto Redi

2011-09-01

Full Text Available Marten H. Hofner (from the Dept. of Pathology of the Groningen University and Jan M. van Deursen (from the Mayo College of Medicine at Rochester, MN, USA provided us with the valuable second edition of Transgenic mouse: in fact, eventhough we are in the –omics era and already equipped with the state-of-the-art techniques in whatsoever field, still we need to have gene(s functional analysis data to understand common and complex deseases. Transgenesis is still an irreplaceable method and protocols to well perform it are more than welcome. Here, how to get genetic modified mice (the quintessential model of so many human deseases considering how much of the human genes are conserved in the mouse and the great block of genic synteny existing between the two genomes is analysed in deep and presented in clearly detailed step by step protocols....

Expression of human erythropoietin gene in the mammary gland of a transgenic mouse

Czech Academy of Sciences Publication Activity Database

Mikuš, Tomáš; Malý, Petr; Poplštein, M.; Landa, Vladimír; Trefil, P.; Lidický, J.

2001-01-01

Roč. 47, č. 6 (2001), s. 187-195 ISSN 0015-5500 Institutional research plan: CEZ:AV0Z5052915 Keywords : erythropoietin, mammary gland, transgenic mouse Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001

Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

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Liu, Bigang; Gong, Shuai; Li, Qiuhui; Chen, Xin; Moore, John; Suraneni, Mahipal V; Badeaux, Mark D; Jeter, Collene R; Shen, Jianjun; Mehmood, Rashid; Fan, Qingxia; Tang, Dean G

2017-08-08

This project was undertaken to address a critical cancer biology question: Is overexpression of the pluripotency molecule Nanog sufficient to initiate tumor development in a somatic tissue? Nanog1 is critical for the self-renewal and pluripotency of ES cells, and its retrotransposed homolog, NanogP8 is preferentially expressed in somatic cancer cells. Our work has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 promotes cancer stem cell phenotypes and properties. To address the key unanswered question whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo , we generated a NanogP8 transgenic mouse model, in which the ARR 2 PB promoter was used to drive NanogP8 cDNA. Surprisingly, the ARR 2 PB-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors in >2 years. Also, both wild type and ARR 2 PB-NanogP8 transgenic mice responded similarly to castration and regeneration and castrated ARR 2 PB-NanogP8 transgenic mice also did not develop tumors. By crossing the ARR 2 PB-NanogP8 transgenic mice with ARR 2 PB-Myc (i.e., Hi-Myc) mice, we found that the double transgenic (i.e., ARR 2 PB-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Interestingly, however, we observed white dots in the ventral lobes of the double transgenic prostates, which were characterized as overgrown ductules/buds featured by crowded atypical Nanog-expressing luminal cells. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model.

A Transgenic Mouse Model of Poliomyelitis.

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Koike, Satoshi; Nagata, Noriyo

2016-01-01

Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model.

Expression of human eryhropoietin gene in the mammary gland of a transgenic mouse

Czech Academy of Sciences Publication Activity Database

Mikuš, T.; Malý, Petr; Poplštein, M.; Landa, Vladimír; Trefil, P.; Lidický, J.

2001-01-01

Roč. 47, č. 6 (2001), s. 187-195 ISSN 0015-5500 R&D Projects: GA MPO PP-Z1/09/96 Keywords : erythropoietin * recombinant protein * transgenic mouse Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001

Towards Transgenic Primates: What can we learn from mouse genetics?

OpenAIRE

KUANG, Hui; WANG, Phillip L.; TSIEN, Joe Z.

2009-01-01

Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases. Various powerful genetic technologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and...

Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake.

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Xie, Ling; Zheng, Wei; Xin, Na; Xie, Jing-Wei; Wang, Tao; Wang, Zhan-You

2012-08-01

Dysregulation of iron homeostasis is involved in the pathological process of Alzheimer's disease (AD). We have recently reported that divalent metal transporter 1 (DMT1) is upregulated in an AD transgenic mouse brain, and that silencing of DMT1, which reduces cellular iron influx, results in inhibition of amyloidogenesis in vitro, suggesting a potential target of DMT1 for AD therapy. In the present study, we tested the hypothesis that inhibition of DMT1 with ebselen, a DMT1 transport inhibitor, could affect tau phosphorylation. Human neuroblastoma SH-SY5Y cells were pre-treated with ebselen and then treated with ferrous sulfate (dissolved in ascorbic acid), and the effects of ebselen on tau phosphorylation and the relative signaling pathways were examined. Our results showed that ebselen decreased iron influx, reduced iron-induced ROS production, inhibited the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3β, and ultimately attenuated the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. The present study indicates that the neuroprotective effect of ebselen on AD is not only related to its antioxidant activity as reported previously, but is also associated with a reduction in tau phosphorylation by inhibition of DMT1. Copyright © 2012 Elsevier Ltd. All rights reserved.

Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe.

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Verwilst, Peter; Kim, Hye-Ri; Seo, Jinho; Sohn, Nak-Won; Cha, Seung-Yun; Kim, Yeongmin; Maeng, Sungho; Shin, Jung-Won; Kwak, Jong Hwan; Kang, Chulhun; Kim, Jong Seung

2017-09-27

The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 ( 306 VQIVYK 311 ) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity.

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Kanae Ando

2016-03-01

Full Text Available Abnormal accumulation of the microtubule-interacting protein tau is associated with neurodegenerative diseases including Alzheimer's disease (AD. β-amyloid (Aβ lies upstream of abnormal tau behavior, including detachment from microtubules, phosphorylation at several disease-specific sites, and self-aggregation into toxic tau species in AD brains. To prevent the cascade of events leading to neurodegeneration in AD, it is essential to elucidate the mechanisms underlying the initial events of tau mismetabolism. Currently, however, these mechanisms remain unclear. In this study, using transgenic Drosophila co-expressing human tau and Aβ, we found that tau phosphorylation at AD-related Ser262/356 stabilized microtubule-unbound tau in the early phase of tau mismetabolism, leading to neurodegeneration. Aβ increased the level of tau detached from microtubules, independent of the phosphorylation status at GSK3-targeted SP/TP sites. Such mislocalized tau proteins, especially the less phosphorylated species, were stabilized by phosphorylation at Ser262/356 via PAR-1/MARK. Levels of Ser262 phosphorylation were increased by Aβ42, and blocking this stabilization of tau suppressed Aβ42-mediated augmentation of tau toxicity and an increase in the levels of tau phosphorylation at the SP/TP site Thr231, suggesting that this process may be involved in AD pathogenesis. In contrast to PAR-1/MARK, blocking tau phosphorylation at SP/TP sites by knockdown of Sgg/GSK3 did not reduce tau levels, suppress tau mislocalization to the cytosol, or diminish Aβ-mediated augmentation of tau toxicity. These results suggest that stabilization of microtubule-unbound tau by phosphorylation at Ser262/356 via the PAR-1/MARK may act in the initial steps of tau mismetabolism in AD pathogenesis, and that such tau species may represent a potential therapeutic target for AD.

Downregulation of the taurine transporter TauT during hypo-osmotic stress in NIH3T3 mouse fibroblasts

DEFF Research Database (Denmark)

Hansen, Daniel Bloch; Friis, Martin Barfred; Hoffmann, Else Kay

2012-01-01

The present work was initiated to investigate regulation of the taurine transporter TauT by reactive oxygen species (ROS) and the tonicity-responsive enhancer binding protein (TonEBP) in NIH3T3 mouse fibroblasts during acute and long-term (4 h) exposure to low-sodium/hypo-osmotic stress. Taurine...... are significantly increased following hyperosmotic exposure. Swelling-induced ROS production in NIH3T3 fibroblasts is generated by NOX4 and by increasing total ROS, by either exogenous application of H(2)O(2) or overexpressing NOX4, we demonstrate that TonEBP activity and taurine influx are regulated negatively...... by ROS under hypo-osmotic, low-sodium conditions, whereas the TauT mRNA level is unaffected. Acute exposure to ROS reduces taurine uptake as a result of modulated TauT transport kinetics. Thus, swelling-induced ROS production could account for the reduced taurine uptake under low...

Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.

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Jin Chu

Full Text Available The 5-lipoxygenase (5LO enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD, and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3 × Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.

Liver BCATm transgenic mouse model reveals the important role of the liver in maintaining BCAA homeostasis.

Science.gov (United States)

Ananieva, Elitsa A; Van Horn, Cynthia G; Jones, Meghan R; Hutson, Susan M

2017-02-01

Unlike other amino acids, the branched-chain amino acids (BCAAs) largely bypass first-pass liver degradation due to a lack of hepatocyte expression of the mitochondrial branched-chain aminotransferase (BCATm). This sets up interorgan shuttling of BCAAs and liver-skeletal muscle cooperation in BCAA catabolism. To explore whether complete liver catabolism of BCAAs may impact BCAA shuttling in peripheral tissues, the BCATm gene was stably introduced into mouse liver. Two transgenic mouse lines with low and high hepatocyte expression of the BCATm transgene (LivTg-LE and LivTg-HE) were created and used to measure liver and plasma amino acid concentrations and determine whether the first two BCAA enzymatic steps in liver, skeletal muscle, heart and kidney were impacted. Expression of the hepatic BCATm transgene lowered the concentrations of hepatic BCAAs while enhancing the concentrations of some nonessential amino acids. Extrahepatic BCAA metabolic enzymes and plasma amino acids were largely unaffected, and no growth rate or body composition differences were observed in the transgenic animals as compared to wild-type mice. Feeding the transgenic animals a high-fat diet did not reverse the effect of the BCATm transgene on the hepatic BCAA catabolism, nor did the high-fat diet cause elevation in plasma BCAAs. However, the high-fat-diet-fed BCATm transgenic animals experienced attenuation in the mammalian target of rapamycin (mTOR) pathway in the liver and had impaired blood glucose tolerance. These results suggest that complete liver BCAA metabolism influences the regulation of glucose utilization during diet-induced obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

Case Study: Polycystic Livers in a Transgenic Mouse Line

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Lovaglio, Jamie A.; Artwohl, James E.; Ward, Christopher J.; Diekwisch, Thomas G. H.; Ito, Yoshihiro; Fortman, Jeffrey D.

2014-04-01

Three mice (2 male, 1 female; age, 5 to 16 mo) from a mouse line transgenic for keratin 14 (K14)-driven LacZ expression and on an outbred Crl:CD1(ICR) background, were identified as having distended abdomens and livers that were diffusely enlarged by numerous cysts (diameter, 0.1 to 2.0 cm). Histopathology revealed hepatic cysts lined by biliary type epithelium and mild chronic inflammation, and confirmed the absence of parasites. Among 21 related mice, 5 additional affected mice were identified via laparotomy. Breeding of these 5 mice (after 5 mo of age) did not result in any offspring; the K14 mice with olycystic livers failed to reproduce. Affected male mice had degenerative testicular lesions, and their sperm was immotile. Nonpolycystic K14 control male mice bred well, had no testicular lesions, and had appropriate sperm motility. Genetic analysis did not identify an association of this phenotype with the transgene or insertion site.

Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation

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Zhao Roong

2001-12-01

Full Text Available Abstract Background Transgenic mice have been used extensively to analyze gene function. Unfortunately, traditional transgenic procedures have only limited use in analyzing alleles that cause lethality because lines of founder mice cannot be established. This is frustrating given that such alleles often reveal crucial aspects of gene function. For this reason techniques that facilitate the generation of embryos expressing such alleles would be of enormous benefit. Although the transient generation of transgenic embryos has allowed limited analysis of lethal alleles, it is expensive, time consuming and technically challenging. Moreover a fundamental limitation with this approach is that each embryo generated is unique and transgene expression is highly variable due to the integration of different transgene copy numbers at random genomic sites. Results Here we describe an alternative method that allows the generation of clonal mouse embryos harboring a single-copy transgene at a defined genomic location. This was facilitated through the production of Hprt negative embryonic stem cells that allow the derivation of embryos by tetraploid embryo complementation. We show that targeting transgenes to the hprt locus in these ES cells by homologous recombination can be efficiently selected by growth in HAT medium. Moreover, embryos derived solely from targeted ES cells containing a single copy LacZ transgene under the control of the α-myosin heavy chain promoter exhibited the expected cardiac specific expression pattern. Conclusion Our results demonstrate that tetraploid embryo complementation by F3 hprt negative ES cells facilitates the generation of transgenic mouse embryos containing a single copy gene at a defined genomic locus. This approach is simple, extremely efficient and bypasses any requirement to generate chimeric mice. Moreover embryos generated by this procedure are clonal in that they are all derived from a single ES cell lines. This

A Mutation of the Prdm9 Mouse Hybrid Sterility Gene Carried by a Transgene.

Science.gov (United States)

Mihola, O; Trachtulec, Z

2017-01-01

PRDM9 is a protein with histone-3-methyltransferase activity, which specifies the sites of meiotic recombination in mammals. Deficiency of the Prdm9 gene in the laboratory mouse results in complete arrest of the meiotic prophase of both sexes. Moreover, the combination of certain PRDM9 alleles from different mouse subspecies causes hybrid sterility, e.g., the male-specific meiotic arrest found in the (PWD/Ph × C57BL/6J)F1 animals. The fertility of all these mice can be rescued using a Prdm9-containing transgene. Here we characterized a transgene made from the clone RP24-346I22 that was expected to encompass the entire Prdm9 gene. Both (PWD/Ph × C57BL/6J)F1 intersubspecific hybrid males and Prdm9-deficient laboratory mice of both sexes carrying this transgene remained sterile, suggesting that Prdm9 inactivation occurred in the Tg(RP24-346I22) transgenics. Indeed, comparative qRT-PCR analysis of testicular RNAs from transgene-positive versus negative animals revealed similar expression levels of Prdm9 mRNAs from the exons encoding the C-terminal part of the protein but elevated expression from the regions coding for the N-terminus of PRDM9, indicating that the transgenic carries a new null Prdm9 allele. Two naturally occurring alternative Prdm9 mRNA isoforms were overexpressed in Tg(RP24-346I22), one formed via splicing to a 3'-terminal exon consisting of short interspersed element B2 and one isoform including an alternative internal exon of 28 base pairs. However, the overexpression of these alternative transcripts was apparently insufficient for Prdm9 function or for increasing the fertility of the hybrid males.

Transgenic Mouse Models Transferred into the Test Tube: New Perspectives for Developmental Toxicity Testing In Vitro?

Science.gov (United States)

Kugler, Josephine; Luch, Andreas; Oelgeschläger, Michael

2016-10-01

Despite our increasing understanding of molecular mechanisms controlling embryogenesis, the identification and characterization of teratogenic substances still heavily relies on animal testing. Embryonic development depends on cell-autonomous and non-autonomous processes including spatiotemporally regulated extracellular signaling activities. These have been elucidated in transgenic mouse models harboring easily detectable reporter genes under the control of evolutionarily conserved signaling cascades. We propose combining these transgenic mouse models and cells derived thereof with existing alternative toxicological testing strategies. This would enable the plausibility of in vitro data to be verified in light of in vivo data and, ultimately, facilitate regulatory acceptance of in vitro test methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cotinine improves visual recognition memory and decreases cortical Tau phosphorylation in the Tg6799 mice.

Science.gov (United States)

Grizzell, J Alex; Patel, Sagar; Barreto, George E; Echeverria, Valentina

2017-08-01

Alzheimer's disease (AD) is associated with the progressive aggregation of hyperphosphorylated forms of the microtubule associated protein Tau in the central nervous system. Cotinine, the main metabolite of nicotine, reduced working memory deficits, synaptic loss, and amyloid β peptide aggregation into oligomers and plaques as well as inhibited the cerebral Tau kinase, glycogen synthase 3β (GSK3β) in the transgenic (Tg)6799 (5XFAD) mice. In this study, the effect of cotinine on visual recognition memory and cortical Tau phosphorylation at the GSK3β sites Serine (Ser)-396/Ser-404 and phospho-CREB were investigated in the Tg6799 and non-transgenic (NT) littermate mice. Tg mice showed short-term visual recognition memory impairment in the novel object recognition test, and higher levels of Tau phosphorylation when compared to NT mice. Cotinine significantly improved visual recognition memory performance increased CREB phosphorylation and reduced cortical Tau phosphorylation. Potential mechanisms underlying theses beneficial effects are discussed. Copyright © 2017. Published by Elsevier Inc.

T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma

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Abschuetz, Oliver [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Osen, Wolfram [Division of Translational Immunology, German Cancer Center, Heidelberg 69120 (Germany); Frank, Kathrin [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany); Kato, Masashi [Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501 (Japan); Schadendorf, Dirk [Department of Dermatology, University Hospital Essen, Essen 45122 (Germany); Umansky, Viktor, E-mail: v.umansky@dkfz.de [Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120 (Germany)

2012-04-26

Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.

A novel transgenic mouse model of lysosomal storage disorder.

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Ortiz-Miranda, Sonia; Ji, Rui; Jurczyk, Agata; Aryee, Ken-Edwin; Mo, Shunyan; Fletcher, Terry; Shaffer, Scott A; Greiner, Dale L; Bortell, Rita; Gregg, Ronald G; Cheng, Alan; Hennings, Leah J; Rittenhouse, Ann R

2016-11-01

Knockout technology has proven useful for delineating functional roles of specific genes. Here we describe and provide an explanation for striking pathology that occurs in a subset of genetically engineered mice expressing a rat Ca V β2a transgene under control of the cardiac α-myosin heavy chain promoter. Lesions were limited to mice homozygous for transgene and independent of native Cacnb2 genomic copy number. Gross findings included an atrophied pancreas; decreased adipose tissue; thickened, orange intestines; and enlarged liver, spleen, and abdominal lymph nodes. Immune cell infiltration and cell engulfment by macrophages were associated with loss of pancreatic acinar cells. Foamy macrophages diffusely infiltrated the small intestine's lamina propria, while similar macrophage aggregates packed liver and splenic red pulp sinusoids. Periodic acid-Schiff-positive, diastase-resistant, iron-negative, Oil Red O-positive, and autofluorescent cytoplasm was indicative of a lipid storage disorder. Electron microscopic analysis revealed liver sinusoids distended by clusters of macrophages containing intracellular myelin "swirls" and hepatocytes with enlarged lysosomes. Additionally, build up of cholesterol, cholesterol esters, and triglycerides, along with changes in liver metabolic enzyme levels, were consistent with a lipid processing defect. Because of this complex pathology, we examined the transgene insertion site. Multiple transgene copies inserted into chromosome 19; at this same site, an approximate 180,000 base pair deletion occurred, ablating cholesterol 25-hydroxylase and partially deleting lysosomal acid lipase and CD95 Loss of gene function can account for the altered lipid processing, along with hypertrophy of the immune system, which define this phenotype, and serendipitously provides a novel mouse model of lysosomal storage disorder. Copyright © 2016 the American Physiological Society.

Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

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2017-12-01

AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis

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Hicks, Sarah M.; Vassallo, Jeffrey D.; Dieter, Matthew Z.; Lewis, Cindy L.; Whiteley, Laurence O.; Fix, Andrew S.; Lehman-McKeeman, Lois D.

2003-01-01

Immunohistochemical methods have been widely used to determine the histogenesis of spontaneous and chemically-induced mouse lung tumors. Typically, antigens for either alveolar Type II cells or bronchiolar epithelial Clara cells are studied. In the present work, the morphological and immunohistochemical phenotype of a transgenic mouse designed to develop lung tumors arising from Clara cells was evaluated. In this model, Clara cell-specific transformation is accomplished by directed expression of the SV40 large T antigen (TAg) under the mouse Clara cell secretory protein (CC10) promoter. In heterozygous mice, early lesions at 1 month of age consisted of hyperplastic bronchiolar epithelial cells. These progressed to adenoma by 2 months as proliferating epithelium extended into adjacent alveolar spaces. By 4 months, a large portion of the lung parenchyma was composed of tumor masses. Expression of constitutive CC10 was diminished in transgenic animals at all time points. Only the occasional cell or segment of the bronchiolar epithelium stained positively for CC10 by immunohistochemistry, and all tumors were found to be uniformly negative for staining. These results were corroborated by Western blotting, where CC10 was readily detectable in whole lung homogenate from nontransgenic animals, but not detected in lung from transgenic animals at any time point. Tumors were also examined for expression of surfactant apoprotein C (SPC), an alveolar Type II cell-specific marker, and found to be uniformly negative for staining. These results indicate that, in this transgenic model, expression of CC10, which is widely used to determine whether lung tumors arise from Clara cells, was reduced and subsequently lost during Clara cell tumor progression

Transgenic Expression of Constitutively Active RAC1 Disrupts Mouse Rod Morphogenesis

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Song, Hongman; Bush, Ronald A.; Vijayasarathy, Camasamudram; Fariss, Robert N.; Kjellstrom, Sten; Sieving, Paul A.

2014-01-01

Purpose. Dominant-active RAC1 rescues photoreceptor structure in Drosophila rhodopsin-null mutants, indicating an important role in morphogenesis. This report assesses the morphogenetic effect of activated RAC1 during mammalian rod photoreceptor development using transgenic mice that express constitutively active (CA) RAC1. Methods. Transgenic mice were generated by expressing CA RAC1 under control of the Rhodopsin promoter, and morphological features of the photoreceptors were evaluated by histology, immunohistochemistry, and transmission electron microscopy. Function was evaluated by electroretinography. Potential protein partners of CA RAC1 were identified by co-immunoprecipitation of retinal extracts. Results. Constitutively active RAC1 expression in differentiating rods disrupted outer retinal lamination as early as postnatal day (P)6, and many photoreceptor cell nuclei were displaced apically into the presumptive subretinal space. These photoreceptors did not develop normal inner and outer segments and had abnormal placement of synaptic elements. Some photoreceptor nuclei were also mislocalized into the inner nuclear layer. Extensive photoreceptor degeneration was subsequently observed in the adult animal. Constitutively active RAC1 formed a complex with the polarity protein PAR6 and with microtubule motor dynein in mouse retina. The normal localization of the PAR6 complex was disrupted in CA RAC1-expressing rod photoreceptors. Conclusions. Constitutively active RAC1 had a profound negative effect on mouse rod cell viability and development. Rod photoreceptors in the CA RAC1 retina exhibited a defect in polarity and migration. Constitutively active RAC1 disrupted rod morphogenesis and gave a phenotype resembling that found in the Crumbs mutant. PAR6 and dynein are two potential downstream effectors that may be involved in CA RAC1-mediated defective mouse photoreceptor morphogenesis. PMID:24651551

BAC-Dkk3-EGFP Transgenic Mouse: An In Vivo Analytical Tool for Dkk3 Expression

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Yuki Muranishi

2012-01-01

Full Text Available Dickkopf (DKK family proteins are secreted modulators of the Wnt signaling pathway and are capable of regulating the development of many organs and tissues. We previously identified Dkk3 to be a molecule predominantly expressed in the mouse embryonic retina. However, which cell expresses Dkk3 in the developing and mature mouse retina remains to be elucidated. To examine the precise expression of the Dkk3 protein, we generated BAC-Dkk3-EGFP transgenic mice that express EGFP integrated into the Dkk3 gene in a BAC plasmid. Expression analysis using the BAC-Dkk3-EGFP transgenic mice revealed that Dkk3 is expressed in retinal progenitor cells (RPCs at embryonic stages and in Müller glial cells in the adult retina. Since Müller glial cells may play a potential role in retinal regeneration, BAC-Dkk3-EGFP mice could be useful for retinal regeneration studies.

Transgenic Mouse Model Harboring the Transcriptional Fusion Ccl20-Luciferase as a Novel Reporter of Pro-Inflammatory Response

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Crispo, Martina; Van Maele, Laurye; Tabareau, Julien; Cayet, Delphine; Errea, Agustina; Ferreira, Ana María; Rumbo, Martin; Sirard, Jean Claude

2013-01-01

The chemokine CCL20, the unique ligand of CCR6 functions as an attractant of immune cells. Expression of CCL20 is induced by Toll-like Receptor (TLR) signaling or proinflammatory cytokine stimulation. However CCL20 is also constitutively produced at specific epithelial sites of mucosa. This expression profile is achieved by transcriptional regulation. In the present work we characterized regulatory features of mouse Ccl20 gene. Transcriptional fusions between the mouse Ccl20 promoter and the firefly luciferase (luc) encoding gene were constructed and assessed in in vitro and in vivo assays. We found that liver CCL20 expression and luciferase activity were upregulated by systemic administration of the TLR5 agonist flagellin. Using shRNA and dominant negative form specific for mouse TLR5, we showed that this expression was controlled by TLR5. To address in situ the regulation of gene activity, a transgenic mouse line harboring a functional Ccl20-luc fusion was generated. The luciferase expression was highly concordant with Ccl20 expression in different tissues. Our data indicate that the transgenic mouse model can be used to monitor activation of innate response in vivo. PMID:24265691

Reduction of the immunostainable length of the hippocampal dentate granule cells’ primary cilia in 3xAD-transgenic mice producing human Aβ1-42 and tau

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Chakravarthy, Balu; Gaudet, Chantal; Ménard, Michel; Brown, Leslie; Atkinson, Trevor; LaFerla, Frank M.; Ito, Shingo; Armato, Ubaldo; Dal Prà, Ilaria; Whitfield, James

2012-01-01

Highlights: ► Aβ and tau-induced neurofibrillary tangles play a key role in Alzheimer’s disease. ► Aβ 1-42 and mutant tau protein together reduce the primary cilium length. ► This shortening likely reduces cilium-dependent neurogenesis and memory function. ► This provides a model of an Aβ/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75 NTR ). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6–24-months-old triple transgenic Alzheimer’s disease model mice (3xTg-AD) producing both Aβ 1-42 and the mutant human tau protein tau P301L, the dentate granule cells still had immunostainable SSTR3- and p75 NTR -bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of Aβ 1-42 or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of Aβ 1-42 and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model

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Teng Wei-Ping

2010-11-01

Full Text Available Abstract Background Although increasing evidence has indicated that brain insulin dysfunction is a risk factor for Alzheimer disease (AD, the underlying mechanisms by which insulin deficiency may impact the development of AD are still obscure. Using a streptozotocin (STZ-induced insulin deficient diabetic AD transgenic mouse model, we evaluated the effect of insulin deficiency on AD-like behavior and neuropathology. Results Our data showed that administration of STZ increased the level of blood glucose and reduced the level of serum insulin, and further decreased the phosphorylation levels of insulin receptors, and increased the activities of glycogen synthase kinase-3α/β and c-Jun N-terminal kinase in the APP/PS1 mouse brain. We further showed that STZ treatment promoted the processing of amyloid-β (Aβ precursor protein resulting in increased Aβ generation, neuritic plaque formation, and spatial memory deficits in transgenic mice. Conclusions Our present data indicate that there is a close link between insulin deficient diabetes and cerebral amyloidosis in the pathogenesis of AD.

Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice

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Bowers William J

2008-08-01

Full Text Available Abstract Background Several transgenic animal models genetically predisposed to develop Alzheimer's disease (AD-like pathology have been engineered to facilitate the study of disease pathophysiology and the vetting of potential disease-modifying therapeutics. The triple transgenic mouse model of AD (3xTg-AD harbors three AD-related genetic loci: human PS1M146V, human APPswe, and human tauP301L. These mice develop both amyloid plaques and neurofibrillary tangle-like pathology in a progressive and age-dependent manner, while these pathological hallmarks are predominantly restricted to the hippocampus, amygdala, and the cerebral cortex the main foci of AD neuropathology in humans. This model represents, at present, one of the most advanced preclinical tools available and is being employed ever increasingly in the study of mechanisms underlying AD, yet a detailed regional and temporal assessment of the subtleties of disease-related pathologies has not been reported. Methods and results In this study, we immunohistochemically documented the evolution of AD-related transgene expression, amyloid deposition, tau phosphorylation, astrogliosis, and microglial activation throughout the hippocampus, entorhinal cortex, primary motor cortex, and amygdala over a 26-month period in male 3xTg-AD mice. Intracellular amyloid-beta accumulation is detectable the earliest of AD-related pathologies, followed temporally by phospho-tau, extracellular amyloid-beta, and finally paired helical filament pathology. Pathology appears to be most severe in medial and caudal hippocampus. While astrocytic staining remains relatively constant at all ages and regions assessed, microglial activation appears to progressively increase temporally, especially within the hippocampal formation. Conclusion These data fulfill an unmet need in the ever-widening community of investigators studying 3xTg-AD mice and provide a foundation upon which to design future experiments that seek to

Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

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Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

2014-06-24

The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

Conditional reverse tet-transactivator mouse strains for the efficient induction of TRE-regulated transgenes in mice.

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Lukas E Dow

Full Text Available Tetracycline or doxycycline (dox-regulated control of genetic elements allows inducible, reversible and tissue specific regulation of gene expression in mice. This approach provides a means to investigate protein function in specific cell lineages and at defined periods of development and disease. Efficient and stable regulation of cDNAs or non-coding elements (e.g. shRNAs downstream of the tetracycline-regulated element (TRE requires the robust expression of a tet-transactivator protein, commonly the reverse tet-transactivator, rtTA. Most rtTA strains rely on tissue specific promoters that often do not provide sufficient rtTA levels for optimal inducible expression. Here we describe the generation of two mouse strains that enable Cre-dependent, robust expression of rtTA3, providing tissue-restricted and consistent induction of TRE-controlled transgenes. We show that these transgenic strains can be effectively combined with established mouse models of disease, including both Cre/LoxP-based approaches and non Cre-dependent disease models. The integration of these new tools with established mouse models promises the development of more flexible genetic systems to uncover the mechanisms of development and disease pathogenesis.

Propofol directly increases tau phosphorylation.

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Robert A Whittington

2011-01-01

Full Text Available In Alzheimer's disease (AD and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of

PICALM modulates autophagy activity and tau accumulation

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Moreau, Kevin; Fleming, Angeleen; Imarisio, Sara; Lopez Ramirez, Ana; Mercer, Jacob L.; Jimenez-Sanchez, Maria; Bento, Carla F.; Puri, Claudia; Zavodszky, Eszter; Siddiqi, Farah; Lavau, Catherine P.; Betton, Maureen; O’Kane, Cahir J.; Wechsler, Daniel S.; Rubinsztein, David C.

2014-01-01

Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover. PMID:25241929

Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model

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Hu, Yanping; Turner, Michael J; Shields, Jacqueline; Gale, Matthew S; Hutto, Elizabeth; Roberts, Bruce L; Siders, William M; Kaplan, Johanne M

2009-01-01

Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of normal and malignant lymphocytes. It is approved for the treatment of B-cell chronic lymphocytic leukaemia and is undergoing Phase III clinical trials for the treatment of multiple sclerosis. The exact mechanism by which alemtuzumab mediates its biological effects in vivo is not clearly defined and mechanism of action studies have been hampered by the lack of cross-reactivity between human and mouse CD52. To address this issue, a transgenic mouse expressing human CD52 (hCD52) was created. Transgenic mice did not display any phenotypic abnormalities and were able to mount normal immune responses. The tissue distribution of hCD52 and the level of expression by various immune cell populations were comparable to those seen in humans. Treatment with alemtuzumab replicated the transient increase in serum cytokines and depletion of peripheral blood lymphocytes observed in humans. Lymphocyte depletion was not as profound in lymphoid organs, providing a possible explanation for the relatively low incidence of infection in alemtuzumab-treated patients. Interestingly, both lymphocyte depletion and cytokine induction by alemtuzumab were largely independent of complement and appeared to be mediated by neutrophils and natural killer cells because removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively, strongly inhibited the activity of alemtuzumab whereas removal of complement by treatment with cobra venom factor had no impact. The hCD52 transgenic mouse appears to be a useful model and has provided evidence for the previously uncharacterized involvement of neutrophils in the activity of alemtuzumab. PMID:19740383

Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement

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Seung-Hye Lee

2016-08-01

Full Text Available The spread of tau pathology correlates with cognitive decline in Alzheimer’s disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation

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Asai, Hirohide; Ikezu, Seiko; Tsunoda, Satoshi; Medalla, Maria; Luebke, Jennifer; Haydar, Tarik; Wolozin, Benjamin; Butovsky, Oleg; Kügler, Sebastian; Ikezu, Tsuneya

2015-01-01

Accumulation of pathological tau protein is a major hallmark of Alzheimer’s disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus–based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target. PMID:26436904

Three-dimensional MR microscopy of a transgenic mouse model of dilated cardiomyopathy

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Sze, R.W.; Strife, J.L. [Dept. of Radiology, Children' s Hospital Medical Center, Cincinnati, OH (United States); Chan, C.B.; Sanbe, A.; Robbins, J. [Div. of Molecular Cardiovascular Biology, Department of Pediatrics, Children' s Hospital Research Foundation, Cincinnati, OH (United States); Dardzinski, B.J.; Dunn, S.; Schmithorst, V.; Holland, S.K. [Imaging Research Center, Children' s Hospital Medical Center, Cincinnati, OH (United States)

2001-02-01

Background. Scientists are now able to alter the genetics of vertebrate embryos routinely to produce animal models of human developmental diseases. However, our understanding of structural changes in these animal models is limited by current methodologies. Histological techniques, although providing great anatomic detail, display only ''static'' data (one time point only) in two dimensions. Ultrasound may be used to generate continuous time course data, but is limited by interobserver variation, limited acoustic windows, and relatively low resolution. Objective. To apply the high resolution, non-destructive, and three-dimensional acquisition capabilities of magnetic resonance (MR) microscopy to compare the hearts of normal mice versus an established transgenic mouse model of dilated cardiomyopathy. Materials and methods. Transgenic mice exhibiting dilated cardiomyopathy were developed via the introduction of a mutated, heart-specific gene (myosin light chain). Post-mortem cardiac imaging was performed on the transgenic mice and normal controls. MR imaging was performed on a Bruker 3T imaging magnet using a custom radiofrequency coil following contrast perfusion of the atrial and ventricular chambers. Image resolution was 156 {mu}m isotropic voxels. MR images were compared to gross pathologic specimens. Imaging data were post-processed using custom software to calculate the volumes of the atria and ventricles and to display the three-dimensional morphology of the chambers and myocardium. Results. Of the seven mice scanned, four exhibited normal right atrial (average = 14.8 {mu}l {+-} 1.4), left atrial (average = 8.5 {mu}l {+-} 0.3), right ventricular (average = 12.9 {mu}l {+-} 2.7), and left ventricular (average 3.3 {mu}l {+-} 0.5) volumes. Three mice exhibited dilatation of the right and left cardiac chambers (RA average = 23.9 {mu}l {+-} 5.6; LA average = 15.9 {mu}l {+-} 4.8; RV average = 32.5 {mu}l {+-} 6.8; LV average 24.0 {mu}l {+-} 1

Pharmacodynamic study of Bay41-4109 in HBV transgenic mouse model

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Xiu-mei LI

2011-09-01

Full Text Available Objective To study the pharmacodynamics of Bay41-4109,a novel anti-HBV compound,in HBV transgenic mouse model.Methods specific pathogen frce(SPF level TgM(HBV D1.3mice were divided into 3 groups: Bay41-4109 group [30mg/(kg·d],lamivudine group [30mg/(kg·d] and vehicle group(0.5% sodium carboxymethycellulose,with 32 in each.Antiviral effect of Bay41-4109 was tested in HBV transgenic mice including the analysis of HBcAg changes in liver tissue by immunohistochemistry,and changes in HBV DNA in liver and serum by quantitative real time PCR analysis.Serum transaminase(ALT and AST and body weight were assayed to evaluate the safety of the compound.Results Oral Bay41-4109 significantly reduced the number of HBV core antigen(HBcAg positive cell nucleus,average area of HBcAg positive cell nucleus and the rate of OD compared with vehicle group after 50 days treatment(P 0.05.However,Bay41-4109 could not significantly reduce HBV-specific DNA in HBV transgenic mice,both in liver and plasma.No significant impact was found on ALT,AST and body weigh of Bay41-4109-treated mice.Conclusions Bay41-4109 can more effectively reduce cytoplasmic HBcAg in liver sections than lamivudine.It is suggested that Bay41-4109,a different mode of action from lamivudine,represents a promising anti-HBV drug candidate with good antiviral effect and safety.

Dipotassium N-stearoyltyrosinate ameliorated pathological injuries in triple-transgenic mouse model of Alzheimer's disease

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Sha Liu

2016-09-01

Full Text Available Recently, anandamide (AEA analogues have been well recognized for its potent neuroprotective effects in counteracting the deterioration of Alzheimer's disease (AD brains through multiple pathological processes. In our previous studies, dipotassium N-stearoyltyrosinate (NSTK, an AEA analogue synthesized by our laboratory was reported to exert significant efficacy through multiple interventions. Within this study, the amyloid precursor protein (APPSWE/presenilin-1 (PS1M146V/TauP301L mouse (3×Tg-AD model was used to explore further the neuroprotective effects of NSTK and its underlying mechanisms. NSTK could increase spontaneous locomotor activity in the open field and low anxiety-like behavior in the elevated plus maze, and improve the spatial memory deficits in the Morris water maze. The biochemical analysis suggested that NSTK could decrease Aβ42 deposition, abnormal tau aggregation, and the expressions of p-APP Thr668, PS1 and p-tau Ser202/Thr205 in the hippocampus of 3×Tg-AD mice. Consistently, NSTK could reduce the level of malondialdehyde, increase the activity of superoxide dismutase and catalase. Up-regulation of Bcl-2, and down-regulation of BAX, caspase-3 and inflammatory cytokines also occurred in the hippocampus of 3×Tg-AD mice after treatment with NSTK. Thus, NSTK could intervene in multiple pathological processes of AD and would be a drug candidate against AD.

Mechanism of testosterone deficiency in the transgenic sickle cell mouse.

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Biljana Musicki

Full Text Available Testosterone deficiency is associated with sickle cell disease (SCD, but its underlying mechanism is not known. We investigated the possible occurrence and mechanism of testosterone deficiency in a mouse model of human SCD. Transgenic sickle male mice (Sickle exhibited decreased serum and intratesticular testosterone and increased luteinizing hormone (LH levels compared with wild type (WT mice, indicating primary hypogonadism in Sickle mice. LH-, dbcAMP-, and pregnenolone- (but not 22-hydroxycholesterol- stimulated testosterone production by Leydig cells isolated from the Sickle mouse testis was decreased compared to that of WT mice, implying defective Leydig cell steroidogenesis. There also was reduced protein expression of steroidogenic acute regulatory protein (STAR, but not cholesterol side-chain cleavage enzyme (P450scc, in the Sickle mouse testis. These data suggest that the capacity of P450scc to support testosterone production may be limited by the supply of cholesterol to the mitochondria in Sickle mice. The sickle mouse testis exhibited upregulated NADPH oxidase subunit gp91phox and increased oxidative stress, measured as 4-hydroxy-2-nonenal, and unchanged protein expression of an antioxidant glutathione peroxidase-1. Mice heterozygous for the human sickle globin (Hemi exhibited intermediate hypogonadal changes between those of WT and Sickle mice. These results demonstrate that testosterone deficiency occurs in Sickle mice, mimicking the human condition. The defects in the Leydig cell steroidogenic pathway in Sickle mice, mainly due to reduced availability of cholesterol for testosterone production, may be related to NADPH oxidase-derived oxidative stress. Our findings suggest that targeting testicular oxidative stress or steroidogenesis mechanisms in SCD offers a potential treatment for improving phenotypic changes associated with testosterone deficiency in this disease.

Tumorigenic potential of pituitary tumor transforming gene (PTTG in vivo investigated using a transgenic mouse model, and effects of cross breeding with p53 (+/− transgenic mice

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Fong Miranda Y

2012-11-01

Full Text Available Abstract Background Pituitary tumor-transforming gene (PTTG is an oncogene that is overexpressed in variety of tumors and exhibits characteristics of a transforming gene. Previous transgenic mouse models to access the tumorigenic potential in the pituitary and ovary have resulted in dysplasia without formation of visible tumors, possibly due to the insufficient expression of PTTG. PTTG expression level is critical for ovarian tumorigenesis in a xenograft model. Therefore, the tumorigenic function of PTTG in vivo remains unclear. We generated a transgenic mouse that overexpresses PTTG driven by the CMV promoter to determine whether PTTG functions as a transforming oncogene that is capable of initiating tumorigenesis. Methods Transgenic animals were generated by microinjection of PTTG transgene into the male pronucleus of FVB 0.5 day old embryos. Expression levels of PTTG in tissues of transgenic animals were analyzed using an immunohistochemical analysis. H&E staining and immunohistostaining were performed to examine the type of tumor in transgenic and PTTG transgenic/p53+/- animals. Results PTTG transgenic offspring (TgPTTG were monitored for tumor development at various ages. H&E analysis was performed to identify the presence of cancer and hyperplastic conditions verified with the proliferation marker PCNA and the microvessel marker CD31. Immunohistochemistry was performed to determine transgene expression, revealing localization to the epithelium of the fallopian tube, with more generalized expression in the liver, lung, kidney, and spleen. At eight months of age, 2 out of 15 TgPTTG developed ovarian cancer, 2 out of 15 developed benign tumors, 2 out of 15 developed cervical dysplasia, and 3 out of 15 developed adenomyosis of the uterus. At ten months of age, 2 out of 10 TgPTTG developed adenocarcinoma of the ovary, 1 out of 10 developed a papillary serous adenocarcinoma, and 2 out of 10 presented with atypia of ovarian epithelial cells

Search for the decays $B_s^0\\to\\tau^+\\tau^-$ and $B^0\\to\\tau^+\\tau^-$

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Aaij, Roel; Adinolfi, Marco; Ajaltouni, Ziad; Akar, Simon; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Archilli, Flavio; d'Argent, Philippe; Arnau Romeu, Joan; Artamonov, Alexander; Artuso, Marina; Aslanides, Elie; Auriemma, Giulio; Baalouch, Marouen; Babuschkin, Igor; Bachmann, Sebastian; Back, John; Badalov, Alexey; Baesso, Clarissa; Baker, Sophie; Balagura, Vladislav; Baldini, Wander; Baranov, Alexander; Barlow, Roger; Barschel, Colin; Barsuk, Sergey; Barter, William; Baryshnikov, Fedor; Baszczyk, Mateusz; Batozskaya, Varvara; Batsukh, Baasansuren; Battista, Vincenzo; Bay, Aurelio; Beaucourt, Leo; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Beiter, Andrew; Bel, Lennaert; Bellee, Violaine; Belloli, Nicoletta; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Beranek, Sarah; Berezhnoy, Alexander; Bernet, Roland; Bertolin, Alessandro; Betancourt, Christopher; Betti, Federico; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bezshyiko, Iaroslava; Bifani, Simone; Billoir, Pierre; Birnkraut, Alex; Bitadze, Alexander; Bizzeti, Andrea; Blake, Thomas; Blanc, Frederic; Blouw, Johan; Blusk, Steven; Bocci, Valerio; Boettcher, Thomas; Bondar, Alexander; Bondar, Nikolay; Bonivento, Walter; Bordyuzhin, Igor; Borgheresi, Alessio; Borghi, Silvia; Borisyak, Maxim; Borsato, Martino; Bossu, Francesco; Boubdir, Meriem; Bowcock, Themistocles; Bowen, Espen Eie; Bozzi, Concezio; Braun, Svende; Britton, Thomas; Brodzicka, Jolanta; Buchanan, Emma; Burr, Christopher; Bursche, Albert; Buytaert, Jan; Cadeddu, Sandro; Calabrese, Roberto; Calvi, Marta; Calvo Gomez, Miriam; Camboni, Alessandro; Campana, Pierluigi; Campora Perez, Daniel Hugo; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Castillo Garcia, Lucia; Cattaneo, Marco; Cavallero, Giovanni; Cenci, Riccardo; Chamont, David; Charles, Matthew; Charpentier, Philippe; Chatzikonstantinidis, Georgios; Chefdeville, Maximilien; Chen, Shanzhen; Cheung, Shu-Faye; Chobanova, Veronika; Chrzaszcz, Marcin; Chubykin, Alexsei; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Cogoni, Violetta; Cojocariu, Lucian; Collins, Paula; Comerma-Montells, Albert; Contu, Andrea; Cook, Andrew; Coombs, George; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Costa Sobral, Cayo Mar; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Cunliffe, Samuel; Currie, Robert; D'Ambrosio, Carmelo; Da Cunha Marinho, Franciole; Dall'Occo, Elena; Dalseno, Jeremy; David, Pieter; Davis, Adam; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Serio, Marilisa; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Deckenhoff, Mirko; Del Buono, Luigi; Dembinski, Hans Peter; Demmer, Moritz; Dendek, Adam; Derkach, Denis; Deschamps, Olivier; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Nezza, Pasquale; Dijkstra, Hans; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Dungs, Kevin; Durante, Paolo; Dzhelyadin, Rustem; Dziewiecki, Michal; Dziurda, Agnieszka; Dzyuba, Alexey; Déléage, Nicolas; Easo, Sajan; Ebert, Marcus; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; Ely, Scott; Esen, Sevda; Evans, Hannah Mary; Evans, Timothy; Falabella, Antonio; Farley, Nathanael; Farry, Stephen; Fay, Robert; Fazzini, Davide; Ferguson, Dianne; Fernandez, Gerard; Fernandez Prieto, Antonio; Ferrari, Fabio; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fini, Rosa Anna; Fiore, Marco; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fleuret, Frederic; Fohl, Klaus; Fontana, Marianna; Fontanelli, Flavio; Forshaw, Dean Charles; Forty, Roger; Franco Lima, Vinicius; Frank, Markus; Frei, Christoph; Fu, Jinlin; Funk, Wolfgang; Furfaro, Emiliano; Färber, Christian; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; Garcia Martin, Luis Miguel; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Garsed, Philip John; Gascon, David; Gaspar, Clara; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; Gersabeck, Marco; Gershon, Timothy; Ghez, Philippe; Gianì, Sebastiana; Gibson, Valerie; Girard, Olivier Göran; Giubega, Lavinia-Helena; Gizdov, Konstantin; Gligorov, Vladimir; Golubkov, Dmitry; Golutvin, Andrey; Gomes, Alvaro; Gorelov, Igor Vladimirovich; Gotti, Claudio; Govorkova, Ekaterina; Graciani Diaz, Ricardo; Granado Cardoso, Luis Alberto; Graugés, Eugeni; Graverini, Elena; Graziani, Giacomo; Grecu, Alexandru; Greim, Roman; Griffith, Peter; Grillo, Lucia; Gruberg Cazon, Barak Raimond; Grünberg, Oliver; Gushchin, Evgeny; Guz, Yury; Gys, Thierry; Göbel, Carla; Hadavizadeh, Thomas; Hadjivasiliou, Christos; Haefeli, Guido; Haen, Christophe; Haines, Susan; Hamilton, Brian; Han, Xiaoxue; Hansmann-Menzemer, Stephanie; Harnew, Neville; Harnew, Samuel; Harrison, Jonathan; Hatch, Mark; He, Jibo; Head, Timothy; Heister, Arno; Hennessy, Karol; Henrard, Pierre; Henry, Louis; van Herwijnen, Eric; Heß, Miriam; Hicheur, Adlène; Hill, Donal; Hombach, Christoph; Hopchev, P H; Huard, Zachary; Hulsbergen, Wouter; Humair, Thibaud; Hushchyn, Mikhail; Hutchcroft, David; Idzik, Marek; Ilten, Philip; Jacobsson, Richard; Jalocha, Pawel; Jans, Eddy; Jawahery, Abolhassan; Jiang, Feng; John, Malcolm; Johnson, Daniel; Jones, Christopher; Joram, Christian; Jost, Beat; Jurik, Nathan; Kandybei, Sergii; Karacson, Matthias; Kariuki, James Mwangi; Karodia, Sarah; Kecke, Matthieu; Kelsey, Matthew; Kenzie, Matthew; Ketel, Tjeerd; Khairullin, Egor; Khanji, Basem; Khurewathanakul, Chitsanu; Kirn, Thomas; Klaver, Suzanne; Klimaszewski, Konrad; Klimkovich, Tatsiana; Koliiev, Serhii; Kolpin, Michael; Komarov, Ilya; Kopecna, Renata; Koppenburg, Patrick; Kosmyntseva, Alena; Kotriakhova, Sofia; Kozachuk, Anastasiia; Kozeiha, Mohamad; Kravchuk, Leonid; Kreps, Michal; Krokovny, Pavel; Kruse, Florian; Krzemien, Wojciech; Kucewicz, Wojciech; Kucharczyk, Marcin; Kudryavtsev, Vasily; Kuonen, Axel Kevin; Kurek, Krzysztof; Kvaratskheliya, Tengiz; Lacarrere, Daniel; Lafferty, George; Lai, Adriano; Lanfranchi, Gaia; Langenbruch, Christoph; Latham, Thomas; Lazzeroni, Cristina; Le Gac, Renaud; van Leerdam, Jeroen; Leflat, Alexander; Lefrançois, Jacques; Lefèvre, Regis; Lemaitre, Florian; Lemos Cid, Edgar; Leroy, Olivier; Lesiak, Tadeusz; Leverington, Blake; Li, Tenglin; Li, Yiming; Li, Zhuoming; Likhomanenko, Tatiana; Lindner, Rolf; Lionetto, Federica; Liu, Xuesong; Loh, David; Longstaff, Iain; Lopes, Jose; Lucchesi, Donatella; Lucio Martinez, Miriam; Luo, Haofei; Lupato, Anna; Luppi, Eleonora; Lupton, Oliver; Lusiani, Alberto; Lyu, Xiao-Rui; Machefert, Frederic; Maciuc, Florin; Maev, Oleg; Maguire, Kevin; Malde, Sneha; Malinin, Alexander; Maltsev, Timofei; Manca, Giulia; Mancinelli, Giampiero; Manning, Peter Michael; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marinangeli, Matthieu; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Martins Tostes, Danielle; Massacrier, Laure Marie; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurice, Emilie; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McNab, Andrew; McNulty, Ronan; Meadows, Brian; Meier, Frank; Melnychuk, Dmytro; Merk, Marcel; Merli, Andrea; Michielin, Emanuele; Milanes, Diego Alejandro; Minard, Marie-Noelle; Mitzel, Dominik Stefan; Mogini, Andrea; Molina Rodriguez, Josue; Monroy, Igancio Alberto; Monteil, Stephane; Morandin, Mauro; Mordà, Alessandro; Morello, Michael Joseph; Morgunova, Olga; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Mulder, Mick; Mussini, Manuel; Müller, Dominik; Müller, Janine; Müller, Katharina; Müller, Vanessa; Naik, Paras; Nakada, Tatsuya; Nandakumar, Raja; Nandi, Anita; Nasteva, Irina; Needham, Matthew; Neri, Nicola; Neubert, Sebastian; Neufeld, Niko; Neuner, Max; Nguyen, Thi Dung; Nguyen-Mau, Chung; Nieswand, Simon; Niet, Ramon; Nikitin, Nikolay; Nikodem, Thomas; Nogay, Alla; Novoselov, Alexey; O'Hanlon, Daniel Patrick; Oblakowska-Mucha, Agnieszka; Obraztsov, Vladimir; Ogilvy, Stephen; Oldeman, Rudolf; Onderwater, Gerco; Ossowska, Anna; Otalora Goicochea, Juan Martin; Owen, Patrick; Oyanguren, Maria Aranzazu; Pais, Preema Rennee; Palano, Antimo; Palutan, Matteo; Papanestis, Antonios; Pappagallo, Marco; Pappalardo, Luciano; Pappenheimer, Cheryl; Parker, William; Parkes, Christopher; Passaleva, Giovanni; Pastore, Alessandra; Patel, Mitesh; Patrignani, Claudia; Pearce, Alex; Pellegrino, Antonio; Penso, Gianni; Pepe Altarelli, Monica; Perazzini, Stefano; Perret, Pascal; Pescatore, Luca; Petridis, Konstantinos; Petrolini, Alessandro; Petrov, Aleksandr; Petruzzo, Marco; Picatoste Olloqui, Eduardo; Pietrzyk, Boleslaw; Pikies, Malgorzata; Pinci, Davide; Pistone, Alessandro; Piucci, Alessio; Placinta, Vlad-Mihai; Playfer, Stephen; Plo Casasus, Maximo; Poikela, Tuomas; Polci, Francesco; Poli Lener, Marco; Poluektov, Anton; Polyakov, Ivan; Polycarpo, Erica; Pomery, Gabriela Johanna; Ponce, Sebastien; Popov, Alexander; Popov, Dmitry; Popovici, Bogdan; Poslavskii, Stanislav; Potterat, Cédric; Price, Eugenia; Prisciandaro, Jessica; Prouve, Claire; Pugatch, Valery; Puig Navarro, Albert; Punzi, Giovanni; Qian, Chen; Qian, Wenbin; Quagliani, Renato; Rachwal, Bartolomiej; Rademacker, Jonas; Rama, Matteo; Ramos Pernas, Miguel; 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Verlage, Tobias Anton; Vernet, Maxime; Vesterinen, Mika; Viana Barbosa, Joao Vitor; Viaud, Benoit; Vieira, Daniel; Vieites Diaz, Maria; Viemann, Harald; Vilasis-Cardona, Xavier; Vitti, Marcela; Volkov, Vladimir; Vollhardt, Achim; Voneki, Balazs; Vorobyev, Alexey; Vorobyev, Vitaly; Voß, Christian; de Vries, Jacco; Vázquez Sierra, Carlos; Waldi, Roland; Wallace, Charlotte; Wallace, Ronan; Walsh, John; Wang, Jianchun; Ward, David; Wark, Heather Mckenzie; Watson, Nigel; Websdale, David; Weiden, Andreas; Whitehead, Mark; Wicht, Jean; Wilkinson, Guy; Wilkinson, Michael; Williams, Mark Richard James; Williams, Matthew; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Winn, Michael Andreas; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wraight, Kenneth; Wyllie, Kenneth; Xie, Yuehong; Xing, Zhou; Xu, Zhirui; Yang, Zhenwei; Yang, Zishuo; Yao, Yuezhe; Yin, Hang; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zarebski, Kristian Alexander; Zavertyaev, Mikhail; Zhang, Liming; Zhang, Yanxi; Zhelezov, Alexey; Zheng, Yangheng; Zhu, Xianglei; Zhukov, Valery; Zucchelli, Stefano

2017-06-21

A search for the rare decays $B_s^0\\to\\tau^+\\tau^-$ and $B^0\\to\\tau^+\\tau^-$ is performed using proton$-$proton collision data collected with the LHCb detector. The data sample corresponds to an integrated luminosity of 3fb$^{-1}$ collected in 2011 and 2012. The $\\tau$ leptons are reconstructed through the decay $\\tau^-\\to\\pi^-\\pi^+\\pi^-\

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

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Chen Xi

2011-11-01

Full Text Available Abstract Background Huntington's disease (HD is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs. Our group has previously demonstrated that calcium (Ca2+ signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128. Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2 and spinocerebellar ataxia 3 (SCA3 mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. Results The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Conclusions Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that Ryan

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model.

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Chen, Xi; Wu, Jun; Lvovskaya, Svetlana; Herndon, Emily; Supnet, Charlene; Bezprozvanny, Ilya

2011-11-25

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model. The application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates. Our results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca2+ signaling stabilizers such as

No Overt Deficits in Aged Tau-Deficient C57Bl/6.Mapttm1(EGFPKit GFP Knockin Mice.

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Annika van Hummel

Full Text Available Several mouse lines with knockout of the tau-encoding MAPT gene have been reported in the past; they received recent attention due to reports that tau reduction prevented Aβ-induced deficits in mouse models of Alzheimer's disease. However, the effects of long-term depletion of tau in vivo remained controversial. Here, we used the tau-deficient GFP knockin line Mapttm1(EGFPkit on a pure C57Bl/6 background and subjected a large cohort of males and females to a range of motor, memory and behavior tests and imaging analysis, at the advanced age of over 16 months. Neither heterozygous nor homozygous Mapttm1(EGFPkit mice presented with deficits or abnormalities compared to wild-type littermates. Differences to reports using other tau knockout models may be due to different genetic backgrounds, respective gene targeting strategies or other confounding factors, such as nutrition. To this end, we report no functional or morphological deficits upon tau reduction or depletion in aged mice.

Insulin dysfunction and Tau pathology

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Noura eEl Khoury

2014-02-01

Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

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Siyuan Kong

2018-04-01

Full Text Available Background Type 2 diabetes is characterized by insulin resistance accompanied by defective insulin secretion. Transgenic mouse models play an important role in medical research. However, single transgenic mouse models may not mimic the complex phenotypes of most cases of type 2 diabetes. Methods Focusing on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors, we generated single-transgenic (C/EBP homology protein, CHOP mice (CHOP mice, dual-transgenic (human islet amyloid polypeptide, hIAPP; CHOP mice (hIAPP-CHOP mice and triple-transgenic (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1; hIAPP; CHOP mice (11β-HSD1-hIAPP- CHOP mice. The latter two types of transgenic (Tg animals were induced with high-fat high-sucrose diets (HFHSD. We analyzed the diabetes-related symptoms and histology features of the transgenic animals. Results Comparing symptoms on the spot-checked points, we determined that the triple-transgene mice were more suitable for systematic study. The results of intraperitoneal glucose tolerance tests (IPGTT of triple-transgene animals began to change 60 days after induction (p < 0.001. After 190 days of induction, the body weights (p < 0.01 and plasma glucose of the animals in Tg were higher than those of the animals in Negative Control (Nc. After sacrificed, large amounts of lipid were found deposited in adipose (p < 0.01 and ectopically deposited in the non-adipose tissues (p < 0.05 or 0.01 of the animals in the Tg HFHSD group. The weights of kidneys and hearts of Tg animals were significantly increased (p < 0.01. Serum C peptide (C-P was decreased due to Tg effects, and insulin levels were increased due to the effects of the HFHSD in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone of Tg was slightly higher than those of Nc due to the

Reduction of the immunostainable length of the hippocampal dentate granule cells' primary cilia in 3xAD-transgenic mice producing human A{beta}{sub 1-42} and tau

Energy Technology Data Exchange (ETDEWEB)

Chakravarthy, Balu, E-mail: Balu.Chakravarthy@nrc-cnrc.gc.ca [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); Gaudet, Chantal; Menard, Michel; Brown, Leslie; Atkinson, Trevor [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); LaFerla, Frank M. [Department of Neurobiology and Behavior, University of California, Irvine, CA (United States); Ito, Shingo [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); Armato, Ubaldo; Dal Pra, Ilaria [Department of Life and Reproduction Sciences, University of Verona Medical School, Verona (Italy); Whitfield, James [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada)

2012-10-12

Highlights: Black-Right-Pointing-Pointer A{beta} and tau-induced neurofibrillary tangles play a key role in Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}{sub 1-42} and mutant tau protein together reduce the primary cilium length. Black-Right-Pointing-Pointer This shortening likely reduces cilium-dependent neurogenesis and memory function. Black-Right-Pointing-Pointer This provides a model of an A{beta}/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75{sup NTR}). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6-24-months-old triple transgenic Alzheimer's disease model mice (3xTg-AD) producing both A{beta}{sub 1-42} and the mutant human tau protein tau{sub P301L,} the dentate granule cells still had immunostainable SSTR3- and p75{sup NTR}-bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of A{beta}{sub 1-42} or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of A{beta}{sub 1-42} and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease.

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Nunes, Marielza Andrade; Schöwe, Natalia Mendes; Monteiro-Silva, Karla Cristina; Baraldi-Tornisielo, Ticiana; Souza, Suzzanna Ingryd Gonçalves; Balthazar, Janaina; Albuquerque, Marilia Silva; Caetano, Ariadiny Lima; Viel, Tania Araujo; Buck, Hudson Sousa

2015-01-01

The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.

Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease.

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Marielza Andrade Nunes

Full Text Available The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd20Lms/2J and their non-transgenic litter mate genetic controls were treated with lithium carbonate (0.25mg/Kg/day in drinking water for 16 or 8 months starting at two and ten months of age, respectively [corrected]. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.

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

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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.

Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse

DEFF Research Database (Denmark)

Shen, P; Canoll, P D; Sap, J

1999-01-01

that goal, we have used this mouse model to map the distribution of the truncated RPTP-kappa/beta-geo fusion protein in the adult mouse brain using beta-galactosidase as a marker enzyme. Visualization of the beta-galactosidase activity revealed a non-random pattern of expression, and identified cells......-6596]. Nevertheless, since the transgene's expression is driven by the endogenous RPTP-kappa promoter, distribution of the truncated RPTP-kappa/beta-geo fusion protein should reflect the regional and cellular expression of wild-type RPTP-kappa, and thus may identify sites where RPTP-kappa is important. Towards...

A Naturally Fluorescent Mgp Transgenic Mouse for Angiogenesis and Glaucoma Longitudinal Studies.

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Asokan, Priyadarsini; Mitra, Rajendra N; Periasamy, Ramesh; Han, Zongchao; Borrás, Teresa

2018-02-01

Our goal was to generate and characterize a new mouse model in which only angiogenesis- and glaucoma-relevant tissues would be naturally fluorescent. The Matrix Gla (MGP) gene is highly expressed in vascular smooth muscle cells (VSMC) and trabecular meshwork (TM). We sought to direct our Mgp-Cre.KI mouse recombinase to VSMC/TM cells to produce their longitudinal fluorescent profiles. Homozygous Mgp-Cre.KI mice were crossed with Ai9 homozygous reporter mice harboring a loxP-flanked STOP cassette preventing transcription of a DsRed fluorescent protein (tdTomato). The F1 double-heterozygous (Mgp-tdTomato) was examined by direct fluorescence, whole mount, histology, and fundus photography. Custom-made filters had 554/23 emission and 609/54 exciter nanometer wavelengths. Proof of concept of the model's usefulness was conducted by inducing guided imaging laser burns. Evaluation of a vessel's leakage and proliferation was followed by noninvasive angiography. The Mgp-tdTomato mouse was viable, fertile, with normal IOP and ERG. Its phenotype exhibited red paws and snout (cartilage expression), which precluded genotyping. A fluorescent red ring was seen at the limbus and confirmed to be TM expression by histology. The entire retinal vasculature was red fluorescent (VSMC) and directly visualized by fundus photography. Laser burns on the Mgp-tdTomato allowed separation of leakiness and neovascularization evaluation parameters. The availability of a transgenic mouse naturally fluorescent in glaucoma-relevant tissues and retinal vasculature brings the unique opportunity to study a wide spectrum of single and combined glaucomatous conditions in vivo. Moreover, the Mgp-tdTomato mouse provides a new tool to study mechanisms and therapeutics of retinal angiogenesis longitudinally.

A Naturally Fluorescent Mgp Transgenic Mouse for Angiogenesis and Glaucoma Longitudinal Studies

Science.gov (United States)

Asokan, Priyadarsini; Mitra, Rajendra N.; Periasamy, Ramesh; Han, Zongchao

2018-01-01

Purpose Our goal was to generate and characterize a new mouse model in which only angiogenesis- and glaucoma-relevant tissues would be naturally fluorescent. The Matrix Gla (MGP) gene is highly expressed in vascular smooth muscle cells (VSMC) and trabecular meshwork (TM). We sought to direct our Mgp-Cre.KI mouse recombinase to VSMC/TM cells to produce their longitudinal fluorescent profiles. Methods Homozygous Mgp-Cre.KI mice were crossed with Ai9 homozygous reporter mice harboring a loxP-flanked STOP cassette preventing transcription of a DsRed fluorescent protein (tdTomato). The F1 double-heterozygous (Mgp-tdTomato) was examined by direct fluorescence, whole mount, histology, and fundus photography. Custom-made filters had 554/23 emission and 609/54 exciter nanometer wavelengths. Proof of concept of the model's usefulness was conducted by inducing guided imaging laser burns. Evaluation of a vessel's leakage and proliferation was followed by noninvasive angiography. Results The Mgp-tdTomato mouse was viable, fertile, with normal IOP and ERG. Its phenotype exhibited red paws and snout (cartilage expression), which precluded genotyping. A fluorescent red ring was seen at the limbus and confirmed to be TM expression by histology. The entire retinal vasculature was red fluorescent (VSMC) and directly visualized by fundus photography. Laser burns on the Mgp-tdTomato allowed separation of leakiness and neovascularization evaluation parameters. Conclusions The availability of a transgenic mouse naturally fluorescent in glaucoma-relevant tissues and retinal vasculature brings the unique opportunity to study a wide spectrum of single and combined glaucomatous conditions in vivo. Moreover, the Mgp-tdTomato mouse provides a new tool to study mechanisms and therapeutics of retinal angiogenesis longitudinally. PMID:29392320

Heterogeneous transgene expression in the retinas of the TH-RFP, TH-Cre, TH-BAC-Cre and DAT-Cre mouse lines.

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Vuong, H E; Pérez de Sevilla Müller, L; Hardi, C N; McMahon, D G; Brecha, N C

2015-10-29

Transgenic mouse lines are essential tools for understanding the connectivity, physiology and function of neuronal circuits, including those in the retina. This report compares transgene expression in the retina of a tyrosine hydroxylase (TH)-red fluorescent protein (RFP) mouse line with three catecholamine-related Cre recombinase mouse lines [TH-bacterial artificial chromosome (BAC)-, TH-, and dopamine transporter (DAT)-Cre] that were crossed with a ROSA26-tdTomato reporter line. Retinas were evaluated and immunostained with commonly used antibodies including those directed to TH, GABA and glycine to characterize the RFP or tdTomato fluorescent-labeled amacrine cells, and an antibody directed to RNA-binding protein with multiple splicing to identify ganglion cells. In TH-RFP retinas, types 1 and 2 dopamine (DA) amacrine cells were identified by their characteristic cellular morphology and type 1 DA cells by their expression of TH immunoreactivity. In the TH-BAC-, TH-, and DAT-tdTomato retinas, less than 1%, ∼ 6%, and 0%, respectively, of the fluorescent cells were the expected type 1 DA amacrine cells. Instead, in the TH-BAC-tdTomato retinas, fluorescently labeled AII amacrine cells were predominant, with some medium diameter ganglion cells. In TH-tdTomato retinas, fluorescence was in multiple neurochemical amacrine cell types, including four types of polyaxonal amacrine cells. In DAT-tdTomato retinas, fluorescence was in GABA immunoreactive amacrine cells, including two types of bistratified and two types of monostratified amacrine cells. Although each of the Cre lines was generated with the intent to specifically label DA cells, our findings show a cellular diversity in Cre expression in the adult retina and indicate the importance of careful characterization of transgene labeling patterns. These mouse lines with their distinctive cellular labeling patterns will be useful tools for future studies of retinal function and visual processing. Published by Elsevier

The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities

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Maekawa Tatsunori

2012-04-01

Full Text Available Abstract Background Leucine-rich repeat kinase 2 (LRRK2 is the gene responsible for autosomal-dominant Parkinson’s disease (PD, PARK8, but the mechanism by which LRRK2 mutations cause neuronal dysfunction remains unknown. In the present study, we investigated for the first time a transgenic (TG mouse strain expressing human LRRK2 with an I2020T mutation in the kinase domain, which had been detected in the patients of the original PARK8 family. Results The TG mouse expressed I2020T LRRK2 in dopaminergic (DA neurons of the substantia nigra, ventral tegmental area, and olfactory bulb. In both the beam test and rotarod test, the TG mice exhibited impaired locomotive ability in comparison with their non-transgenic (NTG littermates. Although there was no obvious loss of DA neurons in either the substantia nigra or striatum, the TG brain showed several neurological abnormalities such as a reduced striatal dopamine content, fragmentation of the Golgi apparatus in DA neurons, and an increased degree of microtubule polymerization. Furthermore, the tyrosine hydroxylase-positive primary neurons derived from the TG mouse showed an increased frequency of apoptosis and had neurites with fewer branches and decreased outgrowth in comparison with those derived from the NTG controls. Conclusions The I2020T LRRK2 TG mouse exhibited impaired locomotive ability accompanied by several dopaminergic neuron abnormalities. The TG mouse should provide valuable clues to the etiology of PD caused by the LRRK2 mutation.

Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20-APP transgenic and wild-type mice.

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Tapia-Rojas, Cheril; Inestrosa, Nibaldo C

2018-02-01

Alzheimer's disease (AD) is a neurodegenerative pathology characterized by aggregates of amyloid-β (Aβ) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD, mainly as a neuroprotective factor against Aβ toxicity and tau phosphorylation. However, dysfunction of Wnt/β-catenin signaling might also play a role in the onset and development of the disease. J20 APPswInd transgenic (Tg) mouse model of AD was treated i.p. with various Wnt signaling inhibitors for 10 weeks during pre-symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and Aβ 1-42 peptide levels, decreased Aβ42/Aβ40 ratio and Aβ 1-42 concentration in the cerebral spinal fluid, and high levels of soluble Aβ species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild-type (WT) mice, including behavioral impairment, tau phosphorylation, increased Aβ 1-42 in the hippocampus, decreased Aβ 1-42 in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg AD mouse model and contributed to the development of Alzheimer's-like changes in WT mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of AD. Read the Editorial Highlight for this article on page 356. © 2017 International Society for Neurochemistry.

PET imaging of brain with the β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease

International Nuclear Information System (INIS)

Toyama, Hiroshi; Ye, Daniel; Cohen, Robert M.; Ichise, Masanori; Liow, Jeih-San; Cai, Lisheng; Musachio, John L.; Hong, Jinsoo; Crescenzo, Mathew; Tipre, Dnyanesh; Lu, Jian-Qiang; Zoghbi, Sami; Vines, Douglass C.; Pike, Victor W.; Innis, Robert B.; Jacobowitz, David; Seidel, Jurgen; Green, Michael V.; Katada, Kazuhiro

2005-01-01

The purpose of this study was to evaluate the capacity of [ 11 C]6-OH-BTA-1 and positron emission tomography (PET) to quantify β-amyloid (Aβ) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0±1.8 months; 23.6±2.6 g) overexpressing a mutated form of human β-amyloid precursor protein (APP) known to result in the production of Aβ plaques, and in six elderly wild-type litter mates (age 21.8±1.6 months; 29.5±4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [ 11 C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. TACs for [ 11 C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06±0.04 vs 0.98±0.07, p=0.04; 1.06±0.09 vs 0.93±0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Aβ plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. Marked reductions in brain uptake of this

An Efficient Method for Generation of Transgenic Rats Avoiding Embryo Manipulation

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Bhola Shankar Pradhan

2016-01-01

Full Text Available Although rats are preferred over mice as an animal model, transgenic animals are generated predominantly using mouse embryos. There are limitations in the generation of transgenic rat by embryo manipulation. Unlike mouse embryos, most of the rat embryos do not survive after male pronuclear DNA injection which reduces the efficiency of generation of transgenic rat by this method. More importantly, this method requires hundreds of eggs collected by killing several females for insertion of transgene to generate transgenic rat. To this end, we developed a noninvasive and deathless technique for generation of transgenic rats by integrating transgene into the genome of the spermatogonial cells by testicular injection of DNA followed by electroporation. After standardization of this technique using EGFP as a transgene, a transgenic disease model displaying alpha thalassemia was successfully generated using rats. This efficient method will ease the generation of transgenic rats without killing the lives of rats while simultaneously reducing the number of rats used for generation of transgenic animal.

7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

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Yang Tan

2016-11-01

Full Text Available 7,8-Dihydroxyflavone (7,8-DHF, a tyrosine kinase B (TrkB agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. 5-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5mg/kg or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterwards, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP as well as AEP-derived truncated tauN368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt/glycogen synthase kinase-3β (GSK-3β pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope. These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tauN368.

Selective loss of mouse embryos due to the expression of transgenic major histocompatibility class I molecules early in embryogenesis.

Science.gov (United States)

Aït-Azzouzene, D; Langkopf, A; Cohen, J; Bleux, C; Gendron, M C; Kanellopoulos-Langevin, C

1998-05-01

Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regulation of expression of the polymorphic major histocompatibility complex (MHC) at the fetal-maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation, the absence of polymorphic MHC molecules on the early embryo, as well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class la gene H-2Kb under the control of a housekeeping gene promoter, the hydroxy-methyl-glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H-2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one-cell stage with the pHMG-Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal-maternal interface and in various transgenic mouse models.

BAG3 facilitates the clearance of endogenous tau in primary neurons.

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Lei, Zhinian; Brizzee, Corey; Johnson, Gail V W

2015-01-01

Tau is a microtubule associated protein that is found primarily in neurons, and in pathologic conditions, such as Alzheimer's disease (AD) it accumulates and contributes to the disease process. Because tau plays a fundamental role in the pathogenesis of AD and other tauopathies, and in AD mouse models reducing tau levels improves outcomes, approaches that facilitate tau clearance are being considered as therapeutic strategies. However, fundamental to the development of such interventions is a clearer understanding of the mechanisms that regulate tau clearance. Here, we report a novel mechanism of tau degradation mediated by the co-chaperone BAG3. BAG3 has been shown to be an essential component of a complex that targets substrates to the autophagy pathway for degradation. In rat primary neurons, activation of autophagy by inhibition of proteasome activity or treatment with trehalose resulted in significant decreases in tau and phospho-tau levels. These treatments also induced an upregulation of BAG3. Proteasome inhibition activated JNK, which was responsible for the upregulation of BAG3 and increased tau clearance. Inhibiting JNK or knocking down BAG3 blocked the proteasome inhibition-induced decreases in tau. Further, BAG3 overexpression alone resulted in significant decreases in tau and phospho-tau levels in neurons. These results indicate that BAG3 plays a critical role in regulating the levels of tau in neurons, and interventions that increase BAG3 levels could provide a therapeutic approach in the treatment of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice.

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Cheng, David; Low, Jac Kee; Logge, Warren; Garner, Brett; Karl, Tim

2014-08-01

Patients suffering from Alzheimer's disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces. Hallmark pathological changes in AD include the aggregation of amyloid-β (Aβ), tau protein hyperphosphorylation as well as pronounced neurodegeneration, neuroinflammation, neurotoxicity and oxidative damage. The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents. Thus we determined the therapeutic-like effects of chronic CBD treatment (20 mg/kg, daily intraperitoneal injections for 3 weeks) on the APPswe/PS1∆E9 (APPxPS1) transgenic mouse model for AD in a number of cognitive tests, including the social preference test, the novel object recognition task and the fear conditioning paradigm. We also analysed the impact of CBD on anxiety behaviours in the elevated plus maze. Vehicle-treated APPxPS1 mice demonstrated impairments in social recognition and novel object recognition compared to wild type-like mice. Chronic CBD treatment reversed these cognitive deficits in APPxPS1 mice without affecting anxiety-related behaviours. This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model. Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.

Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS).

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Mead, Richard J; Bennett, Ellen J; Kennerley, Aneurin J; Sharp, Paul; Sunyach, Claire; Kasher, Paul; Berwick, Jason; Pettmann, Brigitte; Battaglia, Guiseppe; Azzouz, Mimoun; Grierson, Andrew; Shaw, Pamela J

2011-01-01

The human SOD1(G93A) transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS). In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months) is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6) SOD1(G93A) transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

ZyFISH: a simple, rapid and reliable zygosity assay for transgenic mice.

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Donal McHugh

Full Text Available Microinjection of DNA constructs into fertilized mouse oocytes typically results in random transgene integration at a single genomic locus. The resulting transgenic founders can be used to establish hemizygous transgenic mouse lines. However, practical and experimental reasons often require that such lines be bred to homozygosity. Transgene zygosity can be determined by progeny testing assays which are expensive and time-consuming, by quantitative Southern blotting which is labor-intensive, or by quantitative PCR (qPCR which requires transgene-specific design. Here, we describe a zygosity assessment procedure based on fluorescent in situ hybridization (zyFISH. The zyFISH protocol entails the detection of transgenic loci by FISH and the concomitant assignment of homozygosity using a concise and unbiased scoring system. The method requires small volumes of blood, is scalable to at least 40 determinations per assay, and produces results entirely consistent with the progeny testing assay. This combination of reliability, simplicity and cost-effectiveness makes zyFISH a method of choice for transgenic mouse zygosity determinations.

Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.

Science.gov (United States)

Pan, Xiaoli; Gong, Neng; Zhao, Jing; Yu, Zhe; Gu, Fenghua; Chen, Jia; Sun, Xiaojing; Zhao, Lei; Yu, Meijing; Xu, Zhiru; Dong, Wenxin; Qin, Yan; Fei, Guoqiang; Zhong, Chunjiu; Xu, Tian-Le

2010-05-01

Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.

A Novel mouse model of enhanced proteostasis: Full-length human heat shock factor 1 transgenic mice

International Nuclear Information System (INIS)

Pierce, Anson; Wei, Rochelle; Halade, Dipti; Yoo, Si-Eun; Ran, Qitao; Richardson, Arlan

2010-01-01

Research highlights: → Development of mouse overexpressing native human HSF1 in all tissues including CNS. → HSF1 overexpression enhances heat shock response at whole-animal and cellular level. → HSF1 overexpression protects from polyglutamine toxicity and favors aggresomes. → HSF1 overexpression enhances proteostasis at the whole-animal and cellular level. -- Abstract: The heat shock response (HSR) is controlled by the master transcriptional regulator heat shock factor 1 (HSF1). HSF1 maintains proteostasis and resistance to stress through production of heat shock proteins (HSPs). No transgenic model exists that overexpresses HSF1 in tissues of the central nervous system (CNS). We generated a transgenic mouse overexpressing full-length non-mutant HSF1 and observed a 2-4-fold increase in HSF1 mRNA and protein expression in all tissues studied of HSF1 transgenic (HSF1 +/0 ) mice compared to wild type (WT) littermates, including several regions of the CNS. Basal expression of HSP70 and 90 showed only mild tissue-specific changes; however, in response to forced exercise, the skeletal muscle HSR was more elevated in HSF1 +/0 mice compared to WT littermates and in fibroblasts following heat shock, as indicated by levels of inducible HSP70 mRNA and protein. HSF1 +/0 cells elicited a significantly more robust HSR in response to expression of the 82 repeat polyglutamine-YFP fusion construct (Q82YFP) and maintained proteasome-dependent processing of Q82YFP compared to WT fibroblasts. Overexpression of HSF1 was associated with fewer, but larger Q82YFP aggregates resembling aggresomes in HSF1 +/0 cells, and increased viability. Therefore, our data demonstrate that tissues and cells from mice overexpressing full-length non-mutant HSF1 exhibit enhanced proteostasis.

Androgen receptor levels during progression of prostate cancer in the transgenic adenocarcinoma of mouse prostate model

Directory of Open Access Journals (Sweden)

Krisna Murti

2010-02-01

Full Text Available Aim To construct tissue microarrays (TMAs that consisted of prostate tumours from the transgenic adenocarcinoma of mouse prostate (TRAMP mice and non-transgenic murine prostates and to assess androgen receptor (AR levels during progression of prostate cancer in TRAMP mice by immunohistochemistry.Methods Haematoxylin and eosin (H&E sections from the ventral and dorso-lateral prostate lobes of non-transgenic, intact TRAMP and castrated TRAMP were used to demarcate regions of interest for TMAs construction. The samples on TMAs were used to evaluate AR expression using video image analysis (VIA.Results AR was expressed during cancer progression, but AR levels were reduced or absent in late stage disease. Furthermore, when AR levels were compared in tumours from intact and castrate animals, a significant increase in AR levels was observed following androgen ablation.Conclusion Similar to clinical prostate cancer, in the TRAMP model, prostate tumours evolve mechanisms to maintain AR expression and AR responsive gene pathways following castration to facilitate continued tumour growth. (Med J Indones 2010; 19:5-13Keywords : androgen ablation therapy, tissue microarrays, haematoxylin and eosin, video image analysis

Expression of a truncated receptor protein tyrosine phosphatase kappa in the brain of an adult transgenic mouse

DEFF Research Database (Denmark)

Shen, P; Canoll, P D; Sap, J

1999-01-01

processes such as axonal growth and target recognition, as has been demonstrated for certain Drosophila RPTPs. The brain distribution of RPTP-kappa-expressing cells has not been determined, however. In a gene-trap mouse model with a beta-gal+neo (beta-geo) insertion in the endogenous RPTP-kappa gene......-6596]. Nevertheless, since the transgene's expression is driven by the endogenous RPTP-kappa promoter, distribution of the truncated RPTP-kappa/beta-geo fusion protein should reflect the regional and cellular expression of wild-type RPTP-kappa, and thus may identify sites where RPTP-kappa is important. Towards...... that goal, we have used this mouse model to map the distribution of the truncated RPTP-kappa/beta-geo fusion protein in the adult mouse brain using beta-galactosidase as a marker enzyme. Visualization of the beta-galactosidase activity revealed a non-random pattern of expression, and identified cells...

Increased CDK5 expression in HIV encephalitis contributes to neurodegeneration via tau phosphorylation and is reversed with Roscovitine.

Science.gov (United States)

Patrick, Christina; Crews, Leslie; Desplats, Paula; Dumaop, Wilmar; Rockenstein, Edward; Achim, Cristian L; Everall, Ian P; Masliah, Eliezer

2011-04-01

Recent treatments with highly active antiretroviral therapy (HAART) regimens have been shown to improve general clinical status in patients with human immunodeficiency virus (HIV) infection; however, the prevalence of cognitive alterations and neurodegeneration has remained the same or has increased. These deficits are more pronounced in the subset of HIV patients with the inflammatory condition known as HIV encephalitis (HIVE). Activation of signaling pathways such as GSK3β and CDK5 has been implicated in the mechanisms of HIV neurotoxicity; however, the downstream mediators of these effects are unclear. The present study investigated the involvement of CDK5 and tau phosphorylation in the mechanisms of neurodegeneration in HIVE. In the frontal cortex of patients with HIVE, increased levels of CDK5 and p35 expression were associated with abnormal tau phosphorylation. Similarly, transgenic mice engineered to express the HIV protein gp120 exhibited increased brain levels of CDK5 and p35, alterations in tau phosphorylation, and dendritic degeneration. In contrast, genetic knockdown of CDK5 or treatment with the CDK5 inhibitor roscovitine improved behavioral performance in the water maze test and reduced neurodegeneration, abnormal tau phosphorylation, and astrogliosis in gp120 transgenic mice. These findings indicate that abnormal CDK5 activation contributes to the neurodegenerative process in HIVE via abnormal tau phosphorylation; thus, reducing CDK5 might ameliorate the cognitive impairments associated with HIVE. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Systemic and oral immunogenicity of hemagglutinin protein of rinderpest virus expressed by transgenic peanut plants in a mouse model

International Nuclear Information System (INIS)

Khandelwal, Abha; Renukaradhya, G.J.; Rajasekhar, M.; Sita, G. Lakshmi; Shaila, M.S.

2004-01-01

Rinderpest causes a devastating disease, often fatal, in wild and domestic ruminants. It has been eradicated successfully using a live, attenuated vaccine from most part of the world leaving a few foci of disease in parts of Africa, the Middle East, and South Asia. We have developed transgenic peanut (Arachis hypogaea L.) plants expressing hemagglutinin (H) protein of rinderpest virus (RPV), which is antigenically authentic. In this work, we have evaluated the immunogenicity of peanut-expressed H protein using mouse model, administered parenterally as well as orally. Intraperitoneal immunization of mice with the transgenic peanut extract elicited antibody response specific to H. These antibodies neutralized virus infectivity in vitro. Oral immunization of mice with transgenic peanut induced H-specific serum IgG and IgA antibodies. The systemic and oral immunogenicity of plant-derived H in absence of any adjuvant indicates the potential of edible vaccine for rinderpest

Neonatal Death and Heart Failure in Mouse with Transgenic HSP60 Expression

Directory of Open Access Journals (Sweden)

Tsung-Hsien Chen

2015-01-01

Full Text Available Mitochondrial heat shock proteins, such as HSP60, are chaperones responsible for the folding, transport, and quality control of mitochondrial matrix proteins and are essential for maintaining life. Both prosurvival and proapoptotic roles have been proposed for HSP60, and HSP60 is reportedly involved in the initiation of autoimmune, metabolic, and cardiovascular diseases. The role of HSP60 in pathogenesis of these diseases remains unclear, partly because of the lack of mouse models expressing HSP60. In this study we generated HSP60 conditional transgenic mice suitable for investigating in vivo outcomes by expressing HSP60 at the targeted organ in disease models. Ubiquitous HSP60 induction in the embryonic stage caused neonatal death in mice at postnatal day 1. A high incidence of atrial septal defects was observed in HSP60-expressing mice, with increased apoptosis and myocyte degeneration that possibly contributed to massive hemorrhage and sponge-like cardiac muscles. Our results showed that neonatal heart failure through HSP60 induction likely involves developmental defects and excessive apoptosis. The conditional HSP60 mouse model is useful for studying crucial biological questions concerning HSP60.

Modelling $Z\\to\\tau\\tau$ processes in ATLAS with $\\tau$-embedded $Z\\to\\mu\\mu$ data

CERN Document Server

Aad, Georges; Abdallah, Jalal; Abdinov, Ovsat; Aben, Rosemarie; Abolins, Maris; AbouZeid, Ossama; Abramowicz, Halina; Abreu, Henso; Abreu, Ricardo; Abulaiti, Yiming; Acharya, Bobby Samir; Adamczyk, Leszek; Adams, David; Adelman, Jahred; Adomeit, Stefanie; Adye, Tim; Affolder, Tony; Agatonovic-Jovin, Tatjana; Agricola, Johannes; Aguilar-Saavedra, Juan Antonio; Ahlen, Steven; Ahmadov, Faig; Aielli, Giulio; Akerstedt, Henrik; Åkesson, Torsten Paul Ake; Akimov, Andrei; Alberghi, Gian Luigi; Albert, Justin; Albrand, Solveig; Alconada Verzini, Maria Josefina; Aleksa, Martin; Aleksandrov, Igor; Alexa, Calin; Alexander, Gideon; Alexopoulos, Theodoros; Alhroob, Muhammad; Alimonti, Gianluca; Alio, Lion; Alison, John; Alkire, Steven Patrick; Allbrooke, Benedict; Allport, Phillip; Aloisio, Alberto; Alonso, Alejandro; Alonso, Francisco; Alpigiani, Cristiano; Altheimer, Andrew David; Alvarez Gonzalez, Barbara; Άlvarez Piqueras, Damián; Alviggi, Mariagrazia; Amadio, Brian Thomas; Amako, Katsuya; Amaral Coutinho, Yara; Amelung, Christoph; Amidei, Dante; Amor Dos Santos, Susana Patricia; Amorim, Antonio; Amoroso, Simone; Amram, Nir; Amundsen, Glenn; Anastopoulos, Christos; Ancu, Lucian Stefan; Andari, Nansi; Andeen, Timothy; Anders, Christoph Falk; Anders, Gabriel; Anders, John Kenneth; Anderson, Kelby; Andreazza, Attilio; Andrei, George Victor; Angelidakis, Stylianos; Angelozzi, Ivan; Anger, Philipp; Angerami, Aaron; Anghinolfi, Francis; Anisenkov, Alexey; Anjos, Nuno; Annovi, Alberto; Antonelli, Mario; Antonov, Alexey; Antos, Jaroslav; Anulli, Fabio; Aoki, Masato; Aperio Bella, Ludovica; Arabidze, Giorgi; Arai, Yasuo; Araque, Juan Pedro; Arce, Ayana; Arduh, Francisco Anuar; Arguin, Jean-Francois; Argyropoulos, Spyridon; Arik, Metin; Armbruster, Aaron James; Arnaez, Olivier; Arnal, Vanessa; Arnold, Hannah; Arratia, Miguel; Arslan, Ozan; Artamonov, Andrei; Artoni, Giacomo; Asai, Shoji; Asbah, Nedaa; Ashkenazi, Adi; Åsman, Barbro; Asquith, Lily; Assamagan, Ketevi; Astalos, Robert; Atkinson, Markus; Atlay, Naim Bora; Auerbach, Benjamin; Augsten, Kamil; Aurousseau, Mathieu; Avolio, Giuseppe; Axen, Bradley; Ayoub, Mohamad Kassem; Azuelos, Georges; Baak, Max; Baas, Alessandra; Baca, Matthew John; Bacci, Cesare; Bachacou, Henri; Bachas, Konstantinos; Backes, Moritz; Backhaus, Malte; Bagiacchi, Paolo; Bagnaia, Paolo; Bai, Yu; Bain, Travis; Baines, John; Baker, Oliver Keith; Baldin, Evgenii; Balek, Petr; Balestri, Thomas; Balli, Fabrice; Banas, Elzbieta; Banerjee, Swagato; Bannoura, Arwa A E; Bansil, Hardeep Singh; Barak, Liron; Barberio, Elisabetta Luigia; Barberis, Dario; Barbero, Marlon; Barillari, Teresa; Barisonzi, Marcello; Barklow, Timothy; Barlow, Nick; Barnes, Sarah Louise; Barnett, Bruce; Barnett, Michael; Barnovska, Zuzana; Baroncelli, Antonio; Barone, Gaetano; Barr, Alan; Barreiro, Fernando; Barreiro Guimarães da Costa, João; Bartoldus, Rainer; Barton, Adam Edward; Bartos, Pavol; Basalaev, Artem; Bassalat, Ahmed; Basye, Austin; Bates, Richard; Batista, Santiago Juan; Batley, Richard; Battaglia, Marco; Bauce, Matteo; Bauer, Florian; Bawa, Harinder Singh; Beacham, James Baker; Beattie, Michael David; Beau, Tristan; Beauchemin, Pierre-Hugues; Beccherle, Roberto; Bechtle, Philip; Beck, Hans Peter; Becker, Anne Kathrin; Becker, Maurice; Becker, Sebastian; Beckingham, Matthew; Becot, Cyril; Beddall, Andrew; Beddall, Ayda; Bednyakov, Vadim; Bee, Christopher; Beemster, Lars; Beermann, Thomas; Begel, Michael; Behr, Janna Katharina; Belanger-Champagne, Camille; Bell, William; Bella, Gideon; Bellagamba, Lorenzo; Bellerive, Alain; Bellomo, Massimiliano; Belotskiy, Konstantin; Beltramello, Olga; Benary, Odette; Benchekroun, Driss; Bender, Michael; Bendtz, Katarina; Benekos, Nektarios; Benhammou, Yan; Benhar Noccioli, Eleonora; Benitez Garcia, Jorge-Armando; Benjamin, Douglas; Bensinger, James; Bentvelsen, Stan; Beresford, Lydia; Beretta, Matteo; Berge, David; Bergeaas Kuutmann, Elin; Berger, Nicolas; Berghaus, Frank; Beringer, Jürg; Bernard, Clare; Bernard, Nathan Rogers; Bernius, Catrin; Bernlochner, Florian Urs; Berry, Tracey; Berta, Peter; Bertella, Claudia; Bertoli, Gabriele; Bertolucci, Federico; Bertsche, Carolyn; Bertsche, David; Besana, Maria Ilaria; Besjes, Geert-Jan; Bessidskaia Bylund, Olga; Bessner, Martin Florian; Besson, Nathalie; Betancourt, Christopher; Bethke, Siegfried; Bevan, Adrian John; Bhimji, Wahid; Bianchi, Riccardo-Maria; Bianchini, Louis; Bianco, Michele; Biebel, Otmar; Biedermann, Dustin; Bieniek, Stephen Paul; Biglietti, Michela; Bilbao De Mendizabal, Javier; Bilokon, Halina; Bindi, Marcello; Binet, Sebastien; Bingul, Ahmet; Bini, Cesare; Biondi, Silvia; Black, Curtis; Black, James; Black, Kevin; Blackburn, Daniel; Blair, Robert; Blanchard, Jean-Baptiste; Blanco, Jacobo Ezequiel; Blazek, Tomas; Bloch, Ingo; Blocker, Craig; Blum, Walter; Blumenschein, Ulrike; Bobbink, Gerjan; Bobrovnikov, Victor; Bocchetta, Simona Serena; Bocci, Andrea; Bock, Christopher; Boehler, Michael; Bogaerts, Joannes Andreas; Bogavac, Danijela; Bogdanchikov, Alexander; Bohm, Christian; Boisvert, Veronique; Bold, Tomasz; Boldea, Venera; Boldyrev, Alexey; Bomben, Marco; Bona, Marcella; Boonekamp, Maarten; Borisov, Anatoly; Borissov, Guennadi; Borroni, Sara; Bortfeldt, Jonathan; Bortolotto, Valerio; Bos, Kors; Boscherini, Davide; Bosman, Martine; Boudreau, Joseph; Bouffard, Julian; Bouhova-Thacker, Evelina Vassileva; Boumediene, Djamel Eddine; Bourdarios, Claire; Bousson, Nicolas; Boveia, Antonio; Boyd, James; Boyko, Igor; Bozic, Ivan; Bracinik, Juraj; Brandt, Andrew; Brandt, Gerhard; Brandt, Oleg; Bratzler, Uwe; Brau, Benjamin; Brau, James; Braun, Helmut; Brazzale, Simone Federico; Breaden Madden, William Dmitri; Brendlinger, Kurt; Brennan, Amelia Jean; Brenner, Lydia; Brenner, Richard; Bressler, Shikma; Bristow, Kieran; Bristow, Timothy Michael; Britton, Dave; Britzger, Daniel; Brochu, Frederic; Brock, Ian; Brock, Raymond; Bronner, Johanna; Brooijmans, Gustaaf; Brooks, Timothy; Brooks, William; Brosamer, Jacquelyn; Brost, Elizabeth; Brown, Jonathan; Bruckman de Renstrom, Pawel; Bruncko, Dusan; Bruneliere, Renaud; Bruni, Alessia; Bruni, Graziano; Bruschi, Marco; Bruscino, Nello; Bryngemark, Lene; Buanes, Trygve; Buat, Quentin; Buchholz, Peter; Buckley, Andrew; Buda, Stelian Ioan; Budagov, Ioulian; Buehrer, Felix; Bugge, Lars; Bugge, Magnar Kopangen; Bulekov, Oleg; Bullock, Daniel; Burckhart, Helfried; Burdin, Sergey; Burghgrave, Blake; Burke, Stephen; Burmeister, Ingo; Busato, Emmanuel; Büscher, Daniel; Büscher, Volker; Bussey, Peter; Butler, John; Butt, Aatif Imtiaz; Buttar, Craig; Butterworth, Jonathan; Butti, Pierfrancesco; Buttinger, William; Buzatu, Adrian; Buzykaev, Aleksey; Cabrera Urbán, Susana; Caforio, Davide; Cairo, Valentina; Cakir, Orhan; Calace, Noemi; Calafiura, Paolo; Calandri, Alessandro; Calderini, Giovanni; Calfayan, Philippe; Caloba, Luiz; Calvet, David; Calvet, Samuel; Camacho Toro, Reina; Camarda, Stefano; Camarri, Paolo; Cameron, David; Caminal Armadans, Roger; Campana, Simone; Campanelli, Mario; Campoverde, Angel; Canale, Vincenzo; Canepa, Anadi; Cano Bret, Marc; Cantero, Josu; Cantrill, Robert; Cao, Tingting; Capeans Garrido, Maria Del Mar; Caprini, Irinel; Caprini, Mihai; Capua, Marcella; Caputo, Regina; Cardarelli, Roberto; Cardillo, Fabio; Carli, Tancredi; Carlino, Gianpaolo; Carminati, Leonardo; Caron, Sascha; Carquin, Edson; Carrillo-Montoya, German D; Carter, Janet; Carvalho, João; Casadei, Diego; Casado, Maria Pilar; Casolino, Mirkoantonio; Castaneda-Miranda, Elizabeth; Castelli, Angelantonio; Castillo Gimenez, Victoria; Castro, Nuno Filipe; Catastini, Pierluigi; Catinaccio, Andrea; Catmore, James; Cattai, Ariella; Caudron, Julien; Cavaliere, Viviana; Cavalli, Donatella; Cavalli-Sforza, Matteo; Cavasinni, Vincenzo; Ceradini, Filippo; Cerio, Benjamin; Cerny, Karel; Santiago Cerqueira, Augusto; Cerri, Alessandro; Cerrito, Lucio; Cerutti, Fabio; Cerv, Matevz; Cervelli, Alberto; Cetin, Serkant Ali; Chafaq, Aziz; Chakraborty, Dhiman; Chalupkova, Ina; Chang, Philip; Chapman, John Derek; Charlton, Dave; Chau, Chav Chhiv; Chavez Barajas, Carlos Alberto; Cheatham, Susan; Chegwidden, Andrew; Chekanov, Sergei; Chekulaev, Sergey; Chelkov, Gueorgui; Chelstowska, Magda Anna; Chen, Chunhui; Chen, Hucheng; Chen, Karen; Chen, Liming; Chen, Shenjian; Chen, Xin; Chen, Ye; Cheng, Hok Chuen; Cheng, Yangyang; Cheplakov, Alexander; Cheremushkina, Evgenia; Cherkaoui El Moursli, Rajaa; Chernyatin, Valeriy; Cheu, Elliott; Chevalier, Laurent; Chiarella, Vitaliano; Chiarelli, Giorgio; Childers, John Taylor; Chiodini, Gabriele; Chisholm, Andrew; Chislett, Rebecca Thalatta; Chitan, Adrian; Chizhov, Mihail; Choi, Kyungeon; Chouridou, Sofia; Chow, Bonnie Kar Bo; Christodoulou, Valentinos; Chromek-Burckhart, Doris; Chudoba, Jiri; Chuinard, Annabelle Julia; Chwastowski, Janusz; Chytka, Ladislav; Ciapetti, Guido; Ciftci, Abbas Kenan; Cinca, Diane; Cindro, Vladimir; Cioara, Irina Antonela; Ciocio, Alessandra; Citron, Zvi Hirsh; Ciubancan, Mihai; Clark, Allan G; Clark, Brian Lee; Clark, Philip James; Clarke, Robert; Cleland, Bill; Clement, Christophe; Coadou, Yann; Cobal, Marina; Coccaro, Andrea; Cochran, James H; Coffey, Laurel; Cogan, Joshua Godfrey; Colasurdo, Luca; Cole, Brian; Cole, Stephen; Colijn, Auke-Pieter; Collot, Johann; Colombo, Tommaso; Compostella, Gabriele; Conde Muiño, Patricia; Coniavitis, Elias; Connell, Simon Henry; Connelly, Ian; Consonni, Sofia Maria; Consorti, Valerio; Constantinescu, Serban; Conta, Claudio; Conti, Geraldine; Conventi, Francesco; Cooke, Mark; Cooper, Ben; Cooper-Sarkar, Amanda; Cornelissen, Thijs; Corradi, Massimo; Corriveau, Francois; Corso-Radu, Alina; Cortes-Gonzalez, Arely; Cortiana, Giorgio; Costa, Giuseppe; Costa, María José; Costanzo, Davide; Côté, David; Cottin, Giovanna; Cowan, Glen; Cox, Brian; Cranmer, Kyle; Cree, Graham; Crépé-Renaudin, Sabine; Crescioli, Francesco; Cribbs, Wayne Allen; Crispin Ortuzar, Mireia; Cristinziani, Markus; Croft, Vince; Crosetti, Giovanni; Cuhadar Donszelmann, Tulay; Cummings, Jane; Curatolo, Maria; Cuthbert, Cameron; Czirr, Hendrik; Czodrowski, Patrick; D'Auria, Saverio; D'Onofrio, Monica; Da Cunha Sargedas De Sousa, Mario Jose; Da Via, Cinzia; Dabrowski, Wladyslaw; Dafinca, Alexandru; Dai, Tiesheng; Dale, Orjan; Dallaire, Frederick; Dallapiccola, Carlo; Dam, Mogens; Dandoy, Jeffrey Rogers; Dang, Nguyen Phuong; Daniells, Andrew Christopher; Danninger, Matthias; Dano Hoffmann, Maria; Dao, Valerio; Darbo, Giovanni; Darmora, Smita; Dassoulas, James; Dattagupta, Aparajita; Davey, Will; David, Claire; Davidek, Tomas; Davies, Eleanor; Davies, Merlin; Davison, Peter; Davygora, Yuriy; Dawe, Edmund; Dawson, Ian; Daya-Ishmukhametova, Rozmin; De, Kaushik; de Asmundis, Riccardo; De Benedetti, Abraham; De Castro, Stefano; De Cecco, Sandro; De Groot, Nicolo; de Jong, Paul; De la Torre, Hector; De Lorenzi, Francesco; De Nooij, Lucie; De Pedis, Daniele; De Salvo, Alessandro; De Sanctis, Umberto; De Santo, Antonella; De Vivie De Regie, Jean-Baptiste; Dearnaley, William James; Debbe, Ramiro; Debenedetti, Chiara; Dedovich, Dmitri; Deigaard, Ingrid; Del Peso, Jose; Del Prete, Tarcisio; Delgove, David; Deliot, Frederic; Delitzsch, Chris Malena; Deliyergiyev, Maksym; Dell'Acqua, Andrea; Dell'Asta, Lidia; Dell'Orso, Mauro; Della Pietra, Massimo; della Volpe, Domenico; Delmastro, Marco; Delsart, Pierre-Antoine; Deluca, Carolina; DeMarco, David; Demers, Sarah; Demichev, Mikhail; Demilly, Aurelien; Denisov, Sergey; Derendarz, Dominik; Derkaoui, Jamal Eddine; Derue, Frederic; Dervan, Paul; Desch, Klaus Kurt; Deterre, Cecile; Deviveiros, Pier-Olivier; Dewhurst, Alastair; Dhaliwal, Saminder; Di Ciaccio, Anna; Di Ciaccio, Lucia; Di Domenico, Antonio; Di Donato, Camilla; Di Girolamo, Alessandro; Di Girolamo, Beniamino; Di Mattia, Alessandro; Di Micco, Biagio; Di Nardo, Roberto; Di Simone, Andrea; Di Sipio, Riccardo; Di Valentino, David; Diaconu, Cristinel; Diamond, Miriam; Dias, Flavia; Diaz, Marco Aurelio; Diehl, Edward; Dietrich, Janet; Diglio, Sara; Dimitrievska, Aleksandra; Dingfelder, Jochen; Dita, Petre; Dita, Sanda; Dittus, Fridolin; Djama, Fares; Djobava, Tamar; Djuvsland, Julia Isabell; Barros do Vale, Maria Aline; Dobos, Daniel; Dobre, Monica; Doglioni, Caterina; Dohmae, Takeshi; Dolejsi, Jiri; Dolezal, Zdenek; Dolgoshein, Boris; Donadelli, Marisilvia; Donati, Simone; Dondero, Paolo; Donini, Julien; Dopke, Jens; Doria, Alessandra; Dova, Maria-Teresa; Doyle, Tony; Drechsler, Eric; Dris, Manolis; Dubreuil, Emmanuelle; Duchovni, Ehud; Duckeck, Guenter; Ducu, Otilia Anamaria; Duda, Dominik; Dudarev, Alexey; Duflot, Laurent; Duguid, Liam; Dührssen, Michael; Dunford, Monica; Duran Yildiz, Hatice; Düren, Michael; Durglishvili, Archil; Duschinger, Dirk; Dyndal, Mateusz; Eckardt, Christoph; Ecker, Katharina Maria; Edgar, Ryan Christopher; Edson, William; Edwards, Nicholas Charles; Ehrenfeld, Wolfgang; Eifert, Till; Eigen, Gerald; Einsweiler, Kevin; Ekelof, Tord; El Kacimi, Mohamed; Ellert, Mattias; Elles, Sabine; Ellinghaus, Frank; Elliot, Alison; Ellis, Nicolas; Elmsheuser, Johannes; Elsing, Markus; Emeliyanov, Dmitry; Enari, Yuji; Endner, Oliver Chris; Endo, Masaki; Erdmann, Johannes; Ereditato, Antonio; Ernis, Gunar; Ernst, Jesse; Ernst, Michael; Errede, Steven; Ertel, Eugen; Escalier, Marc; Esch, Hendrik; Escobar, Carlos; Esposito, Bellisario; Etienvre, Anne-Isabelle; Etzion, Erez; Evans, Hal; Ezhilov, Alexey; Fabbri, Laura; Facini, Gabriel; Fakhrutdinov, Rinat; Falciano, Speranza; Falla, Rebecca Jane; Faltova, Jana; Fang, Yaquan; Fanti, Marcello; Farbin, Amir; Farilla, Addolorata; Farooque, Trisha; Farrell, Steven; Farrington, Sinead; Farthouat, Philippe; Fassi, Farida; Fassnacht, Patrick; Fassouliotis, Dimitrios; Faucci Giannelli, Michele; Favareto, Andrea; Fayard, Louis; Federic, Pavol; Fedin, Oleg; Fedorko, Wojciech; Feigl, Simon; Feligioni, Lorenzo; Feng, Cunfeng; Feng, Eric; Feng, Haolu; Fenyuk, Alexander; Feremenga, Last; Fernandez Martinez, Patricia; Fernandez Perez, Sonia; Ferrando, James; Ferrari, Arnaud; Ferrari, Pamela; Ferrari, Roberto; Ferreira de Lima, Danilo Enoque; Ferrer, Antonio; Ferrere, Didier; Ferretti, Claudio; Ferretto Parodi, Andrea; Fiascaris, Maria; Fiedler, Frank; Filipčič, Andrej; Filipuzzi, Marco; Filthaut, Frank; Fincke-Keeler, Margret; Finelli, Kevin Daniel; Fiolhais, Miguel; Fiorini, Luca; Firan, Ana; Fischer, Adam; Fischer, Cora; Fischer, Julia; Fisher, Wade Cameron; Fitzgerald, Eric Andrew; Flaschel, Nils; Fleck, Ivor; Fleischmann, Philipp; Fleischmann, Sebastian; Fletcher, Gareth Thomas; Fletcher, Gregory; Fletcher, Rob Roy MacGregor; Flick, Tobias; Floderus, Anders; Flores Castillo, Luis; Flowerdew, Michael; Formica, Andrea; Forti, Alessandra; Fournier, Daniel; Fox, Harald; Fracchia, Silvia; Francavilla, Paolo; Franchini, Matteo; Francis, David; Franconi, Laura; Franklin, Melissa; Frate, Meghan; Fraternali, Marco; Freeborn, David; French, Sky; Friedrich, Felix; Froidevaux, Daniel; Frost, James; Fukunaga, Chikara; Fullana Torregrosa, Esteban; Fulsom, Bryan Gregory; Fusayasu, Takahiro; Fuster, Juan; Gabaldon, Carolina; Gabizon, Ofir; Gabrielli, Alessandro; Gabrielli, Andrea; Gach, Grzegorz; Gadatsch, Stefan; Gadomski, Szymon; Gagliardi, Guido; Gagnon, Pauline; Galea, Cristina; Galhardo, Bruno; Gallas, Elizabeth; Gallop, Bruce; Gallus, Petr; Galster, Gorm Aske Gram Krohn; Gan, KK; Gao, Jun; Gao, Yanyan; Gao, Yongsheng; Garay Walls, Francisca; Garberson, Ford; García, Carmen; García Navarro, José Enrique; Garcia-Sciveres, Maurice; Gardner, Robert; Garelli, Nicoletta; Garonne, Vincent; Gatti, Claudio; Gaudiello, Andrea; Gaudio, Gabriella; Gaur, Bakul; Gauthier, Lea; Gauzzi, Paolo; Gavrilenko, Igor; Gay, Colin; Gaycken, Goetz; Gazis, Evangelos; Ge, Peng; Gecse, Zoltan; Gee, Norman; Geerts, Daniël Alphonsus Adrianus; Geich-Gimbel, Christoph; Geisler, Manuel Patrice; Gemme, Claudia; Genest, Marie-Hélène; Gentile, Simonetta; George, Matthias; George, Simon; Gerbaudo, Davide; Gershon, Avi; Ghasemi, Sara; Ghazlane, Hamid; Giacobbe, Benedetto; Giagu, Stefano; Giangiobbe, Vincent; Giannetti, Paola; Gibbard, Bruce; Gibson, Stephen; Gilchriese, Murdock; Gillam, Thomas; Gillberg, Dag; Gilles, Geoffrey; Gingrich, Douglas; Giokaris, Nikos; Giordani, MarioPaolo; Giorgi, Filippo Maria; Giorgi, Francesco Michelangelo; Giraud, Pierre-Francois; Giromini, Paolo; Giugni, Danilo; Giuliani, Claudia; Giulini, Maddalena; Gjelsten, Børge Kile; Gkaitatzis, Stamatios; Gkialas, Ioannis; Gkougkousis, Evangelos Leonidas; Gladilin, Leonid; Glasman, Claudia; Glatzer, Julian; Glaysher, Paul; Glazov, Alexandre; Goblirsch-Kolb, Maximilian; Goddard, Jack Robert; Godlewski, Jan; Goldfarb, Steven; Golling, Tobias; Golubkov, Dmitry; Gomes, Agostinho; Gonçalo, Ricardo; Goncalves Pinto Firmino Da Costa, Joao; Gonella, Laura; González de la Hoz, Santiago; Gonzalez Parra, Garoe; Gonzalez-Sevilla, Sergio; Goossens, Luc; Gorbounov, Petr Andreevich; Gordon, Howard; Gorelov, Igor; Gorini, Benedetto; Gorini, Edoardo; Gorišek, Andrej; Gornicki, Edward; Goshaw, Alfred; Gössling, Claus; Gostkin, Mikhail Ivanovitch; Goujdami, Driss; Goussiou, Anna; Govender, Nicolin; Gozani, Eitan; Grabas, Herve Marie Xavier; Graber, Lars; Grabowska-Bold, Iwona; Grafström, Per; Grahn, Karl-Johan; Gramling, Johanna; Gramstad, Eirik; Grancagnolo, Sergio; Grassi, Valerio; Gratchev, Vadim; Gray, Heather; Graziani, Enrico; Greenwood, Zeno Dixon; Gregersen, Kristian; Gregor, Ingrid-Maria; Grenier, Philippe; Griffiths, Justin; Grillo, Alexander; Grimm, Kathryn; Grinstein, Sebastian; Gris, Philippe Luc Yves; Grivaz, Jean-Francois; Grohs, Johannes Philipp; Grohsjean, Alexander; Gross, Eilam; Grosse-Knetter, Joern; Grossi, Giulio Cornelio; Grout, Zara Jane; Guan, Liang; Guenther, Jaroslav; Guescini, Francesco; Guest, Daniel; Gueta, Orel; Guido, Elisa; Guillemin, Thibault; Guindon, Stefan; Gul, Umar; Gumpert, Christian; Guo, Jun; Guo, Yicheng; Gupta, Shaun; Gustavino, Giuliano; Gutierrez, Phillip; Gutierrez Ortiz, Nicolas Gilberto; Gutschow, Christian; Guyot, Claude; Gwenlan, Claire; Gwilliam, Carl; Haas, Andy; Haber, Carl; Hadavand, Haleh Khani; Haddad, Nacim; Haefner, Petra; Hageböck, Stephan; Hajduk, Zbigniew; Hakobyan, Hrachya; Haleem, Mahsana; Haley, Joseph; Hall, David; Halladjian, Garabed; Hallewell, Gregory David; Hamacher, Klaus; Hamal, Petr; Hamano, Kenji; Hamer, Matthias; Hamilton, Andrew; Hamity, Guillermo Nicolas; Hamnett, Phillip George; Han, Liang; Hanagaki, Kazunori; Hanawa, Keita; Hance, Michael; Hanke, Paul; Hanna, Remie; Hansen, Jørgen Beck; Hansen, Jorn Dines; Hansen, Maike Christina; Hansen, Peter Henrik; Hara, Kazuhiko; Hard, Andrew; Harenberg, Torsten; Hariri, Faten; Harkusha, Siarhei; Harrington, Robert; Harrison, Paul Fraser; Hartjes, Fred; Hasegawa, Makoto; Hasegawa, Satoshi; Hasegawa, Yoji; Hasib, A; Hassani, Samira; Haug, Sigve; Hauser, Reiner; Hauswald, Lorenz; Havranek, Miroslav; Hawkes, Christopher; Hawkings, Richard John; Hawkins, Anthony David; Hayashi, Takayasu; Hayden, Daniel; Hays, Chris; Hays, Jonathan Michael; Hayward, Helen; Haywood, Stephen; Head, Simon; Heck, Tobias; Hedberg, Vincent; Heelan, Louise; Heim, Sarah; Heim, Timon; Heinemann, Beate; Heinrich, Lukas; Hejbal, Jiri; Helary, Louis; Hellman, Sten; Hellmich, Dennis; Helsens, Clement; Henderson, James; Henderson, Robert; Heng, Yang; Hengler, Christopher; Henrichs, Anna; Henriques Correia, Ana Maria; Henrot-Versille, Sophie; Herbert, Geoffrey Henry; Hernández Jiménez, Yesenia; Herrberg-Schubert, Ruth; Herten, Gregor; Hertenberger, Ralf; Hervas, Luis; Hesketh, Gavin Grant; Hessey, Nigel; Hetherly, Jeffrey Wayne; Hickling, Robert; Higón-Rodriguez, Emilio; Hill, Ewan; Hill, John; Hiller, Karl Heinz; Hillier, Stephen; Hinchliffe, Ian; Hines, Elizabeth; Hinman, Rachel Reisner; Hirose, Minoru; Hirschbuehl, Dominic; Hobbs, John; Hod, Noam; Hodgkinson, Mark; Hodgson, Paul; Hoecker, Andreas; Hoeferkamp, Martin; Hoenig, Friedrich; Hohlfeld, Marc; Hohn, David; Holmes, Tova Ray; Homann, Michael; Hong, Tae Min; Hooft van Huysduynen, Loek; Hopkins, Walter; Horii, Yasuyuki; Horton, Arthur James; Hostachy, Jean-Yves; Hou, Suen; Hoummada, Abdeslam; Howard, Jacob; Howarth, James; Hrabovsky, Miroslav; Hristova, Ivana; Hrivnac, Julius; Hryn'ova, Tetiana; Hrynevich, Aliaksei; Hsu, Catherine; Hsu, Pai-hsien Jennifer; Hsu, Shih-Chieh; Hu, Diedi; Hu, Qipeng; Hu, Xueye; Huang, Yanping; Hubacek, Zdenek; Hubaut, Fabrice; Huegging, Fabian; Huffman, Todd Brian; Hughes, Emlyn; Hughes, Gareth; Huhtinen, Mika; Hülsing, Tobias Alexander; Huseynov, Nazim; Huston, Joey; Huth, John; Iacobucci, Giuseppe; Iakovidis, Georgios; Ibragimov, Iskander; Iconomidou-Fayard, Lydia; Ideal, Emma; Idrissi, Zineb; Iengo, Paolo; Igonkina, Olga; Iizawa, Tomoya; Ikegami, Yoichi; Ikematsu, Katsumasa; Ikeno, Masahiro; Ilchenko, Iurii; Iliadis, Dimitrios; Ilic, Nikolina; Ince, Tayfun; Introzzi, Gianluca; Ioannou, Pavlos; Iodice, Mauro; Iordanidou, Kalliopi; Ippolito, Valerio; Irles Quiles, Adrian; Isaksson, Charlie; Ishino, Masaya; Ishitsuka, Masaki; Ishmukhametov, Renat; Issever, Cigdem; Istin, Serhat; Iturbe Ponce, Julia Mariana; Iuppa, Roberto; Ivarsson, Jenny; Iwanski, Wieslaw; Iwasaki, Hiroyuki; Izen, Joseph; Izzo, Vincenzo; Jabbar, Samina; Jackson, Brett; Jackson, Matthew; Jackson, Paul; Jaekel, Martin; Jain, Vivek; Jakobs, Karl; Jakobsen, Sune; Jakoubek, Tomas; Jakubek, Jan; Jamin, David Olivier; Jana, Dilip; Jansen, Eric; Jansky, Roland; Janssen, Jens; Janus, Michel; Jarlskog, Göran; Javadov, Namig; Javůrek, Tomáš; Jeanty, Laura; Jejelava, Juansher; Jeng, Geng-yuan; Jennens, David; Jenni, Peter; Jentzsch, Jennifer; Jeske, Carl; Jézéquel, Stéphane; Ji, Haoshuang; Jia, Jiangyong; Jiang, Yi; Jiggins, Stephen; Jimenez Pena, Javier; Jin, Shan; Jinaru, Adam; Jinnouchi, Osamu; Joergensen, Morten Dam; Johansson, Per; Johns, Kenneth; Jon-And, Kerstin; Jones, Graham; Jones, Roger; Jones, Tim; Jongmanns, Jan; Jorge, Pedro; Joshi, Kiran Daniel; Jovicevic, Jelena; Ju, Xiangyang; Jung, Christian; Jussel, Patrick; Juste Rozas, Aurelio; Kaci, Mohammed; Kaczmarska, Anna; Kado, Marumi; Kagan, Harris; Kagan, Michael; Kahn, Sebastien Jonathan; Kajomovitz, Enrique; Kalderon, Charles William; Kama, Sami; Kamenshchikov, Andrey; Kanaya, Naoko; Kaneti, Steven; Kantserov, Vadim; Kanzaki, Junichi; Kaplan, Benjamin; Kaplan, Laser Seymour; Kapliy, Anton; Kar, Deepak; Karakostas, Konstantinos; Karamaoun, Andrew; Karastathis, Nikolaos; Kareem, Mohammad Jawad; Karnevskiy, Mikhail; Karpov, Sergey; Karpova, Zoya; Karthik, Krishnaiyengar; Kartvelishvili, Vakhtang; Karyukhin, Andrey; Kashif, Lashkar; Kass, Richard; Kastanas, Alex; Kataoka, Yousuke; Katre, Akshay; Katzy, Judith; Kawagoe, Kiyotomo; Kawamoto, Tatsuo; Kawamura, Gen; Kazama, Shingo; Kazanin, Vassili; Keeler, Richard; Kehoe, Robert; Keller, John; Kempster, Jacob Julian; Keoshkerian, Houry; Kepka, Oldrich; Kerševan, Borut Paul; Kersten, Susanne; Keyes, Robert; Khalil-zada, Farkhad; Khandanyan, Hovhannes; Khanov, Alexander; Kharlamov, Alexey; Khoo, Teng Jian; Khovanskiy, Valery; Khramov, Evgeniy; Khubua, Jemal; Kim, Hee Yeun; Kim, Hyeon Jin; Kim, Shinhong; Kim, Young-Kee; Kimura, Naoki; Kind, Oliver Maria; King, Barry; King, Matthew; King, Samuel Burton; Kirk, Julie; Kiryunin, Andrey; Kishimoto, Tomoe; Kisielewska, Danuta; Kiss, Florian; Kiuchi, Kenji; Kivernyk, Oleh; Kladiva, Eduard; Klein, Matthew Henry; Klein, Max; Klein, Uta; Kleinknecht, Konrad; Klimek, Pawel; Klimentov, Alexei; Klingenberg, Reiner; Klinger, Joel Alexander; Klioutchnikova, Tatiana; Kluge, Eike-Erik; Kluit, Peter; Kluth, Stefan; Knapik, Joanna; Kneringer, Emmerich; Knoops, Edith; Knue, Andrea; Kobayashi, Aine; Kobayashi, Dai; Kobayashi, Tomio; Kobel, Michael; Kocian, Martin; Kodys, Peter; Koffas, Thomas; Koffeman, Els; Kogan, Lucy Anne; Kohlmann, Simon; Kohout, Zdenek; Kohriki, Takashi; Koi, Tatsumi; Kolanoski, Hermann; Koletsou, Iro; Komar, Aston; Komori, Yuto; Kondo, Takahiko; Kondrashova, Nataliia; Köneke, Karsten; König, Adriaan; Kono, Takanori; Konoplich, Rostislav; Konstantinidis, Nikolaos; Kopeliansky, Revital; Koperny, Stefan; Köpke, Lutz; Kopp, Anna Katharina; Korcyl, Krzysztof; Kordas, Kostantinos; Korn, Andreas; Korol, Aleksandr; Korolkov, Ilya; Korolkova, Elena; Kortner, Oliver; Kortner, Sandra; Kosek, Tomas; Kostyukhin, Vadim; Kotov, Vladislav; Kotwal, Ashutosh; Kourkoumeli-Charalampidi, Athina; Kourkoumelis, Christine; Kouskoura, Vasiliki; Koutsman, Alex; Kowalewski, Robert Victor; Kowalski, Tadeusz; Kozanecki, Witold; Kozhin, Anatoly; Kramarenko, Viktor; Kramberger, Gregor; Krasnopevtsev, Dimitriy; Krasny, Mieczyslaw Witold; Krasznahorkay, Attila; Kraus, Jana; Kravchenko, Anton; Kreiss, Sven; Kretz, Moritz; Kretzschmar, Jan; Kreutzfeldt, Kristof; Krieger, Peter; Krizka, Karol; Kroeninger, Kevin; Kroha, Hubert; Kroll, Joe; Kroseberg, Juergen; Krstic, Jelena; Kruchonak, Uladzimir; Krüger, Hans; Krumnack, Nils; Kruse, Amanda; Kruse, Mark; Kruskal, Michael; Kubota, Takashi; Kucuk, Hilal; Kuday, Sinan; Kuehn, Susanne; Kugel, Andreas; Kuger, Fabian; Kuhl, Andrew; Kuhl, Thorsten; Kukhtin, Victor; Kulchitsky, Yuri; Kuleshov, Sergey; Kuna, Marine; Kunigo, Takuto; Kupco, Alexander; Kurashige, Hisaya; Kurochkin, Yurii; Kus, Vlastimil; Kuwertz, Emma Sian; Kuze, Masahiro; Kvita, Jiri; Kwan, Tony; Kyriazopoulos, Dimitrios; La Rosa, Alessandro; La Rosa Navarro, Jose Luis; La Rotonda, Laura; Lacasta, Carlos; Lacava, Francesco; Lacey, James; Lacker, Heiko; Lacour, Didier; Lacuesta, Vicente Ramón; Ladygin, Evgueni; Lafaye, Remi; Laforge, Bertrand; Lagouri, Theodota; Lai, Stanley; Lambourne, Luke; Lammers, Sabine; Lampen, Caleb; Lampl, Walter; Lançon, Eric; Landgraf, Ulrich; Landon, Murrough; Lang, Valerie Susanne; Lange, J örn Christian; Lankford, Andrew; Lanni, Francesco; Lantzsch, Kerstin; Lanza, Agostino; Laplace, Sandrine; Lapoire, Cecile; Laporte, Jean-Francois; Lari, Tommaso; Lasagni Manghi, Federico; Lassnig, Mario; Laurelli, Paolo; Lavrijsen, Wim; Law, Alexander; Laycock, Paul; Lazovich, Tomo; Le Dortz, Olivier; Le Guirriec, Emmanuel; Le Menedeu, Eve; LeBlanc, Matthew Edgar; LeCompte, Thomas; Ledroit-Guillon, Fabienne Agnes Marie; Lee, Claire Alexandra; Lee, Shih-Chang; Lee, Lawrence; Lefebvre, Guillaume; Lefebvre, Michel; Legger, Federica; Leggett, Charles; Lehan, Allan; Lehmann Miotto, Giovanna; Lei, Xiaowen; Leight, William Axel; Leisos, Antonios; Leister, Andrew Gerard; Leite, Marco Aurelio Lisboa; Leitner, Rupert; Lellouch, Daniel; Lemmer, Boris; Leney, Katharine; Lenz, Tatjana; Lenzi, Bruno; Leone, Robert; Leone, Sandra; Leonidopoulos, Christos; Leontsinis, Stefanos; Leroy, Claude; Lester, Christopher; Levchenko, Mikhail; Levêque, Jessica; Levin, Daniel; Levinson, Lorne; Levy, Mark; Lewis, Adrian; Leyko, Agnieszka; Leyton, Michael; Li, Bing; Li, Haifeng; Li, Ho Ling; Li, Lei; Li, Liang; Li, Shu; Li, Yichen; Liang, Zhijun; Liao, Hongbo; Liberti, Barbara; Liblong, Aaron; Lichard, Peter; Lie, Ki; Liebal, Jessica; Liebig, Wolfgang; Limbach, Christian; Limosani, Antonio; Lin, Simon; Lin, Tai-Hua; Linde, Frank; Lindquist, Brian Edward; Linnemann, James; Lipeles, Elliot; Lipniacka, Anna; Lisovyi, Mykhailo; Liss, Tony; Lissauer, David; Lister, Alison; Litke, Alan; Liu, Bo; Liu, Dong; Liu, Hao; Liu, Jian; Liu, Jianbei; Liu, Kun; Liu, Lulu; Liu, Miaoyuan; Liu, Minghui; Liu, Yanwen; Livan, Michele; Lleres, Annick; Llorente Merino, Javier; Lloyd, Stephen; Lo Sterzo, Francesco; Lobodzinska, Ewelina; Loch, Peter; Lockman, William; Loebinger, Fred; Loevschall-Jensen, Ask Emil; Loginov, Andrey; Lohse, Thomas; Lohwasser, Kristin; Lokajicek, Milos; Long, Brian Alexander; Long, Jonathan; Long, Robin Eamonn; Looper, Kristina Anne; Lopes, Lourenco; Lopez Mateos, David; Lopez Paredes, Brais; Lopez Paz, Ivan; Lorenz, Jeanette; Lorenzo Martinez, Narei; Losada, Marta; Loscutoff, Peter; Lösel, Philipp Jonathan; Lou, XinChou; Lounis, Abdenour; Love, Jeremy; Love, Peter; Lu, Nan; Lubatti, Henry; Luci, Claudio; Lucotte, Arnaud; Luehring, Frederick; Lukas, Wolfgang; Luminari, Lamberto; Lundberg, Olof; Lund-Jensen, Bengt; Lynn, David; Lysak, Roman; Lytken, Else; Ma, Hong; Ma, Lian Liang; Maccarrone, Giovanni; Macchiolo, Anna; Macdonald, Calum Michael; Machado Miguens, Joana; Macina, Daniela; Madaffari, Daniele; Madar, Romain; Maddocks, Harvey Jonathan; Mader, Wolfgang; Madsen, Alexander; Maeland, Steffen; Maeno, Tadashi; Maevskiy, Artem; Magradze, Erekle; Mahboubi, Kambiz; Mahlstedt, Joern; Maiani, Camilla; Maidantchik, Carmen; Maier, Andreas Alexander; Maier, Thomas; Maio, Amélia; Majewski, Stephanie; Makida, Yasuhiro; Makovec, Nikola; Malaescu, Bogdan; Malecki, Pawel; Maleev, Victor; Malek, Fairouz; Mallik, Usha; Malon, David; Malone, Caitlin; Maltezos, Stavros; Malyshev, Vladimir; Malyukov, Sergei; Mamuzic, Judita; Mancini, Giada; Mandelli, Beatrice; Mandelli, Luciano; Mandić, Igor; Mandrysch, Rocco; Maneira, José; Manfredini, Alessandro; Manhaes de Andrade Filho, Luciano; Manjarres Ramos, Joany; Mann, Alexander; Manning, Peter; Manousakis-Katsikakis, Arkadios; Mansoulie, Bruno; Mantifel, Rodger; Mantoani, Matteo; Mapelli, Livio; March, Luis; Marchiori, Giovanni; Marcisovsky, Michal; Marino, Christopher; Marjanovic, Marija; Marley, Daniel; Marroquim, Fernando; Marsden, Stephen Philip; Marshall, Zach; Marti, Lukas Fritz; Marti-Garcia, Salvador; Martin, Brian Thomas; Martin, Tim; Martin, Victoria Jane; Martin dit Latour, Bertrand; Martinez, Mario; Martin-Haugh, Stewart; Martoiu, Victor Sorin; Martyniuk, Alex; Marx, Marilyn; Marzano, Francesco; Marzin, Antoine; Masetti, Lucia; Mashimo, Tetsuro; Mashinistov, Ruslan; Masik, Jiri; Maslennikov, Alexey; Massa, Ignazio; Massa, Lorenzo; Massol, Nicolas; Mastrandrea, Paolo; Mastroberardino, Anna; Masubuchi, Tatsuya; Mättig, Peter; Mattmann, Johannes; Maurer, Julien; Maxfield, Stephen; Maximov, Dmitriy; Mazini, Rachid; Mazza, Simone Michele; Mazzaferro, Luca; Mc Goldrick, Garrin; Mc Kee, Shawn Patrick; McCarn, Allison; McCarthy, Robert; McCarthy, Tom; McCubbin, Norman; McFarlane, Kenneth; Mcfayden, Josh; Mchedlidze, Gvantsa; McMahon, Steve; McPherson, Robert; Medinnis, Michael; Meehan, Samuel; Mehlhase, Sascha; Mehta, Andrew; Meier, Karlheinz; Meineck, Christian; Meirose, Bernhard; Mellado Garcia, Bruce Rafael; Meloni, Federico; Mengarelli, Alberto; Menke, Sven; Meoni, Evelin; Mercurio, Kevin Michael; Mergelmeyer, Sebastian; Mermod, Philippe; Merola, Leonardo; Meroni, Chiara; Merritt, Frank; Messina, Andrea; Metcalfe, Jessica; Mete, Alaettin Serhan; Meyer, Carsten; Meyer, Christopher; Meyer, Jean-Pierre; Meyer, Jochen; Middleton, Robin; Miglioranzi, Silvia; Mijović, Liza; Mikenberg, Giora; Mikestikova, Marcela; Mikuž, Marko; Milesi, Marco; Milic, Adriana; Miller, David; Mills, Corrinne; Milov, Alexander; Milstead, David; Minaenko, Andrey; Minami, Yuto; Minashvili, Irakli; Mincer, Allen; Mindur, Bartosz; Mineev, Mikhail; Ming, Yao; Mir, Lluisa-Maria; Mitani, Takashi; Mitrevski, Jovan; Mitsou, Vasiliki A; Miucci, Antonio; Miyagawa, Paul; Mjörnmark, Jan-Ulf; Moa, Torbjoern; Mochizuki, Kazuya; Mohapatra, Soumya; Mohr, Wolfgang; Molander, Simon; Moles-Valls, Regina; Mönig, Klaus; Monini, Caterina; Monk, James; Monnier, Emmanuel; Montejo Berlingen, Javier; Monticelli, Fernando; Monzani, Simone; Moore, Roger; Morange, Nicolas; Moreno, Deywis; Moreno Llácer, María; Morettini, Paolo; Morgenstern, Marcus; Mori, Daniel; Morii, Masahiro; Morinaga, Masahiro; Morisbak, Vanja; Moritz, Sebastian; Morley, Anthony Keith; Mornacchi, Giuseppe; Morris, John; Mortensen, Simon Stark; Morton, Alexander; Morvaj, Ljiljana; Mosidze, Maia; Moss, Josh; Motohashi, Kazuki; Mount, Richard; Mountricha, Eleni; Mouraviev, Sergei; Moyse, Edward; Muanza, Steve; Mudd, Richard; Mueller, Felix; Mueller, James; Mueller, Ralph Soeren Peter; Mueller, Thibaut; Muenstermann, Daniel; Mullen, Paul; Mullier, Geoffrey; Murillo Quijada, Javier Alberto; Murray, Bill; Musheghyan, Haykuhi; Musto, Elisa; Myagkov, Alexey; Myska, Miroslav; Nackenhorst, Olaf; Nadal, Jordi; Nagai, Koichi; Nagai, Ryo; Nagai, Yoshikazu; Nagano, Kunihiro; Nagarkar, Advait; Nagasaka, Yasushi; Nagata, Kazuki; Nagel, Martin; Nagy, Elemer; Nairz, Armin Michael; Nakahama, Yu; Nakamura, Koji; Nakamura, Tomoaki; Nakano, Itsuo; Namasivayam, Harisankar; Naranjo Garcia, Roger Felipe; Narayan, Rohin; Naumann, Thomas; Navarro, Gabriela; Nayyar, Ruchika; Neal, Homer; Nechaeva, Polina; Neep, Thomas James; Nef, Pascal Daniel; Negri, Andrea; Negrini, Matteo; Nektarijevic, Snezana; Nellist, Clara; Nelson, Andrew; Nemecek, Stanislav; Nemethy, Peter; Nepomuceno, Andre Asevedo; Nessi, Marzio; Neubauer, Mark; Neumann, Manuel; Neves, Ricardo; Nevski, Pavel; Newman, Paul; Nguyen, Duong Hai; Nickerson, Richard; Nicolaidou, Rosy; Nicquevert, Bertrand; Nielsen, Jason; Nikiforou, Nikiforos; Nikiforov, Andriy; Nikolaenko, Vladimir; Nikolic-Audit, Irena; Nikolopoulos, Konstantinos; Nilsen, Jon Kerr; Nilsson, Paul; Ninomiya, Yoichi; Nisati, Aleandro; Nisius, Richard; Nobe, Takuya; Nomachi, Masaharu; Nomidis, Ioannis; Nooney, Tamsin; Norberg, Scarlet; Nordberg, Markus; Novgorodova, Olga; Nowak, Sebastian; Nozaki, Mitsuaki; Nozka, Libor; Ntekas, Konstantinos; Nunes Hanninger, Guilherme; Nunnemann, Thomas; Nurse, Emily; Nuti, Francesco; O'Brien, Brendan Joseph; O'grady, Fionnbarr; O'Neil, Dugan; O'Shea, Val; Oakham, Gerald; Oberlack, Horst; Obermann, Theresa; Ocariz, Jose; Ochi, Atsuhiko; Ochoa, Ines; Ochoa-Ricoux, Juan Pedro; Oda, Susumu; Odaka, Shigeru; Ogren, Harold; Oh, Alexander; Oh, Seog; Ohm, Christian; Ohman, Henrik; Oide, Hideyuki; Okamura, Wataru; Okawa, Hideki; Okumura, Yasuyuki; Okuyama, Toyonobu; Olariu, Albert; Olivares Pino, Sebastian Andres; Oliveira Damazio, Denis; Oliver Garcia, Elena; Olszewski, Andrzej; Olszowska, Jolanta; Onofre, António; Onyisi, Peter; Oram, Christopher; Oreglia, Mark; Oren, Yona; Orestano, Domizia; Orlando, Nicola; Oropeza Barrera, Cristina; Orr, Robert; Osculati, Bianca; Ospanov, Rustem; Otero y Garzon, Gustavo; Otono, Hidetoshi; Ouchrif, Mohamed; Ouellette, Eric; Ould-Saada, Farid; Ouraou, Ahmimed; Oussoren, Koen Pieter; Ouyang, Qun; Ovcharova, Ana; Owen, Mark; Owen, Rhys Edward; Ozcan, Veysi Erkcan; Ozturk, Nurcan; Pachal, Katherine; Pacheco Pages, Andres; Padilla Aranda, Cristobal; Pagáčová, Martina; Pagan Griso, Simone; Paganis, Efstathios; Paige, Frank; Pais, Preema; Pajchel, Katarina; Palacino, Gabriel; Palestini, Sandro; Palka, Marek; Pallin, Dominique; Palma, Alberto; 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2015-09-15

This paper describes the concept, technical realisation and validation of a largely data-driven method to model events with $Z\\to\\tau\\tau$ decays. In $Z\\to\\mu\\mu$ events selected from proton-proton collision data recorded at $\\sqrt{s}=8$ TeV with the ATLAS experiment at the LHC in 2012, the $Z$ decay muons are replaced by $\\tau$ leptons from simulated $Z\\to\\tau\\tau$ decays at the level of reconstructed tracks and calorimeter cells. The $\\tau$ lepton kinematics are derived from the kinematics of the original muons. Thus, only the well-understood decays of the $Z$ boson and $\\tau$ leptons as well as the detector response to the $\\tau$ decay products are obtained from simulation. All other aspects of the event, such as the $Z$ boson and jet kinematics as well as effects from multiple interactions, are given by the actual data. This so-called $\\tau$-embedding method is particularly relevant for Higgs boson searches and analyses in $\\tau\\tau$ final states, where $Z\\to\\tau\\tau$ decays constitute a large irreducible...

An Intranasal Formulation of Erythropoietin (Neuro-EPO) Prevents Memory Deficits and Amyloid Toxicity in the APPSwe Transgenic Mouse Model of Alzheimer's Disease.

Science.gov (United States)

Rodríguez Cruz, Yamila; Strehaiano, Manon; Rodríguez Obaya, Teresita; García Rodríguez, Julío César; Maurice, Tangui

2017-01-01

Erythropoietin (EPO) is a cytokine known to have effective cytoprotective action in the brain, particularly in ischemic, traumatic, inflammatory, and neurodegenerative conditions. We previously reported the neuroprotective effect of a low sialic form of EPO, Neuro-EPO, applied intranasally in rodent models of stroke or cerebellar ataxia and in a non-transgenic mouse model of Alzheimer's disease (AD). Here we analyzed the protective effect of Neuro-EPO in APPSwe mice, a reference transgenic mouse model of AD. Mice were administered 3 times a day, 3 days in the week with Neuro-EPO (125, 250 μg/kg) intranasally, between 12 and 14 months of age. Motor responses, general activity, and memory responses were analyzed during and after treatment. The deficits in spontaneous alternation, place learning in the water-maze, and novel object recognition observed in APPSwe mice were alleviated by the low dose of Neuro-EPO. Oxidative stress, neuroinflammation, trophic factor levels, and a synaptic marker were analyzed in the hippocampus or cortex of the animals. The increases in lipid peroxidation or in GFAP and Iba-1 contents in APPSwe mice were significantly reduced after Neuro-EPO. Activation of intrinsic and extrinsic apoptotic pathways was analyzed. The increases in Bax/Bcl-2 ratio, TNFα, or Fas ligand levels observed in APPSwe mice were reduced by Neuro-EPO. Finally, immunohistochemical and ELISA analyses of Aβ1-42 levels in the APPSwe mouse cortex and hippocampus showed a marked reduction in Aβ deposits and in soluble and insoluble Aβ1-42 forms. This study therefore confirmed the neuroprotective activity of EPO, particularly for an intranasally deliverable formulation, devoid of erythropoietic side effects, in a transgenic mouse model of AD. Neuro-EPO alleviated memory alterations, oxidative stress, neuroinflammation, apoptosis induction, and amyloid load in 14-month-old APPSwe mice.

Application of Echocardiography on Transgenic Mice with Cardiomyopathies

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G. Chen

2012-01-01

Full Text Available Cardiomyopathies are common cardiac disorders that primarily affect cardiac muscle resulting in cardiac dysfunction and heart failure. Transgenic mouse disease models have been developed to investigate the cellular mechanisms underlying heart failure and sudden cardiac death observed in cardiomyopathy cases and to explore the therapeutic outcomes in experimental animals in vivo. Echocardiography is an essential diagnostic tool for accurate and noninvasive assessment of cardiac structure and function in experimental animals. Our laboratory has been among the first to apply high-frequency research echocardiography on transgenic mice with cardiomyopathies. In this work, we have summarized our and other studies on assessment of systolic and diastolic dysfunction using conventional echocardiography, pulsed Doppler, and tissue Doppler imaging in transgenic mice with various cardiomyopathies. Estimation of embryonic mouse hearts has been performed as well using this high-resolution echocardiography. Some technical considerations in mouse echocardiography have also been discussed.

Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation.

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Reilly, Patrick; Winston, Charisse N; Baron, Kelsey R; Trejo, Margarita; Rockenstein, Edward M; Akers, Johnny C; Kfoury, Najla; Diamond, Marc; Masliah, Eliezer; Rissman, Robert A; Yuan, Shauna H

2017-10-01

Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, which are associated with the pathological aggregation of tau protein into neurofibrillary tangles (NFT). Studies have characterized tau as a "prion-like" protein given its ability to form distinct, stable amyloid conformations capable of transcellular and multigenerational propagation in clonal fashion. It has been proposed that progression of tauopathy could be due to the prion-like propagation of tau, suggesting the possibility that end-stage pathologies, like NFT formation, may require an instigating event such as tau seeding. To investigate this, we applied a novel human induced pluripotent stem cell (hiPSC) system we have developed to serve as a human neuronal model. We introduced the tau repeat domain (tau-RD) with P301L and V337M (tau-RD-LM) mutations into hiPSC-derived neurons and observed expression of tau-RD at levels similar to total tau in postmortem AD brains. Tau aggregation occurred without the addition of recombinant tau fibrils. The conditioned media from tau-RD cultures contained tau-RD seeds, which were capable of inducing aggregate formation in homotypic mode in non-transduced recipient neuronal cultures. The resultant NFTs were thioflavin-positive, silver stain-positive, and assumed fibrillary appearance on transmission electron microscopy (TEM) with immunogold, which revealed paired helical filament 1 (PHF1)-positive NFTs, representing possible recruitment of endogenous tau in the aggregates. Functionally, expression of tau-RD caused neurotoxicity that manifested as axon retraction, synaptic density reduction, and enlargement of lysosomes. The results of our hiPSC study were reinforced by the observation that Tau-RD-LM is excreted in exosomes, which mediated the transfer of human tau to wild-type mouse neurons in vivo. Our hiPSC human neuronal system provides a model for further studies of tau

Mitochondrial oxidative stress causes hyperphosphorylation of tau.

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Simon Melov

2007-06-01

Full Text Available Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD: tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2 die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576 with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.

Optimised and rapid pre-clinical screening in the SOD1(G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS.

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Richard J Mead

Full Text Available The human SOD1(G93A transgenic mouse has been used extensively since its development in 1994 as a model for amyotrophic lateral sclerosis (ALS. In that time, a great many insights into the toxicity of mutant SOD1 have been gained using this and other mutant SOD transgenic mouse models. They all demonstrate a selective toxicity towards motor neurons and in some cases features of the pathology seen in the human disease. These models have two major drawbacks. Firstly the generation of robust preclinical data in these models has been highlighted as an area for concern. Secondly, the amount of time required for a single preclinical experiment in these models (3-4 months is a hurdle to the development of new therapies. We have developed an inbred C57BL/6 mouse line from the original mixed background (SJLxC57BL/6 SOD1(G93A transgenic line and show here that the disease course is remarkably consistent and much less prone to background noise, enabling reduced numbers of mice for testing of therapeutics. Secondly we have identified very early readouts showing a large decline in motor function compared to normal mice. This loss of motor function has allowed us to develop an early, sensitive and rapid screening protocol for the initial phases of denervation of muscle fibers, observed in this model. We describe multiple, quantitative readouts of motor function that can be used to interrogate this early mechanism. Such an approach will increase throughput for reduced costs, whilst reducing the severity of the experimental procedures involved.

Generation of Pet1210-Cre Transgenic Mouse Line Reveals Non-Serotonergic Expression Domains of Pet1 Both in CNS and Periphery

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Pelosi, Barbara; Migliarini, Sara; Pacini, Giulia; Pratelli, Marta; Pasqualetti, Massimo

2014-01-01

Neurons producing serotonin (5-hydroxytryptamine, 5-HT) constitute one of the most widely distributed neuronal networks in the mammalian central nervous system (CNS) and exhibit a profuse innervation throughout the CNS already at early stages of development. Serotonergic neuron specification is controlled by a combination of secreted molecules and transcription factors such as Shh, Fgf4/8, Nkx2.2, Lmx1b and Pet1. In the mouse, Pet1 mRNA expression appears between 10 and 11 days post coitum (dpc) in serotonergic post-mitotic precursors and persists in serotonergic neurons up to adulthood, where it promotes the expression of genes defining the mature serotonergic phenotype such as tryptophan hydroxylase 2 (Tph2) and serotonin transporter (SERT). Hence, the generation of genetic tools based on Pet1 specific expression represents a valuable approach to study the development and function of the serotonergic system. Here, we report the generation of a Pet1210-Cre transgenic mouse line in which the Cre recombinase is expressed under the control of a 210 kb fragment from the Pet1 genetic locus to ensure a reliable and faithful control of somatic recombination in Pet1 cell lineage. Besides Cre-mediated recombination accurately occurred in the serotonergic system as expected and according to previous studies, Pet1210-Cre transgenic mouse line allowed us to identify novel, so far uncharacterized, Pet1 expression domains. Indeed, we showed that in the raphe Pet1 is expressed also in a non-serotonergic neuronal population intermingled with Tph2-expressing cells and mostly localized in the B8 and B9 nuclei. Moreover, we detected Cre-mediated recombination also in the developing pancreas and in the ureteric bud derivatives of the kidney, where it reflected a specific Pet1 expression. Thus, Pet1210-Cre transgenic mouse line faithfully drives Cre-mediated recombination in all Pet1 expression domains representing a valuable tool to genetically manipulate serotonergic and non

Generation of BAC transgenic epithelial organoids.

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Gerald Schwank

Full Text Available Under previously developed culture conditions, mouse and human intestinal epithelia can be cultured and expanded over long periods. These so-called organoids recapitulate the three-dimensional architecture of the gut epithelium, and consist of all major intestinal cell types. One key advantage of these ex vivo cultures is their accessibility to live imaging. So far the establishment of transgenic fluorescent reporter organoids has required the generation of transgenic mice, a laborious and time-consuming process, which cannot be extended to human cultures. Here we present a transfection protocol that enables the generation of recombinant mouse and human reporter organoids using BAC (bacterial artificial chromosome technology.

PET imaging of brain with the {beta}-amyloid probe, [{sup 11}C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease

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Toyama, Hiroshi [Fujita Health University, Department of Radiology, Aichi (Japan); National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Ye, Daniel; Cohen, Robert M. [National Institutes of Health, Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Ichise, Masanori; Liow, Jeih-San; Cai, Lisheng; Musachio, John L.; Hong, Jinsoo; Crescenzo, Mathew; Tipre, Dnyanesh; Lu, Jian-Qiang; Zoghbi, Sami; Vines, Douglass C.; Pike, Victor W.; Innis, Robert B. [National Institutes of Health, Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland (United States); Jacobowitz, David [USUHS, Department of Anatomy, Physiology, and Genetics, Bethesda, Maryland (United States); Seidel, Jurgen; Green, Michael V. [National Institutes of Health, Department of Nuclear Medicine, Warren Grant Magnuson Clinical Center, Bethesda, Maryland (United States); Katada, Kazuhiro [Fujita Health University, Department of Radiology, Aichi (Japan)

2005-04-01

The purpose of this study was to evaluate the capacity of [{sup 11}C]6-OH-BTA-1 and positron emission tomography (PET) to quantify {beta}-amyloid (A{beta}) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0{+-}1.8 months; 23.6{+-}2.6 g) overexpressing a mutated form of human {beta}-amyloid precursor protein (APP) known to result in the production of A{beta} plaques, and in six elderly wild-type litter mates (age 21.8{+-}1.6 months; 29.5{+-}4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [{sup 11}C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. TACs for [{sup 11}C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06{+-}0.04 vs 0.98{+-}0.07, p=0.04; 1.06{+-}0.09 vs 0.93{+-}0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread A{beta} plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild

Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model.

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Wang, Chun-Yan; Zheng, Wei; Wang, Tao; Xie, Jing-Wei; Wang, Si-Ling; Zhao, Bao-Lu; Teng, Wei-Ping; Wang, Zhan-You

2011-04-01

Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to β-amyloid (Aβ) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3α/β activity, and enhanced the β-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/β-catenin signaling pathway in AD brain.

Gene knockout of tau expression does not contribute to the pathogenesis of prion disease.

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Lawson, Victoria A; Klemm, Helen M; Welton, Jeremy M; Masters, Colin L; Crouch, Peter; Cappai, Roberto; Ciccotosto, Giuseppe D

2011-11-01

Prion diseases or transmissible spongiform encephalopathies are a group of fatal and transmissible disorders affecting the central nervous system of humans and animals. The principal agent of prion disease transmission and pathogenesis is proposed to be an abnormal protease-resistant isoform of the normal cellular prion protein. The microtubule-associated protein tau is elevated in patients with Creutzfeldt-Jakob disease. To determine whether tau expression contributes to prion disease pathogenesis, tau knockout and control wild-type mice were infected with the M1000 strain of mouse-adapted human prions. Immunohistochemical analysis for total tau expression in prion-infected wild-type mice indicated tau aggregation in the cytoplasm of a subpopulation of neurons in regions associated with spongiform change. Western immunoblot analysis of brain homogenates revealed a decrease in total tau immunoreactivity and epitope-specific changes in tau phosphorylation. No significant difference in incubation period or other disease features were observed between tau knockout and wild-type mice with clinical prion disease. These results demonstrate that, in this model of prion disease, tau does not contribute to the pathogenesis of prion disease and that changes in the tau protein profile observed in mice with clinical prion disease occurs as a consequence of the prion-induced pathogenesis.

Handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins in transgenic mice

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Kragh, Peter M; Pedersen, Christina B; Schmidt, Stine P

2007-01-01

Abstract To investigate the in vivo handling of human short-chain acyl-CoA dehydrogenase (SCAD) variant proteins, three transgenic mouse lines were produced by pronuclear injection of cDNA encoding the wild-type, hSCAD-wt, and two disease causing folding variants hSCAD-319C > T and hSCAD-625G > A....... The transgenic mice were mated with an SCAD-deficient mouse strain (BALB/cByJ) and, in the second generation, three mouse lines were obtained without endogenous SCAD expression but harboring hSCAD-wt, hSCAD-319C > T, and hSCAD-625G > A transgenes, respectively. All three lines had expression of the transgene...... developed for any of the lines transgenic for the hSCAD folding variants. The indicated remarkable efficiency of the mouse protein quality control system in the degradation of SCAD folding variants should be further substantiated and investigated, since it might indicate ways to prevent disease...

Transgene mus som sygdomsmodeller

DEFF Research Database (Denmark)

Schuster, Mikkel Bruhn; Porse, Bo Torben

2003-01-01

Transgenic animal models have proven to be useful tools in understanding both basic biology and the events associated with disease. Recent technical advances in the area of genomic manipulation in combination with the availability of the human and murine genomic sequences now allow the precise...... tailoring of the mouse genome. In this review we describe a few systems in which transgenic animal models have been employed for the purpose of studying the etiology of human diseases. Udgivelsesdato: 2003-Feb-17...

Effect of eugenol on the mutagenicity of benzo[a]pyrene and the formation of benzo[a]pyrene-DNA adducts in the X-lacZ-transgenic mouse.

NARCIS (Netherlands)

Rompelberg, C.J.M.; Steenwinkel, M.J.S.T.; Asten, J.G. van; Delft, J.H.M. van; Baan, R.A.; Verhagen, H.

1996-01-01

To study the possible reduction by eugenol of the mutagenicity and genotoxicity of benzoja]pyrene (B[a]P) in vivo, the X-lacZ-transgenic mouse strain 40.6 (Muta(TM)Mouse) was used. Male mice were fed a diet containing 0.4% (w/w) eugenol or a control diet for 58 days. On day 10, half of the mice

Imbalance of Hsp70 family variants fosters tau accumulation.

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Jinwal, Umesh K; Akoury, Elias; Abisambra, Jose F; O'Leary, John C; Thompson, Andrea D; Blair, Laura J; Jin, Ying; Bacon, Justin; Nordhues, Bryce A; Cockman, Matthew; Zhang, Juan; Li, Pengfei; Zhang, Bo; Borysov, Sergiy; Uversky, Vladimir N; Biernat, Jacek; Mandelkow, Eckhard; Gestwicki, Jason E; Zweckstetter, Markus; Dickey, Chad A

2013-04-01

Dysfunctional tau accumulation is a major contributing factor in tauopathies, and the heat-shock protein 70 (Hsp70) seems to play an important role in this accumulation. Several reports suggest that Hsp70 proteins can cause tau degradation to be accelerated or slowed, but how these opposing activities are controlled is unclear. Here we demonstrate that highly homologous variants in the Hsp70 family can have opposing effects on tau clearance kinetics. When overexpressed in a tetracycline (Tet)-based protein chase model, constitutive heat shock cognate 70 (Hsc70) and inducible Hsp72 slowed or accelerated tau clearance, respectively. Tau synergized with Hsc70, but not Hsp72, to promote microtubule assembly at nearly twice the rate of either Hsp70 homologue in reconstituted, ATP-regenerating Xenopus extracts supplemented with rhodamine-labeled tubulin and human recombinant Hsp72 and Hsc70. Nuclear magnetic resonance spectroscopy with human recombinant protein revealed that Hsp72 had greater affinity for tau than Hsc70 (I/I0 ratio difference of 0.3), but Hsc70 was 30 times more abundant than Hsp72 in human and mouse brain tissue. This indicates that the predominant Hsp70 variant in the brain is Hsc70, suggesting that the brain environment primarily supports slower tau clearance. Despite its capacity to clear tau, Hsp72 was not induced in the Alzheimer's disease brain, suggesting a mechanism for age-associated onset of the disease. Through the use of chimeras that blended the domains of Hsp72 and Hsc70, we determined that the reason for these differences between Hsc70 and Hsp72 with regard to tau clearance kinetics lies within their C-terminal domains, which are essential for their interactions with substrates and cochaperones. Hsp72 but not Hsc70 in the presence of tau was able to recruit the cochaperone ubiquitin ligase CHIP, which is known to facilitate the ubiquitination of tau, describing a possible mechanism of how the C-termini of these homologous Hsp70 variants

Intrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation.

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Todd J Cohen

Full Text Available Tau proteins are abnormally aggregated in a range of neurodegenerative tauopathies including Alzheimer's disease (AD. Recently, tau has emerged as an extensively post-translationally modified protein, among which lysine acetylation is critical for normal tau function and its pathological aggregation. Here, we demonstrate that tau isoforms have different propensities to undergo lysine acetylation, with auto-acetylation occurring more prominently within the lysine-rich microtubule-binding repeats. Unexpectedly, we identified a unique intrinsic property of tau in which auto-acetylation induces proteolytic tau cleavage, thereby generating distinct N- and C-terminal tau fragments. Supporting a catalytic reaction-based mechanism, mapping and mutagenesis studies showed that tau cysteines, which are required for acetyl group transfer, are also essential for auto-proteolytic tau processing. Further mass spectrometry analysis identified the C-terminal 2nd and 4th microtubule binding repeats as potential sites of auto-cleavage. The identification of acetylation-mediated auto-proteolysis provides a new biochemical mechanism for tau self-regulation and warrants further investigation into whether auto-catalytic functions of tau are implicated in AD and other tauopathies.

Human amyloid β peptide and tau co-expression impairs behavior and causes specific gene expression changes in Caenorhabditis elegans.

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Wang, Chenyin; Saar, Valeria; Leung, Ka Lai; Chen, Liang; Wong, Garry

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques consisting of Amyloid-β peptide (Aβ) aggregates and neurofibrillary tangles formed by aggregation of hyperphosphorylated microtubule-associated protein tau. We generated a novel invertebrate model of AD by crossing Aβ1-42 (strain CL2355) with either pro-aggregating tau (strain BR5270) or anti-aggregating tau (strain BR5271) pan-neuronal expressing transgenic Caenorhabditis elegans. The lifespan and progeny viability of the double transgenic strains were significantly decreased compared with wild type N2 (P5E-21). RNA interference of 13 available top up-regulated genes in Aβ1-42+pro-aggregating tau animals revealed that F-box family genes and nep-4 could enhance life span deficits and chemotaxis deficits while Y39G8C.2 (TTBK2) could suppress these behaviors. Comparing the list of regulated genes from C. elegans to the top 60 genes related to human AD confirmed an overlap of 8 genes: patched homolog 1, PTCH1 (ptc-3), the Rab GTPase activating protein, TBC1D16 (tbc-16), the WD repeat and FYVE domain-containing protein 3, WDFY3 (wdfy-3), ADP-ribosylation factor guanine nucleotide exchange factor 2, ARFGEF2 (agef-1), Early B-cell Factor, EBF1 (unc-3), d-amino-acid oxidase, DAO (daao-1), glutamate receptor, metabotropic 1, GRM1 (mgl-2), prolyl 4-hydroxylase subunit alpha 2, P4HA2 (dpy-18 and phy-2). Taken together, our C. elegans double transgenic model provides insight on the fundamental neurobiologic processes underlying human AD and recapitulates selected transcriptomic changes observed in human AD brains. Copyright © 2017 Elsevier Inc. All rights reserved.

Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

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Sarah L. DeVos

2018-04-01

Full Text Available Alzheimer's disease (AD is defined by the presence of intraneuronal neurofibrillary tangles (NFTs composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau

Cholinergic Basal Forebrain Lesion Decreases Neurotrophin Signaling without Affecting Tau Hyperphosphorylation in Genetically Susceptible Mice.

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Turnbull, Marion T; Coulson, Elizabeth J

2017-01-01

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and are a major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in sporadic AD are unknown. Here we investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or a resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Our results reveal that the loss of BFCNs in pre-symptomatic pR5 (P301L) tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals' performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.

Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment.

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Sohn, Peter Dongmin; Tracy, Tara E; Son, Hye-In; Zhou, Yungui; Leite, Renata E P; Miller, Bruce L; Seeley, William W; Grinberg, Lea T; Gan, Li

2016-06-29

Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Loss of polarized distribution of the axonal protein tau is an early sign of Alzheimer's disease (AD) and other neurodegenerative disorders. The cytoskeletal network in the axon initial segment (AIS) forms a barrier between the axon and the somatodentritic compartment, contributing to axonal retention of tau. Although perturbation of the AIS cytoskeleton has been implicated in neurological disorders, the molecular triggers and functional consequence of AIS perturbation are incompletely understood. Here we report that tau acetylation and consequent destabilization of the AIS cytoskeleton promote the somatodendritic mislocalization of tau. AIS cytoskeletal proteins, including ankyrin G and βIV-spectrin, were downregulated in AD brains and negatively correlated with an increase in tau acetylated at K274 and K281. AIS proteins were also diminished in transgenic mice expressing tauK274/281Q, a tau mutant that mimics K274 and K281 acetylation. In primary neuronal cultures, the tauK274/281Q mutant caused hyperdynamic microtubules (MTs) in the AIS, shown by live-imaging of MT mobility and fluorescence recovery after photobleaching. Using photoconvertible tau constructs, we found that axonal tauK274/281Q was missorted into the somatodendritic compartment. Stabilizing MTs with epothilone D to restore the cytoskeletal barrier in the AIS prevented tau mislocalization in primary neuronal cultures. Together, these findings demonstrate that tau acetylation contributes to the pathogenesis of neurodegenerative disease by compromising the cytoskeletal sorting machinery in the AIS.

Curcumin Inhibits Tau Aggregation and Disintegrates Preformed Tau Filaments in vitro.

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Rane, Jitendra Subhash; Bhaumik, Prasenjit; Panda, Dulal

2017-01-01

The pathological aggregation of tau is a common feature of most of the neuronal disorders including frontotemporal dementia, Parkinson's disease, and Alzheimer's disease. The inhibition of tau aggregation is considered to be one of the important strategies for treating these neurodegenerative diseases. Curcumin, a natural polyphenolic molecule, has been reported to have neuroprotective ability. In this work, curcumin was found to bind to adult tau and fetal tau with a dissociation constant of 3.3±0.4 and 8±1 μM, respectively. Molecular docking studies indicated a putative binding site of curcumin in the microtubule-binding region of tau. Using several complementary techniques, including dynamic light scattering, thioflavin S fluorescence, 90° light scattering, electron microscopy, and atomic force microscopy, curcumin was found to inhibit the aggregation of tau. The dynamic light scattering analysis and atomic force microscopic images revealed that curcumin inhibits the oligomerization of tau. Curcumin also disintegrated preformed tau oligomers. Using Far-UV circular dichroism, curcumin was found to inhibit the β-sheets formation in tau indicating that curcumin inhibits an initial step of tau aggregation. In addition, curcumin inhibited tau fibril formation. Furthermore, the effect of curcumin on the preformed tau filaments was analyzed by atomic force microscopy, transmission electron microscopy, and 90° light scattering. Curcumin treatment disintegrated preformed tau filaments. The results indicated that curcumin inhibited the oligomerization of tau and could disaggregate tau filaments.

Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice.

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Egashira, Nobuaki; Iwasaki, Katsunori; Takashima, Akihiko; Watanabe, Takuya; Kawabe, Hideyuki; Matsuda, Tomomi; Mishima, Kenichi; Chidori, Shozo; Nishimura, Ryoji; Fujiwara, Michihiro

2005-10-12

Mutant R406W human tau was originally identified in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and causes a hereditary tauopathy that clinically resembles Alzheimer's disease (AD). In the current study, we examined the performance of R406W transgenic (Tg) mice in the forced swimming test, a test with high predictivity of antidepressant efficacy in human depression, and found an enhancement of the immobility time. In contrast, the motor function and anxiety-related emotional response of R406W Tg mice were normal. Furthermore, a selective serotonin reuptake inhibitor (SSRI), fluvoxamine (100 mg/kg, p.o.), significantly reduced this enhancement of the immobility time, whereas a noradrenaline reuptake inhibitor, desipramine, had no effect. In an in vivo microdialysis study, R406W Tg mice exhibited a significantly decreased extracellular 5-hydroxyindoleacetic acid (5-HIAA) level in the frontal cortex and also exhibited a tendency toward a decreased extracellular 5-hydroxytryptamine (5-HT) level. Moreover, fluvoxamine, which reduced the enhancement of the immobility time, significantly increased the extracellular 5-HT level in R406W Tg mice. These results suggest that R406W Tg mice exhibit changes in depression-related behavior involving serotonergic neurons and provide an animal model for investigating AD with depression.

Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

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Ge Li

2016-04-01

Full Text Available Tumor necrosis factor alpha (TNFα plays a key role in the pathogenesis of rheumatoid arthritis (RA. Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.

A transgenic approach to study argininosuccinate synthetase gene expression

Science.gov (United States)

2014-01-01

Background Argininosuccinate synthetase (ASS) participates in urea, nitric oxide and arginine production. Besides transcriptional regulation, a post-transcriptional regulation affecting nuclear precursor RNA stability has been reported. To study whether such post-transcriptional regulation underlines particular temporal and spatial ASS expression, and to investigate how human ASS gene behaves in a mouse background, a transgenic mouse system using a modified bacterial artificial chromosome carrying the human ASS gene tagged with EGFP was employed. Results Two lines of ASS-EGFP transgenic mice were generated: one with EGFP under transcriptional control similar to that of the endogenous ASS gene, another with EGFP under both transcriptional and post-transcriptional regulation as that of the endogenous ASS mRNA. EGFP expression in the liver, the organ for urea production, and in the intestine and kidney that are responsible for arginine biosynthesis, was examined. Organs taken from embryos E14.5 stage to young adult were examined under a fluorescence microscope either directly or after cryosectioning. The levels of EGFP and endogenous mouse Ass mRNAs were also quantified by S1 nuclease mapping. EGFP fluorescence and EGFP mRNA levels in both the liver and kidney were found to increase progressively from embryonic stage toward birth. In contrast, EGFP expression in the intestine was higher in neonates and started to decline at about 3 weeks after birth. Comparison between the EGFP profiles of the two transgenic lines indicated the developmental and tissue-specific regulation was mainly controlled at the transcriptional level. The ASS transgene was of human origin. EGFP expression in the liver followed essentially the mouse Ass pattern as evidenced by zonation distribution of fluorescence and the level of EGFP mRNA at birth. However, in the small intestine, Ass mRNA level declined sharply at 3 week of age, and yet substantial EGFP mRNA was still detectable at this stage

PET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide

DEFF Research Database (Denmark)

Nielsen, Carsten Haagen; Kimura, Richard H; Withofs, Nadia

2010-01-01

for a noninvasive detection and characterization of smaller lung nodules, thus increasing the chances of positive treatment outcome. In this study, we investigate the ability to characterize lung tumors that spontaneously arise in a transgenic mouse model. The tumors are first identified with small animal CT...... peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from the surrounding...... followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with the knottin...

First Observation of {tau}{r_arrow}3{pi}{eta}{nu}{sub {tau}} and {tau}{r_arrow} {ital f}{sub 1}{pi}{nu}{sub {tau}} Decays

Energy Technology Data Exchange (ETDEWEB)

Bergfeld, T.; Eisenstein, B.I.; Ernst, J.; Gladding, G.E.; Gollin, G.D.; Hans, R.M.; Johnson, E.; Karliner, I.; Marsh, M.A.; Palmer, M.; Selen, M.; Thaler, J.J. [University of Illinois, Champaign-Urbana, Illinois 61801 (United States); Edwards, K.W.; Edwards, K.W. [the Institute of Particle Physics, Montreal, Quebec (Canada); Bellerive, A.; Bellerive, A.; Janicek, R.; Janicek, R.; MacFarlane, D.B.; MacFarlane, D.B.; Patel, P.M.; Patel, P.M. [the Institute of Particle Physics, Montreal, Quebec (Canada); Sadoff, A.J. [Ithaca College, Ithaca, New York 14850 (United States); Ammar, R.; Baringer, P.; Bean, A.; Besson, D.; Coppage, D.; Darling, C.; Davis, R.; Hancock, N.; Kotov, S.; Kravchenko, I.; Kwak, N. [University of Kansas, Lawrence, Kansas 66045 (United States); Anderson, S.; Kubota, Y.; Lee, S.J.; ONeill, J.J.; Patton, S.; Poling, R.; Riehle, T.; Savinov, V.; Smith, A. [University of Minnesota, Minneapolis, Minnesota 55455 (United States); Alam, M.S.; Athar, S.B.; Ling, Z.; Mahmood, A.H.; Severini, H.; Timm, S.; Wappler, F. [State University of New York at Albany, Albany, New York 12222 (United States); Anastassov, A.; Blinov, S.; Duboscq, J.E.; Fujino, D.; Gan, K.K.; Hart, T.; Honscheid, K.; Kagan, H.; Kass, R.; Lee, J.; Spencer, M.B.; Sung, M.; Undrus, A.; Wanke, R.; Wolf, A.; Zoeller, M.M. [The Ohio State University, Columbus, Ohio 43210 (United States); Nemati, B.; Richichi, S.J.; Ross, W.R.; Skubic, P. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Bishai, M.; Fast, J.; Gerndt, E.; Hinson, J.W.; Menon, N.; Miller, D.H.; Shibata, E.I.; Shipsey, I.P.; Yurko, M. [Purdue University, West Lafayette, Indiana 47907 (United States); Gibbons, L.; Glenn, S.; Johnson, S.D.; Kwon, Y.; Roberts, S.; Thorndike, E.H. [University of Rochester, Rochester, New York 14627 (United States); Jessop, C.P.; Lingel, K.; Marsiske, H.; Perl, M.L.; Ugolini, D.; Wang, R.; Zhou, X.; and others

1997-09-01

We have observed new channels for {tau} decays with an {eta} in the final state. We study 3-prong tau decays, using the {eta}{r_arrow}{gamma}{gamma} and {eta}{r_arrow}3{pi}{sup 0} decay modes and 1-prong decays with two {pi}{sup 0} {close_quote}s using the {eta}{r_arrow}{gamma}{gamma} channel. The measured branching fractions are B({tau}{sup {minus}}{r_arrow}{pi}{sup {minus}} {pi}{sup {minus}}{pi}{sup +}{eta}{nu}{sub {tau}})=(3.4{sup +0.6}{sub {minus}0.5} {plus_minus}0.6){times}10{sup {minus}4} and B({tau}{sup {minus}}{r_arrow}{pi}{sup {minus}} 2{pi}{sup 0}{eta}{nu}{sub {tau}}) =(1.4{plus_minus}0.6{plus_minus}0.3){times}10{sup {minus}4} . We observe clear evidence for f{sub 1}{r_arrow}{eta}{pi}{pi} substructure and measure B({tau}{sup {minus}}{r_arrow}f{sub 1}{pi}{sup {minus}}{nu}{sub {tau}})=(5.8{sup +1.4 }{sub {minus}1.3}{plus_minus}1.8){times}10{sup {minus}4} . We have also searched for {eta}{sup {prime}}(958) production and obtain 90{percent} C.L.upper limits B({tau}{sup {minus}}{r_arrow}{pi}{sup {minus}} {eta}{sup {prime}}{nu}{sub {tau}}){lt} 7.4{times}10{sup {minus}5} and B({tau}{sup {minus}}{r_arrow}{pi}{sup {minus}} {pi}{sup 0}{eta}{sup {prime}}{nu}{sub {tau} }){lt}8.0{times}10{sup {minus}5} . {copyright} {ital 1997} {ital The American Physical Society}

Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease.

Directory of Open Access Journals (Sweden)

Yazi D Ke

Full Text Available Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD and frontotemporal lobar degeneration (FTLD. Here, we performed an unbiased SAGE (serial analysis of gene expression of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD, and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

Mouse and Human Models for Investigating Influences of Tau on Progression of Alzheimer’s Disease Following Traumatic Neuronal Injury

Science.gov (United States)

2017-10-01

injury ( top ) or post-injury (bottom). Note differences in spacing and geometry of puncta. 4. Observed differences in amyloid and phosphor-tau...injury, Abeta increases were amplified, and P-tau and P-tau/tau increases were observed. Fig 4. Levels of secreted Ab (A) and intracellular total...Levels of secreted Ab40 (left graph), Ab42 (middle graph) at time =0, 24, 48, 72 hr, and intracellular total tau and P- tau (right graphs) at 72h

Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport.

Directory of Open Access Journals (Sweden)

Michelle H Le

Full Text Available Stress exposure or increased levels of corticotropin-releasing factor (CRF induce hippocampal tau phosphorylation (tau-P in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1. Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD, the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr and chronic (2hr CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF, this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD.

Studies for reconstruction efficiency and background measurements of {tau} lepton identification in Z {yields} {tau}{tau} decays in data of the ATLAS experiment; Studien zur Messung von Rekonstruktionseffizienz und Untergrund der {tau}-Lepton-Identifikation im Zerfall Z {yields} {tau}{tau} beim ATLAS-Experiment aus Daten

Energy Technology Data Exchange (ETDEWEB)

Johnert, Sebastian

2008-11-15

In this diploma thesis two methods are presented, by which {tau} leptons shall be studied in the future data of the ATLAS experiment. The first part is formed by the determination of misidentification rates of jets from QCD 2-jet events as {tau} particles. The second part is the development of a method for the determination of the {tau} reconstruction and identification efficiency relatively to the {mu} efficiency. In this connection invariant masses from Z{yields}ll events are determined, the masses from Z{yields}{tau}{tau} events compared with those from Z{yields}ee and Z{yields}{mu}{mu}, {tau} efficiencies averaged over all ranges and in different {eta} ranges calculated as well as a mehtod for the determination of {tau} efficiencies in different transverse-momentum ranges presented. Furthermore an improved estimation of the QCD background is performed and the behaviour of the {tau} efficiency under regardment of the trigger studied. [German] In dieser Diplomarbeit werden zwei Methoden vorgestellt, mit denen {tau}-Leptonen in den zukuenftigen Daten des ATLAS-Experiments untersucht werden sollen. Den ersten Teil bildet die Bestimmung von Missidentifikationsraten von Jets aus QCD-2-Jet-Ereignissen als {tau}-Leptonen. Der zweite Teil ist die Entwicklung einer Methode zur Bestimmung der {tau}-Rekonstruktions und -Identifikationseffizienz relativ zur {mu}-Effizienz. In diesem Zusammenhang werden invariante Massen aus Z {yields} ll-Ereignissen bestimmt, die Massen aus Z {yields} {tau}{tau}-Ereignissen mit denen aus Z {yields} ee und Z {yields} {mu}{mu} verglichen, {tau}-Effizienzen gemittelt ueber alle Bereiche und in verschiedenen {eta}-Bereichen berechnet sowie eine Moeglichkeit zur Bestimmung von {tau}-Effizienzen in unterschiedlichen Transversalimpulsbereichen vorgestellt. Des Weiteren wird eine verbesserte Abschaetzung des QCD-Untergrunds vorgenommen und das Verhalten der {tau}-Effizienz unter Beruecksichtigung des Triggers untersucht. (orig.)

Increased infectivity of anchorless mouse scrapie prions in transgenic mice overexpressing human prion protein.

Science.gov (United States)

Race, Brent; Phillips, Katie; Meade-White, Kimberly; Striebel, James; Chesebro, Bruce

2015-06-01

Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal. Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by

Mutagenicity of ultraviolet A radiation in the lacI transgene in Big Blue mouse embryonic fibroblasts

International Nuclear Information System (INIS)

Kim, Sang-in; Pfeifer, Gerd P.; Besaratinia, Ahmad

2007-01-01

Sunlight ultraviolet A (UVA) irradiation has been implicated in the etiology of human skin cancer. A genotoxic mode of action for UVA radiation has been suggested that involves photosensitization reactions giving rise to promutagenic DNA lesions. We investigated the mutagenicity of UVA in the lacI transgene in Big Blue mouse embryonic fibroblasts. UVA irradiation of these cells at a physiologically relevant dose of 18 J/cm 2 caused a 2.8-fold increase in the lacI mutant frequency relative to control, i.e., 12.12 ± 1.84 versus 4.39 ± 1.99 x 10 -5 (mean ± S.D.). DNA sequencing analysis showed that of 100 UVA-induced mutant plaques and 54 spontaneously arisen control plaques, 97 and 51, respectively, contained a minimum of one mutation along the lacI transgene. The vast majority of both induced- and spontaneous mutations were single base substitutions, although less frequently, there were also single and multiple base deletions and insertions, and tandem base substitutions. Detailed mutation spectrometry analysis revealed that G:C → T:A transversions, the signature mutations of oxidative DNA damage, were significantly induced by UVA irradiation (P -5 ; P < 0.00001). These findings are in complete agreement with those previously observed in the cII transgene of the same model system, and reaffirm the notion that intracellular photosensitization reactions causing promutagenic oxidative DNA damage are involved in UVA genotoxicity

Serum β-amyloid peptide levels spike in the early stage of Alzheimer-like plaque pathology in an APP/PS1 double transgenic mouse model.

Science.gov (United States)

He, Jue; Qiao, Jin-Ping; Zhu, Shenghua; Xue, Mengzhou; Chen, Wenwu; Wang, Xinchun; Tempier, Adrien; Huang, Qingjun; Kong, Jiming; Li, Xin-Min

2013-11-01

Serum levels of β-amyloid (Aβ) peptides may represent an early biomarker in the diagnosis of Alzheimer's disease (AD). In the present study, we investigated the temporal kinetic changes in the levels of serum Aβ 1-42 and 40 in an amyloid precursor protein (APP)/presenilin (PS)1 double transgenic mouse model of AD. Serum Aβ peptide levels in 2-, 3-, 6-, 9- and 18-month old, and liver Aβ 1-40 level in 6-month old mice were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results revealed that serum Aβ levels peaked in 3-month old transgenic mice, and the Aβ level in non-transgenic and transgenic mice is comparable in liver. Compared to the 6-month old transgenic mice, Congo red staining showed that the 3-month old transgenic mice had minimum brain Aβ plaques, corresponding to the early stage of Alzheimer-like plaque pathology, and confocal microscope images showed that the deposition of Aβ in their cerebral vessels was minimal. Furthermore, results of the water maze test, showed that memory was normal for the 3- month old transgenic mice when compared to age-matched non-transgenic mice. These results suggest that serum Aβ peptide levels may be peaked during the early stage of AD. Monitoring serum Aβ peptide levels in the potential AD population may provide an early diagnosis of AD prior to the appearance of clinical symptoms.

Determination of the {tau}-lepton reconstruction and identification efficiency using Z {yields} {tau}{tau} events in first data at ATLAS

Energy Technology Data Exchange (ETDEWEB)

Fischer, Gordon

2011-10-15

The Large Hadron Collider (LHC) at CERN started operation in November 2009. At the same time the ATLAS experiment started data taking. Since this time a large number of Z-bosons is produced. An important decay channel of the Z-boson is the decay into two {tau} -leptons. The large mass of the {tau}-lepton allows the decay into pions or kaons. In many models considering new physics the {tau}-lepton is an important final state. The LHC is a proton-proton collider and for that reason, the hadronic {tau}-lepton decay is difficult to distinguish from QCD multi-jet background. For the selection of hadronically decaying {tau}-leptons, reconstruction and identification algorithms were developed in order to suppress this background. In order to measure the Z-boson production cross section or possible new particles decaying into {tau}-leptons, the estimation of the {tau}-lepton reconstruction and identification efficiency is required. Furthermore, for detector calibration the Z-boson as well as the {tau}-lepton are helpful probes. In this thesis two methods are discussed which provide an estimation of {tau}-lepton reconstruction and identification efficiencies from data. The full selection of Z {yields} {tau}{tau} events including data-driven techniques for background extraction is discussed. The semi-leptonic Z {yields} {tau}{tau} channel promises a good QCD multi-jet suppression because of the selected additional lepton. For that reason also the leptonically decaying {tau}-lepton is discussed. The Z-boson production cross section can be calculated with the estimated efficiencies. (orig.)

Targeting NADPH oxidase decreases oxidative stress in the transgenic sickle cell mouse penis.

Science.gov (United States)

Musicki, Biljana; Liu, Tongyun; Sezen, Sena F; Burnett, Arthur L

2012-08-01

Sickle cell disease (SCD) is a state of chronic vasculopathy characterized by endothelial dysfunction and increased oxidative stress, but the sources and mechanisms responsible for reactive oxygen species (ROS) production in the penis are unknown. We evaluated whether SCD activates NADPH oxidase, induces endothelial nitric oxide synthase (eNOS) uncoupling, and decreases antioxidants in the SCD mouse penis. We further tested the hypothesis that targeting NADPH oxidase decreases oxidative stress in the SCD mouse penis. SCD transgenic (sickle) mice were used as an animal model of SCD. Hemizygous (hemi) mice served as controls. Mice received an NADPH oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Penes were excised at baseline for molecular studies. Markers of oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NADPH oxidase subunits p67(phox) , p47(phox) , and gp91(phox) ), and enzymatic antioxidants (superoxide dismutase [SOD]1, SOD2, catalase, and glutathione peroxidase-1 [GPx1]) were measured by Western blot in penes. Sources of ROS, oxidative stress, and enzymatic antioxidants in the SCD penis. Relative to hemi mice, SCD increased (Ppenis. Apocynin treatment of sickle mice reversed (P0.05) prevented eNOS uncoupling in the penis. Apocynin treatment of hemi mice did not affect any of these parameters. NADPH oxidase and eNOS uncoupling are sources of oxidative stress in the SCD penis; decreased GPx1 further contributes to oxidative stress. Inhibition of NADPH oxidase upregulation decreases oxidative stress, implying a major role for NADPH oxidase as a ROS source and a potential target for improving vascular function in the SCD mouse penis. © 2012 International Society for Sexual Medicine.

Search for neutrinoless {tau} decays: {tau}{r_arrow}e{gamma} and {tau}{r_arrow}{mu}{gamma}

Energy Technology Data Exchange (ETDEWEB)

Edwards, K.W. [Carleton University, Ottawa, Ontario, K1S 5B6 (CANADA); Bellerive, A.; Janicek, R.; MacFarlane, D.B.; McLean, K.W.; Patel, P.M. [McGill University, Montreal, Quebec, H3A 2T8 (CANADA); Sadoff, A.J. [Ithaca College, Ithaca, New York 14850 (United States); Ammar, R.; Baringer, P.; Bean, A.; Besson, D.; Coppage, D.; Darling, C.; Davis, R.; Hancock, N.; Kotov, S.; Kravchenko, I.; Kwak, N. [University of Kansas, Lawrence, Kansas 66045 (United States); Anderson, S.; Kubota, Y.; Lattery, M.; ONeill, J.J.; Patton, S.; Poling, R.; Riehle, T.; Savinov, V.; Smith, A. [University of Minnesota, Minneapolis, Minnesota 55455 (United States); Alam, M.S.; Athar, S.B.; Ling, Z.; Mahmood, A.H.; Severini, H.; Timm, S.; Wappler, F. [State University of New York at Albany, Albany, New York 12222 (United States); Anastassov, A.; Blinov, S.; Duboscq, J.E.; Fujino, D.; Fulton, R.; Gan, K.K.; Hart, T.; Honscheid, K.; Kagan, H.; Kass, R.; Lee, J.; Spencer, M.B.; Sung, M.; Undrus, A.; Wanke, R.; Wolf, A.; Zoeller, M.M. [Ohio State University, Columbus, Ohio 43210 (United States); Nemati, B.; Richichi, S.J.; Ross, W.R.; Skubic, P.; Wood, M. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Bishai, M.; Fast, J.; Gerndt, E.; Hinson, J.W.; Menon, N.; Miller, D.H.; Shibata, E.I.; Shipsey, I.P.; Yurko, M. [Purdue University, West Lafayette, Indiana 47907 (United States); Gibbons, L.; Johnson, S.D.; Kwon, Y.; Roberts, S.; Thorndike, E.H. [University of Rochester, Rochester, New York 14627 (United States); Jessop, C.P.; Lingel, K.; Marsiske, H.; Perl, M.L.; Schaffner, S.F.; Ugolini, D.; Wang, R.; Zhou, X. [Stanford Linear Accelerator Center, Stanford University, Stanford, California 94309 (United States); Coan, T.E.; Fadeyev, V.; Korolkov, I.; Maravin, Y.; Narsky, I.; Shelkov, V.; Staeck, J.; Stroynowski, R.; Volobouev, I.; Ye, J. [Southern Methodist University, Dallas, Texas 75275 (United States); Artuso, M.; Efimov, A.; Frasconi, F.; Gao, M.

1997-04-01

A search for the lepton-family-number-violating decays {tau}{r_arrow}e{gamma} and {tau}{r_arrow}{mu}{gamma} has been performed using CLEO II data. No evidence of a signal has been found and the corresponding upper limits are B({tau}{r_arrow}e{gamma}){lt}2.7{times}10{sup {minus}6} and B({tau}{r_arrow}{mu}{gamma}){lt}3.0{times}10{sup {minus}6} at 90{percent} C.L. {copyright} {ital 1997} {ital The American Physical Society}

Tau hadronic branching ratios

CERN Document Server

Buskulic, Damir; De Bonis, I; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Odier, P; Pietrzyk, B; Ariztizabal, F; Chmeissani, M; Crespo, J M; Efthymiopoulos, I; Fernández, E; Fernández-Bosman, M; Gaitan, V; Martínez, M; Orteu, S; Pacheco, A; Padilla, C; Palla, Fabrizio; Pascual, A; Perlas, J A; Sánchez, F; Teubert, F; Colaleo, A; Creanza, D; De Palma, M; Farilla, A; Gelao, G; Girone, M; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Natali, S; Nuzzo, S; Ranieri, A; Raso, G; Romano, F; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Bonvicini, G; Cattaneo, M; Comas, P; Coyle, P; Drevermann, H; Engelhardt, A; Forty, Roger W; Frank, M; Hagelberg, R; Harvey, J; Jacobsen, R; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Markou, C; Martin, E B; Mato, P; Minten, Adolf G; Miquel, R; Oest, T; Palazzi, P; Pater, J R; Pusztaszeri, J F; Ranjard, F; Rensing, P E; Rolandi, Luigi; Schlatter, W D; Schmelling, M; Schneider, O; Tejessy, W; Tomalin, I R; Venturi, A; Wachsmuth, H W; Wiedenmann, W; Wildish, T; Witzeling, W; Wotschack, J; Ajaltouni, Ziad J; Bardadin-Otwinowska, Maria; Barrès, A; Boyer, C; Falvard, A; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rossignol, J M; Saadi, F; Fearnley, Tom; Hansen, J B; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Kyriakis, A; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Zachariadou, K; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Passalacqua, L; Rougé, A; Rumpf, M; Tanaka, R; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Focardi, E; Parrini, G; Corden, M; Delfino, M C; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Pepé-Altarelli, M; Dorris, S J; Halley, A W; ten Have, I; Knowles, I G; Lynch, J G; Morton, W T; O'Shea, V; Raine, C; Reeves, P; Scarr, J M; Smith, K; Smith, M G; Thompson, A S; Thomson, F; Thorn, S; Turnbull, R M; Becker, U; Braun, O; Geweniger, C; Graefe, G; Hanke, P; Hepp, V; Kluge, E E; Putzer, A; Rensch, B; Schmidt, M; Sommer, J; Stenzel, H; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Colling, D J; Dornan, Peter J; Konstantinidis, N P; Moneta, L; Moutoussi, A; Nash, J; San Martin, G; Sedgbeer, J K; Stacey, A M; Dissertori, G; Girtler, P; Kuhn, D; Rudolph, G; Bowdery, C K; Brodbeck, T J; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Sloan, Terence; Whelan, E P; Williams, M I; Galla, A; Greene, A M; Kleinknecht, K; Quast, G; Raab, J; Renk, B; Sander, H G; Wanke, R; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Bencheikh, A M; Benchouk, C; Bonissent, A; Bujosa, G; Calvet, D; Carr, J; Diaconu, C A; Etienne, F; Thulasidas, M; Nicod, D; Payre, P; Rousseau, D; Talby, M; Abt, I; Assmann, R W; Bauer, C; Blum, Walter; Brown, D; Dietl, H; Dydak, Friedrich; Ganis, G; Gotzhein, C; Jakobs, K; Kroha, H; Lütjens, G; Lutz, Gerhard; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Saint-Denis, R; Wolf, G; Alemany, R; Boucrot, J; Callot, O; Cordier, A; Courault, F; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Jacquet, M; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Musolino, G; Nikolic, I A; Park, H J; Park, I C; Schune, M H; Simion, S; Veillet, J J; Videau, I; Abbaneo, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Rizzo, G; Sanguinetti, G; Sciabà, A; Spagnolo, P; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Triggiani, G; Vannini, C; Verdini, P G; Walsh, J; Betteridge, A P; Blair, G A; Bryant, L M; Cerutti, F; Gao, Y; Green, M G; Johnson, D L; Medcalf, T; Mir, L M; Perrodo, P; Strong, J A; Bertin, V; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Edwards, M; Maley, P; Norton, P R; Thompson, J C; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Marx, B; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Johnson, R P; Kim, H Y; Litke, A M; McNeil, M A; Taylor, G; Beddall, A; Booth, C N; Boswell, R; Cartwright, S L; Combley, F; Dawson, I; Köksal, A; Letho, M; Newton, W M; Rankin, C; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Feigl, E; Grupen, Claus; Lutters, G; Minguet-Rodríguez, J A; Rivera, F; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Ragusa, F; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Bellantoni, L; Elmer, P; Feng, Z; Ferguson, D P S; Gao, Y S; González, S; Grahl, J; Harton, J L; Hayes, O J; Hu, H; McNamara, P A; Nachtman, J M; Orejudos, W; Pan, Y B; Saadi, Y; Schmitt, M; Scott, I J; Sharma, V; Turk, J; Walsh, A M; Wu Sau Lan; Wu, X; Yamartino, J M; Zheng, M; Zobernig, G

1996-01-01

From 64492 selected \\tau-pair events, produced at the Z^0 resonance, the measurement of the tau decays into hadrons from a global analysis using 1991, 1992 and 1993 ALEPH data is presented. Special emphasis is given to the reconstruction of photons and \\pi^0's, and the removal of fake photons. A detailed study of the systematics entering the \\pi^0 reconstruction is also given. A complete and consistent set of tau hadronic branching ratios is presented for 18 exclusive modes. Most measurements are more precise than the present world average. The new level of precision reached allows a stringent test of \\tau-\\mu universality in hadronic decays, g_\\tau/g_\\mu \\ = \\ 1.0013 \\ \\pm \\ 0.0095, and the first measurement of the vector and axial-vector contributions to the non-strange hadronic \\tau decay width: R_{\\tau ,V} \\ = \\ 1.788 \\ \\pm \\ 0.025 and R_{\\tau ,A} \\ = \\ 1.694 \\ \\pm \\ 0.027. The ratio (R_{\\tau ,V} - R_{\\tau ,A}) / (R_{\\tau ,V} + R_{\\tau ,A}), equal to (2.7 \\pm 1.3) \\ \\%, is a measure of the importance of Q...

Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a Gaucher mutation.

Science.gov (United States)

Fishbein, Ianai; Kuo, Yien-Ming; Giasson, Benoit I; Nussbaum, Robert L

2014-12-01

The involvement of the protein α-synuclein (SNCA) in the pathogenesis of Parkinson's disease is strongly supported by the facts that (i) missense and copy number mutations in the SNCA gene can cause inherited Parkinson's disease; and (ii) Lewy bodies in sporadic Parkinson's disease are largely composed of aggregated SNCA. Unaffected heterozygous carriers of Gaucher disease mutations have an increased risk for Parkinson's disease. As mutations in the GBA gene encoding glucocerebrosidase (GBA) are known to interfere with lysosomal protein degradation, GBA heterozygotes may demonstrate reduced lysosomal SNCA degradation, leading to increased steady-state SNCA levels and promoting its aggregation. We have created mouse models to investigate the interaction between GBA mutations and synucleinopathies. We investigated the rate of SNCA degradation in cultured primary cortical neurons from mice expressing wild-type mouse SNCA, wild-type human SNCA, or mutant A53T SNCA, in a background of either wild-type Gba or heterozygosity for the L444P GBA mutation associated with Gaucher disease. We also tested the effect of this Gaucher mutation on motor and enteric nervous system function in these transgenic animals. We found that human SNCA is stable, with a half-life of 61 h, and that the A53T mutation did not significantly affect its half-life. Heterozygosity for a naturally occurring Gaucher mutation, L444P, reduced GBA activity by 40%, reduced SNCA degradation and triggered accumulation of the protein in culture. This mutation also resulted in the exacerbation of motor and gastrointestinal deficits found in the A53T mouse model of Parkinson's disease. This study demonstrates that heterozygosity for a Gaucher disease-associated mutation in Gba interferes with SNCA degradation and contributes to its accumulation, and exacerbates the phenotype in a mouse model of Parkinson's disease. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain

Radio-deoxynucleoside Analogs used for Imaging tk Expression in a Transgenic Mouse Model of Induced Hepatocellular Carcinoma

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Haibin Tian, Xincheng Lu, Hong Guo, David Corn, Joseph Molter, Bingcheng Wang, Guangbin Luo, Zhenghong Lee

2012-01-01

Full Text Available Purpose: A group of radiolabeled thymidine analogs were developed as radio-tracers for imaging herpes viral thymidine kinase (HSV1-tk or its variants used as reporter gene. A transgenic mouse model was created to express tk upon liver injury or naturally occurring hepatocellular carcinoma (HCC. The purpose of this study was to use this unique animal model for initial testing with radio-labeled thymidine analogs, mainly a pair of newly emerging nucleoside analogs, D-FMAU and L-FMAU.Methods: A transgeneic mouse model was created by putting a fused reporter gene system, firefly luciferase (luc and HSV1-tk, under the control of mouse alpha fetoprotein (Afp promoter. Initial multimodal imaging, which was consisted of bioluminescent imaging (BLI and planar gamma scintigraphy with [125I]-FIAU, was used for examining the model creation in the new born and liver injury in the adult mice. Carcinogen diethylnitrosamine (DEN was then administrated to induce HCC in these knock-in mice such that microPET imaging could be used to track the activity of Afp promoter during tumor development and progression by imaging tk expression first with [18F]-FHBG. Dynamic PET scans with D-[18F]-FMAU and L-[18F]-FMAU were then performed to evaluate this pair of relatively new tracers. Cells were derived from these liver tumors for uptake assays using H-3 labeled version of PET tracers.Results: The mouse model with dual reporters: HSV1-tk and luc placed under the transcriptional control of an endogenous Afp promoter was used for imaging studies. The expression of the Afp gene was highly specific in proliferative hepatocytes, in regenerative liver, and in developing fetal liver, and thus provided an excellent indicator for liver injury and cancer development in adult mice. Both D-FMAU and L-FMAU showed stable liver tumor uptake where the tk gene was expressed under the Afp promoter. The performance of this pair of tracers was slightly different in terms of signal

Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer.

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Shih Ping Yao

2002-04-01

Full Text Available Abstract Background Transgenic animals have become valuable tools for both research and applied purposes. The current method of gene transfer, microinjection, which is widely used in transgenic mouse production, has only had limited success in producing transgenic animals of larger or higher species. Here, we report a linker based sperm-mediated gene transfer method (LB-SMGT that greatly improves the production efficiency of large transgenic animals. Results The linker protein, a monoclonal antibody (mAb C, is reactive to a surface antigen on sperm of all tested species including pig, mouse, chicken, cow, goat, sheep, and human. mAb C is a basic protein that binds to DNA through ionic interaction allowing exogenous DNA to be linked specifically to sperm. After fertilization of the egg, the DNA is shown to be successfully integrated into the genome of viable pig and mouse offspring with germ-line transfer to the F1 generation at a highly efficient rate: 37.5% of pigs and 33% of mice. The integration is demonstrated again by FISH analysis and F2 transmission in pigs. Furthermore, expression of the transgene is demonstrated in 61% (35/57 of transgenic pigs (F0 generation. Conclusions Our data suggests that LB-SMGT could be used to generate transgenic animals efficiently in many different species.

Actin Nemaline Myopathy Mouse Reproduces Disease, Suggests Other Actin Disease Phenotypes and Provides Cautionary Note on Muscle Transgene Expression

Science.gov (United States)

Ravenscroft, Gianina; Jackaman, Connie; Sewry, Caroline A.; McNamara, Elyshia; Squire, Sarah E.; Potter, Allyson C.; Papadimitriou, John; Griffiths, Lisa M.; Bakker, Anthony J.; Davies, Kay E.; Laing, Nigel G.; Nowak, Kristen J.

2011-01-01

Mutations in the skeletal muscle α-actin gene (ACTA1) cause congenital myopathies including nemaline myopathy, actin aggregate myopathy and rod-core disease. The majority of patients with ACTA1 mutations have severe hypotonia and do not survive beyond the age of one. A transgenic mouse model was generated expressing an autosomal dominant mutant (D286G) of ACTA1 (identified in a severe nemaline myopathy patient) fused with EGFP. Nemaline bodies were observed in multiple skeletal muscles, with serial sections showing these correlated to aggregates of the mutant skeletal muscle α-actin-EGFP. Isolated extensor digitorum longus and soleus muscles were significantly weaker than wild-type (WT) muscle at 4 weeks of age, coinciding with the peak in structural lesions. These 4 week-old mice were ∼30% less active on voluntary running wheels than WT mice. The α-actin-EGFP protein clearly demonstrated that the transgene was expressed equally in all myosin heavy chain (MHC) fibre types during the early postnatal period, but subsequently became largely confined to MHCIIB fibres. Ringbinden fibres, internal nuclei and myofibrillar myopathy pathologies, not typical features in nemaline myopathy or patients with ACTA1 mutations, were frequently observed. Ringbinden were found in fast fibre predominant muscles of adult mice and were exclusively MHCIIB-positive fibres. Thus, this mouse model presents a reliable model for the investigation of the pathobiology of nemaline body formation and muscle weakness and for evaluation of potential therapeutic interventions. The occurrence of core-like regions, internal nuclei and ringbinden will allow analysis of the mechanisms underlying these lesions. The occurrence of ringbinden and features of myofibrillar myopathy in this mouse model of ACTA1 disease suggests that patients with these pathologies and no genetic explanation should be screened for ACTA1 mutations. PMID:22174871

Characteristics of tau oligomers

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Yan eRen

2013-07-01

Full Text Available In Alzheimer disease (AD and other tauopathies, microtubule-associated protein tau becomes hyperphosphorylated, undergoes conformational changes, aggregates, eventually becoming neurofibrillary tangles (NFTs. As accumulating evidence suggests that NFTs themselves may not be toxic, attention is now turning toward the role of intermediate tau oligomers in AD pathophysiology. Sarkosyl extraction is a standard protocol for investigating insoluble tau aggregates in brains. There is a growing consensus that sarkosyl-insoluble tau correlates with the pathological features of tauopathy. While sarkosyl-insoluble tau from tauopathy brains has been well characterized as a pool of filamentous tau, other dimers, multimers, and granules of tau are much less well understood. There are protocols for identifying these tau oligomers. In this mini review, we discuss the characteristics of tau oligomers isolated via different methods and materials.

Tau leptons

Energy Technology Data Exchange (ETDEWEB)

Gan, K. K.

1992-12-15

Once an oddity, tau leptons are now being mass produced at electron-positron colliders, and tau physics is becoming daily life. This was reflected at the Second Workshop on Tau Lepton Physics, held at Ohio State University, September 8-11. This workshop was the sequel to the successful workshop organized by Michel Davier and Bernard Jean-Marie at Orsay in 1990.

Tau leptons

International Nuclear Information System (INIS)

Gan, K.K.

1992-01-01

Once an oddity, tau leptons are now being mass produced at electron-positron colliders, and tau physics is becoming daily life. This was reflected at the Second Workshop on Tau Lepton Physics, held at Ohio State University, September 8-11. This workshop was the sequel to the successful workshop organized by Michel Davier and Bernard Jean-Marie at Orsay in 1990

A novel transgenic mouse model of lysosomal storage disorder

OpenAIRE

Ortiz-Miranda, Sonia; Ji, Rui; Jurczyk, Agata; Aryee, Ken-Edwin; Mo, Shunyan; Fletcher, Terry; Shaffer, Scott A.; Greiner, Dale L.; Bortell, Rita; Gregg, Ronald G.; Cheng, Alan; Hennings, Leah J.; Rittenhouse, Ann R.

2016-01-01

We provide an explanation for striking pathology found in a subset of genetically engineered mice homozygous for a rat CaVβ2a transgene (Tg+/+). Multiple transgene (Tg) copies inserted into chromosome 19; at this same site a large deletion occurred, ablating cholesterol 25-hydroxylase and partially deleting lysosomal acid lipase and CD95. Their loss of function can account for lipid build up and immune system hypertrophy, which defines this phenotype and serendipitously provides a novel model...

Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro.

Science.gov (United States)

Pérez, Mar; Medina, Miguel; Hernández, Félix; Avila, Jesús

2018-03-05

The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasing evidence in recent years supports the notion that Tau pathology spreading throughout the brain in AD and other Tauopathies is the consequence of the propagation of specific Tau species along neuroanatomically connected brain regions in a so-called "prion-like" manner. A number of steps are assumed to be involved in this process, including secretion, cellular uptake, transcellular transfer and/or seeding, although the precise mechanisms underlying propagation of Tau pathology are not fully understood yet. This review summarizes recent evidence on the nature of the specific Tau species that are propagated and the different mechanisms of Tau pathology spreading.

Interferon-gamma (IFN-γ-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse.

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Shahid Husain

Full Text Available We have recently demonstrated the characterization of human tyrosinase TCR bearing h3T-A2 transgenic mouse model, which exhibits spontaneous autoimmune vitiligo and retinal dysfunction. The purpose of current study was to determine the role of T cells and IFN-γ in retina dysfunction and retinal ganglion cell (RGC death using this model. RGC function was measured by pattern electroretinograms (ERGs in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde-labeling. Expression of CD3, IFN-γ, GFAP, and caspases was measured by immunohistochemistry and Western blotting. All functional and structural changes were measured in 12-month-old h3T-A2 mice and compared with age-matched HLA-A2 wild-type mice. Both pattern-ERGs (42%, p = 0.03 and RGC numbers (37%, p = 0.0001 were reduced in h3T-A2 mice when compared with wild-type mice. The level of CD3 expression was increased in h3T-A2 mice (h3T-A2: 174 ± 27% vs. HLA-A2: 100%; p = 0.04. The levels of effector cytokine IFN-γ were also increased significantly in h3T-A2 mice (h3T-A2: 189 ± 11% vs. HLA-A2: 100%; p = 0.023. Both CD3 and IFN-γ immunostaining were increased in nerve fiber (NF and RGC layers of h3T-A2 mice. In addition, we have seen a robust increase in GFAP staining in h3T-A2 mice (mainly localized to NF layer, which was substantially reduced in IFN-γ ((-/- knockout h3T-A2 mice. We also have seen an up-regulation of caspase-3 and -9 in h3T-A2 mice. Based on our data we conclude that h3T-A2 transgenic mice exhibit visual defects that are mostly associated with the inner retinal layers and RGC function. This novel h3T-A2 transgenic mouse model provides opportunity to understand RGC pathology and test neuroprotective strategies to rescue RGCs.

Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

Directory of Open Access Journals (Sweden)

Henrik H Hansen

Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.

Science.gov (United States)

Booth, Clair A; Witton, Jonathan; Nowacki, Jakub; Tsaneva-Atanasova, Krasimira; Jones, Matthew W; Randall, Andrew D; Brown, Jonathan T

2016-01-13

The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention. Copyright © 2016 Booth, Witton et al.

Hyperphosphorylated tau in the brains of mice and monkeys with long-term administration of ketamine.

Science.gov (United States)

Yeung, L Y; Wai, Maria S M; Fan, Ming; Mak, Y T; Lam, W P; Li, Zhen; Lu, Gang; Yew, David T

2010-03-15

Ketamine, a non-competitive antagonist at the glutamatergic N-methyl-d-aspartate (NMDA) receptor, might impair memory function of the brain. Loss of memory is also a characteristic of aging and Alzheimer's disease. Hyperphosphorylation of tau is an early event in the aging process and Alzheimer's disease. Therefore, we aimed to find out whether long-term ketmaine administration is related to hyperphosphorylation of tau or not in the brains of mice and monkeys. Results showed that after 6 months' administration of ketamine, in the prefrontal and entorhinal cortical sections of mouse and monkey brains, there were significant increases of positive sites for the hyperphosphorylated tau protein as compared to the control animals receiving no ketamine administration. Furthermore, about 15% of hyperphosphorylated tau positive cells were also positively labeled by terminal dUTP nick end labeling (TUNEL) indicating there might be a relationship between hyperphosphorylation of tau and apoptosis. Therefore, the long-term ketamine toxicity might involve neurodegenerative process similar to that of aging and/or Alzheimer's disease. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Observation of W{yields} {tau}{nu}{sub {tau}} decays with the ATLAS experiment

Energy Technology Data Exchange (ETDEWEB)

Nunes Hanninger, Guilherme

2011-04-15

Physics studies of processes with {tau} leptons in the final state, while challenging at hadron colliders, are of great importance at the LHC. The {tau} leptons provide important signatures in searches for the Higgs boson as well as for new physics in a wide range of theoretical models. Decays of Standard Model particles to {tau} leptons, in particular Z {yields} {tau}{tau} and W {yields} {tau}{nu}{sub {tau}}, are important background processes in those searches and their cross sections need to be measured first. This thesis reports the first observation of W {yields} {tau}{nu}{sub {tau}} decays and of hadronically decaying {tau} leptons with the ATLAS experiment at the LHC. The analysis is based on a data sample corresponding to an integrated luminosity of 546 nb{sup -1}, which was recorded at a proton-proton centre-of-mass energy of 7TeV. A total of 78 data events are selected, with an estimated background of 11.1 {+-} 2.3{sub (stat.)} {+-} 3.2{sub (syst.)} events from QCD processes, and of 11.8 {+-} 0.4{sub (stat.)} {+-} 3.7{sub (syst.)} events from other W and Z decays. The observed excess of data events over the total background is compatible with the SM expectation for W {yields} {tau}{nu}{sub {tau}} decays, both in the number of events and in the shapes of distributions of characteristic variables. (orig.)

A transgenic mouse model for trilateral retinoblastoma

NARCIS (Netherlands)

O'Brien, J.M.; Marcus, D.M.; Bernards, R.A.; Carpenter, J.L.; Windle, J.J.; Mellon, P.; Albert, D.M.

1990-01-01

We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically

Upper limits on the branching ratios $\\tau$ --> $\\mu\\gamma$ and $\\tau$ --> e$\\gamma$

CERN Document Server

Abreu, P; Adye, T; Agasi, E; Ajinenko, I; Aleksan, Roy; Alekseev, G D; Allport, P P; Almehed, S; Alvsvaag, S J; Amaldi, Ugo; Amato, S; Andreazza, A; Andrieux, M L; Antilogus, P; Apel, W D; Arnoud, Y; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Bambade, P; Barão, F; Barate, R; Barbiellini, Guido; Bardin, Dimitri Yuri; Barker, G J; Baroncelli, A; Bärring, O; Barrio, J A; Bartl, Walter; Bates, M J; Battaglia, Marco; Baubillier, M; Baudot, J; Becks, K H; Begalli, M; Beillière, P; Belokopytov, Yu A; Benvenuti, Alberto C; Berggren, M; Bertrand, D; Bianchi, F; Bigi, M; Bilenky, S M; Billoir, P; Bloch, D; Blume, M; Blyth, S; Bocci, V; Bolognese, T; Bonesini, M; Bonivento, W; Booth, P S L; Borisov, G; Bosio, C; Bosworth, S; Botner, O; Boudinov, E; Bouquet, B; Bourdarios, C; Bowcock, T J V; Bozzo, M; Branchini, P; Brand, K D; Brenke, T; Brenner, R A; Bricman, C; Brillault, L; Brown, R C A; Brückman, P; Brunet, J M; Bugge, L; Buran, T; Burgsmüller, T; Buschmann, P; Buys, A; Caccia, M; Calvi, M; Camacho-Rozas, A J; Camporesi, T; Canale, V; Canepa, M; Cankocak, K; Cao, F; Carena, F; Carrilho, P; Carroll, L; Caso, Carlo; Castillo-Gimenez, M V; Cattai, A; Cavallo, F R; Cerrito, L; Chabaud, V; Chapkin, M M; Charpentier, P; Chaussard, L; Chauveau, J; Checchia, P; Chelkov, G A; Chierici, R; Chliapnikov, P V; Chochula, P; Chorowicz, V; Cindro, V; Collins, P; Contreras, J L; Contri, R; Cortina, E; Cosme, G; Cossutti, F; Crawley, H B; Crennell, D J; Crosetti, G; Cuevas-Maestro, J; Czellar, S; Dahl-Jensen, Erik; Dahm, J; D'Almagne, B; Dam, M; Damgaard, G; Daum, A; Dauncey, P D; Davenport, Martyn; Da Silva, W; Defoix, C; Della Ricca, G; Delpierre, P A; Demaria, N; De Angelis, A; De Boeck, H; de Boer, Wim; De Brabandere, S; De Clercq, C; La Vaissière, C de; De Lotto, B; De Min, A; De Paula, L S; De Saint-Jean, C; Dijkstra, H; Di Ciaccio, Lucia; Djama, F; Dolbeau, J; Dönszelmann, M; Doroba, K; Dracos, M; Drees, J; Drees, K A; Dris, M; Dufour, Y; Dupont, F; Edsall, D M; Ehret, R; Eigen, G; Ekelöf, T J C; Ekspong, Gösta; Elsing, M; Engel, J P; Ershaidat, N; Erzen, B; Espirito-Santo, M C; Falk, E; Fassouliotis, D; Feindt, Michael; Ferrer, A; Filippas-Tassos, A; Firestone, A; Fischer, P A; Föth, H; Fokitis, E; Fontanelli, F; Formenti, F; Franek, B J; Frenkiel, P; Fries, D E C; Frodesen, A G; Frühwirth, R; Fulda-Quenzer, F; Fuster, J A; Galloni, A; Gamba, D; Gandelman, M; García, C; García, J; Gaspar, C; Gasparini, U; Gavillet, P; Gazis, E N; Gelé, D; Gerber, J P; Gibbs, M; Gokieli, R; Golob, B; Gopal, Gian P; Gorn, L; Górski, M; Guz, Yu; Gracco, Valerio; Graziani, E; Grosdidier, G; Gunnarsson, P; Günther, M; Guy, J; Haedinger, U; Hahn, F; Hahn, M; Hahn, S; Hajduk, Z; Hallgren, A; Hamacher, K; Hao, W; Harris, F J; Hedberg, V; Henriques, R P; Hernández, J J; Herquet, P; Herr, H; Hessing, T L; Higón, E; Hilke, Hans Jürgen; Hill, T S; Holmgren, S O; Holt, P J; Holthuizen, D J; Houlden, M A; Hrubec, Josef; Huet, K; Hultqvist, K; Ioannou, P; Jackson, J N; Jacobsson, R; Jalocha, P; Janik, R; Jarlskog, G; Jarry, P; Jean-Marie, B; Johansson, E K; Jönsson, L B; Jönsson, P E; Joram, Christian; Juillot, P; Kaiser, M; Kapusta, F; Karlsson, M; Karvelas, E; Katsanevas, S; Katsoufis, E C; Keränen, R; Khomenko, B A; Khovanskii, N N; King, B J; Kjaer, N J; Klein, H; Klovning, A; Kluit, P M; Köhne, J H; Köne, B; Kokkinias, P; Koratzinos, M; Kostyukhin, V; Kourkoumelis, C; Kuznetsov, O; Kramer, P H; Krammer, Manfred; Kreuter, C; Królikowski, J; Kronkvist, I J; Krumshtein, Z; Krupinski, W; Kubinec, P; Kucewicz, W; Kurvinen, K L; Lacasta, C; Laktineh, I; Lamblot, S; Lamsa, J; Lanceri, L; Lane, D W; Langefeld, P; Lapin, V; Last, I; Laugier, J P; Lauhakangas, R; Ledroit, F; Lefébure, V; Legan, C K; Leitner, R; Lemoigne, Y; Lemonne, J; Lenzen, Georg; Lepeltier, V; Lesiak, T; Liko, D; Lindner, R; Lipniacka, A; Lippi, I; Lörstad, B; Lokajícek, M; Loken, J G; López, J M; López-Fernandez, A; López-Aguera, M A; Loukas, D; Lutz, P; Lyons, L; MacNaughton, J N; Maehlum, G; Maio, A; Malychev, V; Mandl, F; Marco, J; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Maron, T; Martínez-Rivero, C; Martínez-Vidal, F; Martí i García, S; Marvik, K; Matorras, F; Matteuzzi, C; Matthiae, Giorgio; Mazzucato, M; McCubbin, M L; McKay, R; McNulty, R; Medbo, J; Meroni, C; Meyer, W T; Michelotto, M; Migliore, E; Mirabito, L; Mitaroff, Winfried A; Mjörnmark, U; Moa, T; Møller, R; Mönig, K; Monge, M R; Morettini, P; Müller, H; Mundim, L M; Murray, W J; Muryn, B; Myatt, Gerald; Naraghi, F; Navarria, Francesco Luigi; Navas, S; Negri, P; Némécek, S; Neumann, W; Neumeister, N; Nicolaidou, R; Nielsen, B S; Nieuwenhuizen, M; Nikolaenko, V; Niss, P; Nomerotski, A; Normand, Ainsley; Oberschulte-Beckmann, W; Obraztsov, V F; Olshevskii, A G; Orava, Risto; Österberg, K; Ouraou, A; Paganini, P; Paganoni, M; Pagès, P; Palka, H; Papadopoulou, T D; Pape, L; Parkes, C; Parodi, F; Passeri, A; Pegoraro, M; Peralta, L; Pernegger, H; Pernicka, Manfred; Perrotta, A; Petridou, C; Petrolini, A; Phillips, H T; Piana, G; Pierre, F; Pimenta, M; Pindo, M; Plaszczynski, S; Podobrin, O; Pol, M E; Polok, G; Poropat, P; Pozdnyakov, V; Prest, M; Privitera, P; Pukhaeva, N; Pullia, Antonio; Radojicic, D; Ragazzi, S; Rahmani, H; Rames, J; Ratoff, P N; Read, A L; Reale, M; Rebecchi, P; Redaelli, N G; Regler, Meinhard; Reid, D; Renton, P B; Resvanis, L K; Richard, F; Richardson, J; Rídky, J; Rinaudo, G; Ripp, I; Romero, A; Roncagliolo, I; Ronchese, P; Roos, L; Rosenberg, E I; Rosso, E; Roudeau, Patrick; Rovelli, T; Rückstuhl, W; Ruhlmann-Kleider, V; Ruiz, A; Rybicki, K; Saarikko, H; Sacquin, Yu; Sadovskii, A; Sajot, G; Salt, J; Sánchez, J; Sannino, M; Schneider, H; Schyns, M A E; Sciolla, G; Scuri, F; Sedykh, Yu; Segar, A M; Seitz, A; Sekulin, R L; Shellard, R C; Siccama, I; Siegrist, P; Simonetti, S; Simonetto, F; Sissakian, A N; Sitár, B; Skaali, T B; Smadja, G; Smirnov, N; Smirnova, O G; Smith, G R; Sosnowski, R; Souza-Santos, D; Spassoff, Tz; Spiriti, E; Sponholz, P; Squarcia, S; Stanescu, C; Stapnes, Steinar; Stavitski, I; Stepaniak, K; Stichelbaut, F; Stocchi, A; Strauss, J; Strub, R; Stugu, B; Szczekowski, M; Szeptycka, M; Tabarelli de Fatis, T; Tavernet, J P; Chikilev, O G; Tilquin, A; Timmermans, J; Tkatchev, L G; Todorov, T; Toet, D Z; Tomaradze, A G; Tomé, B; Tortora, L; Tranströmer, G; Treille, D; Trischuk, W; Tristram, G; Trombini, A; Troncon, C; Tsirou, A L; Turluer, M L; Tyapkin, I A; Tyndel, M; Tzamarias, S; Überschär, B; Ullaland, O; Uvarov, V; Valenti, G; Vallazza, E; Van der Velde, C; van Apeldoorn, G W; van Dam, P; Van Doninck, W K; Van Eldik, J; Vassilopoulos, N; Vegni, G; Ventura, L; Venus, W A; Verbeure, F; Verlato, M; Vertogradov, L S; Vilanova, D; Vincent, P; Vitale, L; Vlasov, E; Vodopyanov, A S; Vrba, V; Wahlen, H; Walck, C; Weierstall, M; Weilhammer, Peter; Wetherell, Alan M; Wicke, D; Wickens, J H; Wielers, M; Wilkinson, G R; Williams, W S C; Winter, M; Witek, M; Woschnagg, K; Yip, K; Yushchenko, O P; Zach, F; Zacharatou-Jarlskog, C; Zaitsev, A; Zalewska-Bak, A; Zalewski, Piotr; Zavrtanik, D; Zevgolatakos, E; Zimin, N I; Zito, M; Zontar, D; Zuberi, R; Zucchelli, G C; Zumerle, G

1995-01-01

The DELPHI collaboration has searched for lepton flavour violating decays \\tau \\rightarrow \\mu \\gamma and \\tau \\rightarrow e \\gamma using a data sample of about 70~pb^{-1} of integrated luminosity corresponding to 81 000 produced \\tau^+ \\tau^- events. No candidates were found for either of the two modes. This yields branching ratio upper limits of \\rm{B}( \\tau \\rightarrow e \\gamma ) < 1.1 \\times 10^{-4} and \\rm{B} ( \\tau \\rightarrow \\mu \\gamma) < 6.2 \\times 10^{-5} at 90\\% confidence level.

In Vivo Imaging of Tau Pathology Using Magnetic Resonance Imaging Textural Analysis

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Niall Colgan

2017-11-01

Full Text Available Background: Non-invasive characterization of the pathological features of Alzheimer's disease (AD could enhance patient management and the development of therapeutic strategies. Magnetic resonance imaging texture analysis (MRTA has been used previously to extract texture descriptors from structural clinical scans in AD to determine cerebral tissue heterogeneity. In this study, we examined the potential of MRTA to specifically identify tau pathology in an AD mouse model and compared the MRTA metrics to histological measures of tau burden.Methods: MRTA was applied to T2 weighted high-resolution MR images of nine 8.5-month-old rTg4510 tau pathology (TG mice and 16 litter matched wild-type (WT mice. MRTA comprised of the filtration-histogram technique, where the filtration step extracted and enhanced features of different sizes (fine, medium, and coarse texture scales, followed by quantification of texture using histogram analysis (mean gray level intensity, mean intensity, entropy, uniformity, skewness, standard-deviation, and kurtosis. MRTA was applied to manually segmented regions of interest (ROI drawn within the cortex, hippocampus, and thalamus regions and the level of tau burden was assessed in equivalent regions using histology.Results: Texture parameters were markedly different between WT and TG in the cortex (E, p < 0.01, K, p < 0.01, the hippocampus (K, p < 0.05 and in the thalamus (K, p < 0.01. In addition, we observed significant correlations between histological measurements of tau burden and kurtosis in the cortex, hippocampus and thalamus.Conclusions: MRTA successfully differentiated WT and TG in brain regions with varying degrees of tau pathology (cortex, hippocampus, and thalamus based on T2 weighted MR images. Furthermore, the kurtosis measurement correlated with histological measures of tau burden. This initial study indicates that MRTA may have a role in the early diagnosis of AD and the assessment of tau pathology using

Beyond the tau: Other directions in tau physics

International Nuclear Information System (INIS)

Perl, M.L.

1992-12-01

This paper calls attention to four topics in tau lepton physics which are outside our present areas of tau physics research: τ + τ - atoms, τ - nucleus atoms, photoproduction of τ's, and heavy ion production of τ's

Tissue-specific in vivo genetic toxicity of nine polycyclic aromatic hydrocarbons assessed using the Muta™Mouse transgenic rodent assay

Energy Technology Data Exchange (ETDEWEB)

Long, Alexandra S., E-mail: alexandra.long@hc-sc.gc.ca [Faculty of Graduate and Postdoctoral Studies, Department of Biology, University of Ottawa, Ottawa, ON (Canada); Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON (Canada); Lemieux, Christine L. [Air Health Science Division, Water and Air Quality Bureau, Health Canada, Ottawa, ON (Canada); Arlt, Volker M. [Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment and Health, King' s College London, London (United Kingdom); White, Paul A. [Faculty of Graduate and Postdoctoral Studies, Department of Biology, University of Ottawa, Ottawa, ON (Canada); Mechanistic Studies Division, Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON (Canada)

2016-01-01

Test batteries to screen chemicals for mutagenic hazard include several endpoints regarded as effective for detecting genotoxic carcinogens. Traditional in vivo methods primarily examine clastogenic endpoints in haematopoietic tissues. Although this approach is effective for identifying systemically distributed clastogens, some mutagens may not induce clastogenic effects; moreover, genotoxic effects may be restricted to the site of contact and/or related tissues. An OECD test guideline for transgenic rodent (TGR) gene mutation assays was released in 2011, and the TGR assays permit assessment of mutagenicity in any tissue. This study assessed the responses of two genotoxicity endpoints following sub-chronic oral exposures of male Muta™Mouse to 9 carcinogenic polycyclic aromatic hydrocarbons (PAHs). Clastogenicity was assessed via induction of micronuclei in peripheral blood, and mutagenicity via induction of lacZ transgene mutations in bone marrow, glandular stomach, small intestine, liver, and lung. Additionally, the presence of bulky PAH-DNA adducts was examined. Five of the 9 PAHs elicited positive results across all endpoints in at least one tissue, and no PAHs were negative or equivocal across all endpoints. All PAHs were positive for lacZ mutations in at least one tissue (sensitivity = 100%), and for 8 PAHs, one or more initial sites of chemical contact (i.e., glandular stomach, liver, small intestine) yielded a greater response than bone marrow. Five PAHs were positive in the micronucleus assay (sensitivity = 56%). Furthermore, all PAHs produced DNA adducts in at least one tissue. The results demonstrate the utility of the TGR assay for mutagenicity assessment, especially for compounds that may not be systemically distributed. - Highlights: • The Muta™Mouse is a reliable tool for in vivo mutagenicity assessment of PAHs. • All 9 PAHs induced lacZ transgene mutations in small intestine. • Only 5 of 9 PAHs induced lacZ mutations and micronuclei in

Immunoglobulin gene expression and regulation of rearrangement in kappa transgenic mice

International Nuclear Information System (INIS)

Ritchie, K.A.

1986-01-01

Transgenic mice were produced by microinjection of the functionally rearranged immunoglobulin kappa gene from the myeloma MOPC-21 into the male pronucleus of fertilized mouse eggs, and implantation of the microinjected embryos into foster mothers. Mice that integrated the injected gene were detected by hybridizing tail DNA dots with radioactively labelled pBR322 plasmid DNA, which detects pBR322 sequences left as a tag on the microinjected DNA. Mice that integrated the injected gene (six males) were mated and the DNA, RNA and serum kappa chains of their offspring were analyzed. A rabbit anti-mouse kappa chain antiserum was also produced for use in detection of mouse kappa chains on protein blots. Hybridomas were produced from the spleen cells of these kappa transgenic mice to immortalize representative B cells and to investigate expression of the transgenic kappa gene, its effect on allelic exclusion, and its effect on the control of light chain gene rearrangement and expression. The results show that the microinjected DNA is integrated as concatamers in unique single or, rarely, two separate sites in the genome. The concatamers are composed of several copies (16 to 64) of injected DNA arranged in a head to tail fashion. The transgene is expressed into protein normally and in a tissue specific fashion. For the first time in these transgenic mice, all tissues contain a functionally rearranged and potentially expressible immunoglobulin gene. The transgene is expressed only in B cells and not in hepatocytes, for example. This indicates that rearrangement of immunoglobulin genes is necessary but not sufficient for the tissue specific expression of these genes by B cells

Cellular Models of Aggregation-dependent Template-directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer Disease.

Science.gov (United States)

Harrington, Charles R; Storey, John M D; Clunas, Scott; Harrington, Kathleen A; Horsley, David; Ishaq, Ahtsham; Kemp, Steven J; Larch, Christopher P; Marshall, Colin; Nicoll, Sarah L; Rickard, Janet E; Simpson, Michael; Sinclair, James P; Storey, Lynda J; Wischik, Claude M

2015-04-24

Alzheimer disease (AD) is a degenerative tauopathy characterized by aggregation of Tau protein through the repeat domain to form intraneuronal paired helical filaments (PHFs). We report two cell models in which we control the inherent toxicity of the core Tau fragment. These models demonstrate the properties of prion-like recruitment of full-length Tau into an aggregation pathway in which template-directed, endogenous truncation propagates aggregation through the core Tau binding domain. We use these in combination with dissolution of native PHFs to quantify the activity of Tau aggregation inhibitors (TAIs). We report the synthesis of novel stable crystalline leucomethylthioninium salts (LMTX®), which overcome the pharmacokinetic limitations of methylthioninium chloride. LMTX®, as either a dihydromesylate or a dihydrobromide salt, retains TAI activity in vitro and disrupts PHFs isolated from AD brain tissues at 0.16 μM. The Ki value for intracellular TAI activity, which we have been able to determine for the first time, is 0.12 μM. These values are close to the steady state trough brain concentration of methylthioninium ion (0.18 μM) that is required to arrest progression of AD on clinical and imaging end points and the minimum brain concentration (0.13 μM) required to reverse behavioral deficits and pathology in Tau transgenic mice. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Stable Skin-specific Overexpression of Human CTLA4-Ig in Transgenic Mice through Seven Generations

Institute of Scientific and Technical Information of China (English)

Yong WANG; Yong NI; Hong WEI; Feng-Chao WANG; Liang-Peng GE; Xiang GAO

2006-01-01

Skin graft rejection is a typical cellular immune response, mainly mediated by T cells. Cytotoxic T lymphocyte associated antigen 4-immunoglobin (CTLA4-Ig) extends graft survival by blocking the T cell co-stimulation pathway and inhibiting T cell activation. To investigate the efficacy of CTLA4-Ig in prolonging skin graft survival, human CTLA4-Ig (hCTLA4-Ig) was engineered to overexpress in mouse skin by transgenesis using the K14 promoter. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assay indicated that the expression of CTLA4-Ig remained skin-specific and relatively constant compared to the internal control protein, AKT, through seven generations. The presence and concentration of the hCTLA4-Ig protein in transgenic mouse sera was determined by enzyme-linked immunosorbent assay (ELISA), and the results indicated that the serum CTLA4-Ig concentration also remained constant through generations. Survival of transgenic mouse skins grafted onto rat wounds was remarkably prolonged compared to that of wild-type skins from the same mouse strain, and remained comparable among all seven generations. This suggested that the bioactive hCTLA4-Ig protein was stably expressed in transgenical mice through at least seven generations, which was consistent with the stable skin-specific CTLA4-Ig expression.The results demonstrated that the transgenic expression of hCTLA4-Ig in skin driven by the K14 promoter remained constant through generations, and a transgenic line can be established to provide transgenic skin with extended survival reproducibly.

SM and MSSM $H\\rightarrow\\tau\\tau$

CERN Document Server

Schwindt, Thomas; The ATLAS collaboration

2014-01-01

After the discovery of a Higgs boson at the LHC in $\\gamma\\gamma$, $ZZ$ and $WW$ final states in 2012, the ATLAS collaboration also observes an excess of data over the predicted background in $\\tau\\tau$ final states, which is consistent with the decay of the discovered Higgs boson with $m_H\\approx125$ GeV. With an observed (expected) significance of 4.1$\\sigma$ (3.2$\\sigma$), this is evidence for the coupling of this Higgs boson to fermions. The multi-variate analysis of a dataset corresponding to 20.3 fb$^{-1}$ of $pp$ collisions at $\\sqrt{s}=8$ TeV is presented together with a separate cut-based analysis of the same dataset searching for $h/H/A{\\rightarrow}\\tau^+\\tau^-$ decays in the context of the Minimal Supersymmetric Standard Model (MSSM). No excess of data over the expected backgrounds is observed in this search for additional Higgs bosons, and exclusion limits on the production cross section times branching fraction are derived and interpreted in the MSSM parameter space for different scenarios.

Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer?s disease

OpenAIRE

HAN, KUN; JIA, NING; LI, JI; YANG, LI; MIN, LIAN-QIU

2013-01-01

The objective of this study was to investigate the effects of varying doses of caffeine on memory impairment and the expression of brain neurotrophic derived factor (BNDF) and TrkB in PS1/APP double transgenic mouse models. PS1/APP double transgenic mice were administered 0.3 ml/day of saline, 1.5 mg/day of caffeine or 0.75 mg/day of caffeine for eight weeks. A water maze test and western blotting were used to determine the memory capability and expression of hippocampal BNDF and TrkB of the ...

CCL2-ethanol interactions and hippocampal synaptic protein expression in a transgenic mouse model

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Donna eGruol

2014-04-01

Full Text Available Chronic exposure to ethanol produces a number of detrimental effects on behavior. Neuroadaptive changes in brain structure or function underlie these behavioral changes and may be transient or persistent in nature. Central to the functional changes are alterations in the biology of neuronal and glial cells of the brain. Recent data show that ethanol induces glial cells of the brain to produce elevated levels of neuroimmune factors including CCL2, a key innate immune chemokine. Depending on the conditions of ethanol exposure, the upregulated levels of CCL2 can be transient or persistent and outlast the period of ethanol exposure. Importantly, results indicate that the upregulated levels of CCL2 may lead to CCL2-ethanol interactions that mediate or regulate the effects of ethanol on the brain. Glial cells are in close association with neurons and regulate many neuronal functions. Therefore, effects of ethanol on glial cells may underlie some of the effects of ethanol on neurons. To investigate this possibility, we are studying the effects of chronic ethanol on hippocampal synaptic function in a transgenic mouse model that expresses elevated levels of CCL2 in the brain through enhanced glial expression, a situation know to occur in alcoholics. Both CCL2 and ethanol have been reported to alter synaptic function in the hippocampus. In the current study, we determined if interactions are evident between CCL2 and ethanol at level of hippocampal synaptic proteins. Two ethanol exposure paradigms were used; the first involved ethanol exposure by drinking and the second involved ethanol exposure in a paradigm that combines drinking plus ethanol vapor. The first paradigm does not produce dependence on ethanol, whereas the second paradigm is commonly used to produce ethanol dependence. Results show modest effects of both ethanol exposure paradigms on the level of synaptic proteins in the hippocampus of CCL2 transgenic mice compared with their non-transgenic

Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly.

Science.gov (United States)

Chhatwal, Jasmeer P; Schultz, Aaron P; Marshall, Gad A; Boot, Brendon; Gomez-Isla, Teresa; Dumurgier, Julien; LaPoint, Molly; Scherzer, Clemens; Roe, Allyson D; Hyman, Bradley T; Sperling, Reisa A; Johnson, Keith A

2016-08-30

To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of (18)F-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p-tau), and β-amyloid 1-42 (Aβ42). T-tau, p-tau, and Aβ42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of (18)F-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. After controlling for sex and age, total cortical (18)F-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional (18)F-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with (18)F-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. These data support the link between (18)F-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with (18)F-T807 binding largely restricted to the temporal lobe, (18)F-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure. © 2016 American Academy of Neurology.

Bidirectional interplay of HSF1 degradation and UPR activation promotes tau hyperphosphorylation.

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Eunhee Kim

2017-07-01

Full Text Available The unfolded protein response (UPR in the endoplasmic reticulum (ER and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1 activation have previously been considered as attractive potential therapeutic targets for Alzheimer's disease (AD-a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221, identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRD ΔK280 (N2a-TauRD ΔK280. We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78 suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRD ΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78. Our work reveals how the bidirectional crosstalk between the two stress response systems

Measurement of Tau Polarisation in $Z/\\gamma^{*}\\rightarrow\\tau\\tau$ Decays in Proton-Proton Collisions at $\\sqrt{s}=8$ TeV with the ATLAS Detector

CERN Document Server

The ATLAS collaboration

2017-01-01

This note presents a measurement of the polarisation of $\\tau$ leptons produced in $Z/\\gamma^{*}\\rightarrow\\tau\\tau$ decays which is performed with a dataset of proton-proton collisions at $\\sqrt{s}=8$ TeV corresponding to an integrated luminosity of 20.2 fb$^{-1}$ recorded with the ATLAS detector at the LHC in 2012. The $Z/\\gamma^{*}\\rightarrow\\tau\\tau$ decays are reconstructed from a hadronically decaying $\\tau$ lepton ($\\tau \\rightarrow \\text{hadrons + } \

Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

Science.gov (United States)

Swanson, Eric; Breckenridge, Leigham; McMahon, Lloyd; Som, Sreemoyee; McConnell, Ian; Bloom, George S.

2017-01-01

Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. PMID:28482642

Review of tau lepton properties

International Nuclear Information System (INIS)

Feldman, G.J.

1978-11-01

The review of tau particle properties includes measurements of the branching ratios, the general modes, then a more detailed look at the semi-hadronic modes, and the upper limits for rare modes. Measurements of the tau mass, spin, and lifetime, the tau - ν/sub tau/ coupling and the ν/sub tau/ are considered mass. Finally, the lepton classification of the tau is discussed. 43 references

Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia.

Science.gov (United States)

Gonçalves, Nélio; Simões, Ana T; Prediger, Rui D; Hirai, Hirokazu; Cunha, Rodrigo A; Pereira de Almeida, Luís

2017-03-01

Machado-Joseph disease (MJD) is a neurodegenerative spinocerebellar ataxia (SCA) associated with an expanded polyglutamine tract within ataxin-3 for which there is currently no available therapy. We previously showed that caffeine, a nonselective adenosine receptor antagonist, delays the appearance of striatal damage resulting from expression of full-length mutant ataxin-3. Here we investigated the ability of caffeine to alleviate behavioral deficits and cerebellar neuropathology in transgenic mice with a severe ataxia resulting from expression of a truncated fragment of polyglutamine-expanded ataxin-3 in Purkinje cells. Control and transgenic c57Bl6 mice expressing in the mouse cerebella a truncated form of human ataxin-3 with 69 glutamine repeats were allowed to freely drink water or caffeinated water (1g/L). Treatments began at 7 weeks of age, when motor and ataxic phenotype emerges in MJD mice, and lasted up to 20 weeks. Mice were tested in a panel of locomotor behavioral paradigms, namely rotarod, beam balance and walking, pole, and water maze cued-platform version tests, and then sacrificed for cerebellar histology. Caffeine consumption attenuated the progressive loss of general and fine-tuned motor function, balance, and grip strength, in parallel with preservation of cerebellar morphology through decreasing the loss of Purkinje neurons and the thinning of the molecular layer in different folia. Caffeine also rescued the putative striatal-dependent executive and cognitive deficiencies in MJD mice. Our findings provide the first in vivo demonstration that caffeine intake alleviates behavioral disabilities in a severely impaired animal model of SCA. Ann Neurol 2017;81:407-418. © 2016 American Neurological Association.

Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

Science.gov (United States)

Planel, Emmanuel; Bretteville, Alexis; Liu, Li; Virag, Laszlo; Du, Angela L.; Yu, Wai Haung; Dickson, Dennis W.; Whittington, Robert A.; Duff, Karen E.

2009-01-01

Alzheimer’s disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer’s disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.—Planel, E., Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. PMID:19279139

Tau protein

DEFF Research Database (Denmark)

Frederiksen, Jette Lautrup Battistini; Kristensen, Kim; Bahl, Jmc

2011-01-01

Background: Tau protein has been proposed as biomarker of axonal damage leading to irreversible neurological impairment in MS. CSF concentrations may be useful when determining risk of progression from ON to MS. Objective: To investigate the association between tau protein concentration and 14......-3-3 protein in the cerebrospinal fluid (CSF) of patients with monosymptomatic optic neuritis (ON) versus patients with monosymptomatic onset who progressed to multiple sclerosis (MS). To evaluate results against data found in a complete literature review. Methods: A total of 66 patients with MS and/or ON from...... the Department of Neurology of Glostrup Hospital, University of Copenhagen, Denmark, were included. CSF samples were analysed for tau protein and 14-3-3 protein, and clinical and paraclinical information was obtained from medical records. Results: The study shows a significantly increased concentration of tau...

Measurement of the transverse spin correlations in the decay $Z \\rightarrow \\tau^+\\tau^-$

CERN Document Server

Barate, R; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Nief, J Y; Pietrzyk, B; Casado, M P; Chmeissani, M; Comas, P; Crespo, J M; Delfino, M C; Fernández, E; Fernández-Bosman, M; Garrido, L; Juste, A; Martínez, M; Miquel, R; Mir, L M; Orteu, S; Padilla, C; Park, I C; Pascual, A; Perlas, J A; Riu, I; Sánchez, F; Teubert, F; Colaleo, A; Creanza, D; De Palma, M; Gelao, G; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Nuzzo, S; Ranieri, A; Raso, G; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Tricomi, A; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Abbaneo, D; Alemany, R; Becker, U; Bazarko, A O; Bright-Thomas, P G; Cattaneo, M; Cerutti, F; Dissertori, G; Drevermann, H; Forty, Roger W; Frank, M; Hagelberg, R; Hansen, J B; Harvey, J; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Lutters, G; Mato, P; Minten, Adolf G; Moneta, L; Pacheco, A; Pusztaszeri, J F; Ranjard, F; Rizzo, G; Rolandi, Luigi; Rousseau, D; Schlatter, W D; Schmitt, M; Schneider, O; Tejessy, W; Tomalin, I R; Wachsmuth, H W; Wagner, A; Ajaltouni, Ziad J; Barrès, A; Boyer, C; Falvard, A; Ferdi, C; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rosnet, P; Rossignol, J M; Fearnley, Tom; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Rensch, B; Wäänänen, A; Daskalakis, G; Kyriakis, A; Markou, C; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Rougé, A; Rumpf, M; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Focardi, E; Parrini, G; Zachariadou, K; Corden, M; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Casper, David William; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Passalacqua, L; Pepé-Altarelli, M; Curtis, L; Dorris, S J; Halley, A W; Knowles, I G; Lynch, J G; O'Shea, V; Raine, C; Scarr, J M; Smith, K; Teixeira-Dias, P; Thompson, A S; Thomson, E; Thomson, F; Turnbull, R M; Geweniger, C; Graefe, G; Hanke, P; Hansper, G; Hepp, V; Kluge, E E; Putzer, A; Schmidt, M; Sommer, J; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, Peter J; Girone, M; Goodsir, S M; Martin, E B; Moutoussi, A; Nash, J; Sedgbeer, J K; Spagnolo, P; Stacey, A M; Williams, M D; Ghete, V M; Girtler, P; Kuhn, D; Rudolph, G; Betteridge, A P; Bowdery, C K; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Jones, R W L; Sloan, Terence; Williams, M I; Galla, A; Giehl, I; Greene, A M; Hoffmann, C; Jakobs, K; Kleinknecht, K; Quast, G; Renk, B; Rohne, E; Sander, H G; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Benchouk, C; Bonissent, A; Bujosa, G; Calvet, D; Carr, J; Coyle, P; Diaconu, C A; Etienne, F; Konstantinidis, N P; Leroy, O; Motsch, F; Payre, P; Talby, M; Sadouki, A; Thulasidas, M; Trabelsi, K; Aleppo, M; Ragusa, F; Berlich, R; Blum, Walter; Büscher, V; Dietl, H; Ganis, G; Gotzhein, C; Kroha, H; Lütjens, G; Lutz, Gerhard; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Saint-Denis, R; Stenzel, H; Wiedenmann, W; Wolf, G; Boucrot, J; Callot, O; Chen, S; Choi, Y; Cordier, A; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Höcker, A; Jacholkowska, A; Jacquet, M; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Nikolic, I A; Schune, M H; Simion, S; Tournefier, E; Veillet, J J; Videau, I; Zerwas, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Palla, Fabrizio; Sanguinetti, G; Sciabà, A; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Vannini, C; Venturi, A; Verdini, P G; Blair, G A; Bryant, L M; Chambers, J T; Gao, Y; Green, M G; Medcalf, T; Perrodo, P; Strong, J A; Von Wimmersperg-Töller, J H; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Maley, P; Norton, P R; Thompson, J C; Wright, A E; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Black, S N; Dann, J H; Johnson, R P; Kim, H Y; Litke, A M; McNeil, M A; Taylor, G; Booth, C N; Boswell, R; Brew, C A J; Cartwright, S L; Combley, F; Kelly, M S; Lehto, M H; Newton, W M; Reeve, J; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Grupen, Claus; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Musolino, G; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Charles, E; Elmer, P; Ferguson, D P S; González, S; Greening, T C; Hayes, O J; Hu, H; Jin, S; McNamara, P A; Nachtman, J M; Nielsen, J; Orejudos, W; Pan, Y B; Saadi, Y; Scott, I J; Walsh, J; Wu Sau Lan; Wu, X; Yamartino, J M; Zobernig, G

1997-01-01

For tau leptons produced in e^+e^- -> tau^+ tau^- interactions there are, in addition to the longitudinal spin correlations, two independent transverse spin correlations associated with the transverse (within the production plane) and normal (to the production plane) polarization components. A measurement of the transverse-transverse and transverse-normal tau spin correlations in the decay Z -> tau^+ tau^-, C_{TT} and C_{TN}, is presented based on the aplanarity angle of the decay products of both tau leptons. Using 80 pb^{-1} of data collected by ALEPH on the peak of the Z resonance, the results are C_{TT} = 1.06 +- 0.13 (stat) +- 0.05 (syst), and C_{TN} = 0.08 +- 0.13 (stat) +- 0.04 (syst). These values are in agreement with the Standard Model predictions, C_{TT} = 0.99 and C_{TN} = -0.01.

Non-motor and motor features in LRRK2 transgenic mice.

Directory of Open Access Journals (Sweden)

Zoë Bichler

Full Text Available Non-motor symptoms are increasingly recognized as important features of Parkinson's disease (PD. LRRK2 mutations are common causes of familial and sporadic PD. Non-motor features have not been yet comprehensively evaluated in LRRK2 transgenic mouse models.Using a transgenic mouse model overexpressing the R1441G mutation of the human LRRK2 gene, we have investigated the longitudinal correlation between motor and non-motor symptoms and determined if specific non-motor phenotypes precede motor symptoms.We investigated the onset of motor and non-motor phenotypes on the LRRK2(R1441G BAC transgenic mice and their littermate controls from 4 to 21 month-old using a battery of behavioral tests. The transgenic mutant mice displayed mild hypokinesia in the open field from 16 months old, with gastrointestinal dysfunctions beginning at 6 months old. Non-motor features such as depression and anxiety-like behaviors, sensorial functions (pain sensitivity and olfaction, and learning and memory abilities in the passive avoidance test were similar in the transgenic animals compared to littermate controls.LRRK2(R1441G BAC transgenic mice displayed gastrointestinal dysfunction at an early stage but did not have abnormalities in fine behaviors, olfaction, pain sensitivity, mood disorders and learning and memory compared to non-transgenic littermate controls. The observations on olfaction and gastrointestinal dysfunction in this model validate findings in human carriers. These mice did recapitulate mild Parkinsonian motor features at late stages but compensatory mechanisms modulating the progression of PD in these models should be further evaluated.

Hypocretin in cerebrospinal fluid is positively correlated with Tau and pTau.

Science.gov (United States)

Deuschle, Michael; Schilling, Claudia; Leweke, F Markus; Enning, Frank; Pollmächer, Thomas; Esselmann, Hermann; Wiltfang, Jens; Frölich, Lutz; Heuser, Isabella

2014-02-21

It has been suggested that sleep-wake regulation as well as hypocretins play a role in the pathophysiology of Alzheimer's disease. We analyzed Aβ40, Aβ42, Tau protein, phosphorylated Tau (pTau) protein as well as hypocretin-1 concentrations in the CSF of a detection sample of 10 patients with Alzheimer's disease (AD) as well as 10 age- and gender-matched patients with major depression as a comparison group of different pathology. In order to replicate the findings, we used a confirmation sample of 17 AD patients and 8 patients with major depression. We found hypocretin-1 concentrations in CSF not to differ between patients with depression and AD. However, hypocretin-1 was significantly related to Tau (r=0.463, phypocretin-1 may play a role in the metabolism of Tau proteins across different diagnostic entities including AD. It has to be determined whether there is a causal relationship between hypocretin-1 and Tau as well as pTau. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Lentiviral-Mediated Transgene Expression Can Potentiate Intestinal Mesenchymal-Epithelial Signaling

Directory of Open Access Journals (Sweden)

Kohn Aimee

2009-01-01

Full Text Available Abstract Mesenchymal-epithelial signaling is essential for the development of many organs and is often disrupted in disease. In this study, we demonstrate the use of lentiviral-mediated transgene delivery as an effective approach for ectopic transgene expression and an alternative to generation of transgenic animals. One benefit to this approach is that it can be used independently or in conjunction with established transgenic or knockout animals for studying modulation of mesenchymal-epithelial interactions. To display the power of this approach, we explored ectopic expression of a Wnt ligand in the mouse intestinal mesenchyme and demonstrate its functional influence on the adjacent epithelium. Our findings highlight the efficient use of lentiviral-mediated transgene expression for modulating mesenchymal-epithelial interactions in vivo.

Lentiviral-Mediated Transgene Expression Can Potentiate Intestinal Mesenchymal-Epithelial Signaling

Directory of Open Access Journals (Sweden)

Dismuke Adria D

2009-07-01

Full Text Available Abstract Mesenchymal-epithelial signaling is essential for the development of many organs and is often disrupted in disease. In this study, we demonstrate the use of lentiviral-mediated transgene delivery as an effective approach for ectopic transgene expression and an alternative to generation of transgenic animals. One benefit to this approach is that it can be used independently or in conjunction with established transgenic or knockout animals for studying modulation of mesenchymal-epithelial interactions. To display the power of this approach, we explored ectopic expression of a Wnt ligand in the mouse intestinal mesenchyme and demonstrate its functional influence on the adjacent epithelium. Our findings highlight the efficient use of lentiviral-mediated transgene expression for modulating mesenchymal-epithelial interactions in vivo.

Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer.

OpenAIRE

Chang, Keejong; Qian, Jin; Jiang, MeiSheng; Liu, Yi-Hsin; Wu, Ming-Che; Chen, Chi-Dar; Lai, Chao-Kuen; Lo, Hsin-Lung; Hsiao, Chin-Ton; Brown, Lucy; Bolen, James; Huang, Hsiao-I; Ho, Pei-Yu; Shih, Ping Yao; Yao, Chen-Wen

2002-01-01

Abstract Background Transgenic animals have become valuable tools for both research and applied purposes. The current method of gene transfer, microinjection, which is widely used in transgenic mouse production, has only had limited success in producing transgenic animals of larger or higher species. Here, we report a linker based sperm-mediated gene transfer method (LB-SMGT) that greatly improves the production efficiency of large transgenic animals. Results The linker protein, a monoclonal ...

Transgenic RNAi in mouse oocytes: The first decade

Czech Academy of Sciences Publication Activity Database

Malík, Radek; Svoboda, Petr

2012-01-01

Roč. 134, 1-2 (2012), s. 64-68 ISSN 0378-4320 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 Keywords : RNAi * oocyte * transgene * silencing Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.897, year: 2012

Expression of Tau Pathology-Related Proteins in Different Brain Regions: A Molecular Basis of Tau Pathogenesis.

Science.gov (United States)

Hu, Wen; Wu, Feng; Zhang, Yanchong; Gong, Cheng-Xin; Iqbal, Khalid; Liu, Fei

2017-01-01

Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD) brains. The tau pathology starts from the entorhinal cortex (EC), spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC), but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau) was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC), occipital-temporal cortex (OTC), striatum, thalamus, olfactory bulb (OB) and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.

Higgs $\\to \\tau \\tau $ Analysis in the CMS Experiment

CERN Document Server

Olszewski, Michal

2016-01-01

In July 2012, the CMS and ATLAS collaborations announced the discovery of a Higgs boson with a mass of about 125 GeV and properties in agreement with expected from the Standard Model. In this note, we review the analysis performed for the H $\\to \\tau \\tau$ decay mode during the first stage of the LHC operation in the CMS. Further, we present the work done during the First Long Shutdown and the first stage of Run 2 of the LHC on the field of hadronic tau lepton offline reconstruction.

Oral carcinogenesis is not achieved in different carcinogen-treated PAI-1 transgenic and wild-type mouse models.

Science.gov (United States)

Avgoustidis, Dimitris; Nisyrios, Themistoklis; Nkenke, Emeka; Lijnen, Roger; Ragos, Vassilis; Perrea, Despina; Donta, Ismini; Vaena, Apostolia; Yapijakis, Christos; Vairaktaris, Eleftherios

2012-01-01

In an effort to assess the role of plasminogen activator inhibitor-1 (PAI-1) in oral squamous cancer development and progression, two different carcinogen treatment protocols were conducted. Protocol I included mice from a PAI-1 transgenic (Tg) breed (n=56) and their wild-type (WT) counterparts (n=56), divided into one control group and two main experimental groups, treated with 7,12-dimethylbenz[a]anthracene (DMBA) for 8 and 16 weeks, respectively. Protocol II included the same number and types of animals and groups, which were similarly treated with 4-Nitroquinoline 1-oxide (4-NQO) in drinking water. Two drugs that affect plasma PAI-1 levels, enalapril and pravastatin, were administered to certain subgroups of animals in both protocols. None of the animals developed macroscopically-visible oral cancer lesions. Eleven animals under Protocol I and 52 animals under Protocol II died. Skin lesions were noted only in DMBA-treated animals (n=9). Almost all animals administered with 4-NQO developed alopecia and lost weight, while two of them developed stomach tumours, and one female mouse developed a large ovarian cyst. Transgenic mice may respond differently when used in well-established carcinogen models and oral carcinogenesis is hard to achieve in these rodents.

In vivo axonal transport deficits in a mouse model of fronto-temporal dementia.

Science.gov (United States)

Majid, Tabassum; Ali, Yousuf O; Venkitaramani, Deepa V; Jang, Ming-Kuei; Lu, Hui-Chen; Pautler, Robia G

2014-01-01

Axonal transport is vital for neurons and deficits in this process have been previously reported in a few mouse models of Alzheimer's disease prior to the appearance of plaques and tangles. However, it remains to be determined whether axonal transport is defective prior to the onset of neurodegeneration. The rTg4510 mouse, a fronto-temporal dementia and parkinsonism-17 (FTDP-17) tauopathy model, over-express tau-P301L mutation found in familial forms of FTDP-17, in the forebrain driven by the calcium-calmodulin kinase II promoter. This mouse model exhibits tau pathology, neurodegeneration in the forebrain, and associated behavioral deficits beginning at 4-5 months of age. rTg4510 transgenic mice were used in these studies. Mice were given 2 μL of MnCl2 in each nostril 1 h prior to Magnetic Resonance Imaging (MRI). Following MnCl2 nasal lavage, mice were imaged using Manganese enhanced Magnetic Resonance Imaging (MEMRI) Protocol with TE = 8.5 ms, TR = 504 ms, FOV = 3.0 cm, matrix size = 128 × 128 × 128, number of cycles = 15 with each cycle taking approximately 2 min, 9 s, and 24 ms using Paravision software (BrukerBioSpin, Billerica, MA). During imaging, body temperature was maintained at 37.0 °C using an animal heating system (SA Instruments, Stony Brook, NY). Resulting images were analyzed using Paravision software. Regions of interest (ROI) within the olfactory neuronal layer (ONL) and the water phantom consisting of one pixel (ONL) and 9 pixels (water) were selected and copied across each of the 15 cycles. Signal intensities (SI) of ONL and water phantom ROIs were measured. SI values obtained for ONL were then normalized the water phantom SI values. The correlation between normalized signal intensity in the ONL and time were assessed using Prism (GraphPad Software, San Diego, CA). Using the MEMRI technique on 1.5, 3, 5, and 10-month old rTg4510 mice and littermate controls, we found significant axonal transport deficits present in

Properties of the tau lepton

International Nuclear Information System (INIS)

Feldman, G.J.

1978-06-01

The measured properties of the tau lepton and its neutrino are reviewed. A constrained fit to the world data gives a tau branching fraction to an electron plus neutrinos (B/sub e/) of (17.4 +- 2.1)% and B/sub mu//B/sub e/ = 1.07 +- 0.17. New data on the tau → pi nu mode are in agreement with the expected branching fraction. There is evidence for the tau → A 1 nu mode, but the A 1 resonance cannot be conclusively established from the current data. The DELCO experiment establishes the tau mass to be 1782 /sup +2//sub - 7/ MeV/c 2 and the nu/sub tau/ mass to be less than 250 MeV/c 2 . It also excludes V + A as a tau - nu/sub tau/ coupling and strongly favors V - A

LHCb; Neutral Higgs $ \\to \\tau \\tau$ Limits at LHCb

CERN Multimedia

Ilten, P

2013-01-01

LHCb is fully instrumented in the forward region, $2 \\leq \\eta \\leq 5$, and provides compelentary results to the central measurements of ATLAS and CMS. Preliminary limits are presented on neutral Higgs production usint $\\tau \\tau$ final states in the forward region of LHCb.

Tau-Induced Ca2+/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation.

Science.gov (United States)

Wei, Yu-Ping; Ye, Jin-Wang; Wang, Xiong; Zhu, Li-Ping; Hu, Qing-Hua; Wang, Qun; Ke, Dan; Tian, Qing; Wang, Jian-Zhi

2018-04-01

Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells. Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca 2+ concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca 2+ concentration with a simultaneous increase in the phosphorylation of Ca 2+ /calmodulin-dependent protein kinase IV (CaMKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca 2+ /CaMKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation of the Ca 2+ /calmodulin complex abolished the okadaic acid-induced tau hyperphosphorylation in the nuclear fraction. We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca 2+ /CaMKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca 2+ concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.

Beneficial effect of antibodies against β- secretase cleavage site of APP on Alzheimer's-like pathology in triple-transgenic mice.

Directory of Open Access Journals (Sweden)

Inna Rabinovich-Nikitin

Full Text Available The toxicity of amyloid β and tau, the two hallmark proteins in Alzheimer's disease (AD, has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the β secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Aβ and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3β which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Aβ in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease.

Radiation arteriopathy in the transgenic arteriovenous fistula model.

Science.gov (United States)

Lawton, Michael T; Arnold, Christine M; Kim, Yung J; Bogarin, Ernesto A; Stewart, Campbell L; Wulfstat, Amanda A; Derugin, Nikita; Deen, Dennis; Young, William L

2008-05-01

The transgenic arteriovenous fistula model, surgically constructed with transgenic mouse aorta interposed in common carotid artery-to-external jugular vein fistulae in nude rats, has a 4-month experimental window because patency and transgenic phenotype are lost over time. We adapted this model to investigate occlusive arteriopathy in brain arteriovenous malformations after radiosurgery by radiating grafted aorta before insertion in the fistula. We hypothesized that high-dose radiation would reproduce the arteriopathy observed clinically within the experimental time window and that deletions of endoglin (ENG) and endothelial nitric oxide synthase (eNOS) genes would modify the radiation response. Radiation arteriopathy in the common carotid arteries of 171 wild-type mice was examined with doses of 25, 80, 120, or 200 Gy (Experiment 1). Radiation arteriopathy in 68 wild-type arteriovenous fistulae was examined histologically and morphometrically with preoperative radiation doses of 0, 25, or 200 Gy (Experiment 2). Radiation arteriopathy in 51 transgenic arteriovenous fistulae (36 ENG and 15 eNOS knock-out fistulae) was examined using preoperative radiation doses of 0, 25, or 200 Gy (Experiment 3). High-dose radiation (200 Gy) of mouse common carotid arteries induced only mild arteriopathy (mean score, 0.66) without intimal hyperplasia and with high mortality (68%). Radiation arteriopathy in wild-type arteriovenous fistulae was severe (mean score, 3.5 at 200 Gy), with intimal hyperplasia and medial disruption at 3 months, decreasing luminal areas with increasing dose, and no mortality. Arteriopathy was robust in transgenic arteriovenous fistulae with ENG +/- and with eNOS +/-, with thick intimal hyperplasia in the former and distinct smooth muscle cell proliferation in the latter. The transgenic arteriovenous fistula model can be adapted to rapidly reproduce radiation arteriopathy observed in resected brain arteriovenous malformations after radiosurgery. High

Final NOMAD results on {nu}{sub {mu}}{yields}{nu}{sub {tau}} and {nu}{sub e}{yields}{nu}{sub {tau}} oscillations including a new search for {nu}{sub {tau}} appearance using hadronic {tau} decays

Energy Technology Data Exchange (ETDEWEB)

Astier, P.; Autiero, D.; Baldisseri, A.; Baldo-Ceolin, M.; Banner, M.; Bassompierre, G.; Benslama, K.; Besson, N.; Bird, I.; Blumenfeld, B.; Bobisut, F.; Bouchez, J.; Boyd, S.; Bueno, A.; Bunyatov, S.; Camilleri, L.; Cardini, A.; Cattaneo, P.W.; Cavasinni, V.; Cervera-Villanueva, A.; Chukanov, A.; Collazuol, G.; Conforto, G.; Conta, C.; Contalbrigo, M.; Cousins, R.; Daniels, D.; Degaudenzi, H.; Del Prete, T.; De Santo, A.; Dignan, T.; Di Lella, L.; Couto e Silva, E. do; Dumarchez, J.; Ellis, M.; Feldman, G.J.; Ferrari, R.; Ferrere, D.; Flaminio, V.; Fraternali, M.; Gaillard, J.-M.; Gangler, E.; Geiser, A.; Geppert, D.; Gibin, D.; Gninenko, S.; Godley, A.; Gomez-Cadenas, J.-J.; Gosset, J.; Goessling, C.; Gouanere, M.; Grant, A.; Graziani, G.; Guglielmi, A.; Hagner, C.; Hernando, J.; Hubbard, D.; Hurst, P.; Hyett, N.; Iacopini, E.; Joseph, C.; Juget, F.; Kirsanov, M.; Klimov, O.; Kokkonen, J.; Kovzelev, A.; Krasnoperov, A.; Kustov, D.; Kuznetsov, V.E.; Lacaprara, S.; Lachaud, C.; Lakic, B.; Lanza, A.; La Rotonda, L.; Laveder, M.; Letessier-Selvon, A.; Levy, J.-M.; Linssen, L.; Ljubic, A.; Long, J.; Lupi, A.; Marchionni, A.; Martelli, F.; Mechain, X.; Mendiburu, J.-P.; Meyer, J.-P.; Mezzetto, M.; Mishra, S.R.; Moorhead, G.F.; Naumov, D.; Nedelec, P.; Nefedov, Yu.; Nguyen-Mau, C.; Orestano, D.; Pastore, F.; Peak, L.S.; Pennacchio, E.; Pessard, H.; Petti, R. E-mail: roberto.petti@cern.ch; Placci, A.; Polesello, G.; Pollmann, D.; Polyarush, A.; Popov, B.; Poulsen, C.; Rico, J.; Riemann, P.; Roda, C.; Rubbia, A.; Salvatore, F.; Schahmaneche, K.; Schmidt, B.; Schmidt, T.; Sconza, A.; Sevior, M.; Sillou, D.; Soler, F.J.P.; Sozzi, G.; Steele, D.; Stiegler, U.; Stipc, M.; Stolarczyk, Th.; Tareb-Reyes, M.; Taylor, G.N.; Tereshchenko, V.; Toropin, A.; Touchard, A.-M.; Tovey, S.N.; Tran, M.-T.; Tsesmelis, E.; Ulrichs, J.; Vacavant, L.; Valdata-Nappi, M.; Valuev, V.; Vannucci, F.; Varvell, K.E.; Veltri, M.; Vercesi, V.; Vidal-Sitjes, G.; Vieira, J.-M.; Vinogradova, T.[and others

2001-09-17

Results from the {nu}{sub {tau}} appearance search in a neutrino beam using the full NOMAD data sample are reported. A new analysis unifies all the hadronic {tau} decays, significantly improving the overall sensitivity of the experiment to oscillations. The 'blind analysis' of all topologies yields no evidence for an oscillation signal. In the two-family oscillation scenario, this sets a 90% CL allowed region in the sin{sup 2}2{theta}{sub {mu}}{sub {tau}}-{delta}m{sup 2} plane which includes sin{sup 2}2{theta}{sub {mu}}{sub {tau}}<3.3x10{sup -4} at large {delta}m{sup 2} and {delta}m{sup 2}< 0.7 eV{sup 2}/c{sup 4} at sin{sup 2}2{theta}{sub {mu}}{sub {tau}}=1. The corresponding contour in the {nu}{sub e}{yields}{nu}{sub {tau}} oscillation hypothesis results in sin{sup 2}2{theta}{sub e{tau}}<1.5x10{sup -2} at large {delta}m{sup 2} and {delta}m{sup 2}<5.9 eV{sup 2}/c{sup 4} at sin{sup 2}2{theta}{sub e{tau}}=1. We also derive limits on effective couplings of the {tau} lepton to {nu}{sub {mu}} or {nu}{sub e}.

Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer's disease: Identification as the microtubule-associated protein tau

International Nuclear Information System (INIS)

Goedert, M.; Wischik, C.M.; Crowther, R.A.; Walker, J.E.; Klug, A.

1988-01-01

Screening of cDNA libraries prepared from the frontal cortex of an Alzheimer's disease patient and from fetal human brain has led to isolation of the cDNA for a core protein of the paired helical filament of Alzheimer's disease. The partial amino acid sequence of this core protein was used to design synthetic oligonucleotide probes. The cDNA encodes a protein of 352 amino acids that contains a characteristic amino acid repeat in its carboxyl-terminal half. This protein is highly homologous to the sequence of the mouse microtubule-associated protein tau and thus constitutes the human equivalent of mouse tau. RNA blot analysis indicates the presence of two major transcripts, 6 and 2 kilobases long, with a wide distribution in normal human brain. Tau protein mRNAs were found in normal amounts in the frontal cortex from patients with Alzheimer's disease. The proof that at least part of tau protein forms a component of the paired helical filament core opens the way to understanding the mode of formation of paired helical filaments and thus, ultimately, the pathogenesis of Alzheimer's disease

Tau-charm factory..

Energy Technology Data Exchange (ETDEWEB)

Anon.

1995-10-15

In addition to hearing the latest experimental and theoretical developments at the 17th International Symposium on Lepton Photon Interactions in Beijing, delegates were brought up-to-date on the substantial progress towards the realization of a Tau-Charm Factory in the Chinese capital. Opening the Symposium, Zhou Guangzhao, President of the Chinese Academy of Sciences, expressed a commitment of the Chinese government to basic research and its interest in the continuing development high energy physics in China. Following the very successful construction and operation of Beijing's Electron-Positron Collider, BEPC, the Chinese government has provided 5M yuan ($US 600,000) for a feasibility study by the end of 1996 for a Tau-Charm Factory at Beijing's Institute of High Energy Physics (IHEP). Professor Zhou expressed his belief that, once approved, such a factory would greatly enhance high energy physics in China. He warmly welcomed international collaboration both in the construction of the accelerator and in the experimental programme. His comments were reinforced in the following welcome speech by IHEP Director Zheng Zhipeng. Conference delegates had the opportunity to inspect the BEPC injector and collider, built almost entirely by Chinese industry. The International Committee for Future Accelerators (ICFA) met during the Symposium, with Tau- Charm Factory business on the agenda. In his subsequent report, ICFA Chairman John Peoples said that a Tau-Charm Factory provides a unique experimental environment for the precision studies of tau, charm and light quark-gluon spectroscopy, and that some issues in these fields are not satisfactorily addressed solely by B Factories or fixed-target experiments. The committee expressed a strong interest in seeing a Tau-Charm Factory built and noted the serious interest, especially in China, and looks forward to operation and exploitation by the international physics community. In their Beijing summary talks, both Sam Ting and T

Tau-charm factory..

International Nuclear Information System (INIS)

Anon.

1995-01-01

In addition to hearing the latest experimental and theoretical developments at the 17th International Symposium on Lepton Photon Interactions in Beijing, delegates were brought up-to-date on the substantial progress towards the realization of a Tau-Charm Factory in the Chinese capital. Opening the Symposium, Zhou Guangzhao, President of the Chinese Academy of Sciences, expressed a commitment of the Chinese government to basic research and its interest in the continuing development high energy physics in China. Following the very successful construction and operation of Beijing's Electron-Positron Collider, BEPC, the Chinese government has provided 5M yuan ($US 600,000) for a feasibility study by the end of 1996 for a Tau-Charm Factory at Beijing's Institute of High Energy Physics (IHEP). Professor Zhou expressed his belief that, once approved, such a factory would greatly enhance high energy physics in China. He warmly welcomed international collaboration both in the construction of the accelerator and in the experimental programme. His comments were reinforced in the following welcome speech by IHEP Director Zheng Zhipeng. Conference delegates had the opportunity to inspect the BEPC injector and collider, built almost entirely by Chinese industry. The International Committee for Future Accelerators (ICFA) met during the Symposium, with Tau- Charm Factory business on the agenda. In his subsequent report, ICFA Chairman John Peoples said that a Tau-Charm Factory provides a unique experimental environment for the precision studies of tau, charm and light quark-gluon spectroscopy, and that some issues in these fields are not satisfactorily addressed solely by B Factories or fixed-target experiments. The committee expressed a strong interest in seeing a Tau-Charm Factory built and noted the serious interest, especially in China, and looks forward to operation and exploitation by the international physics community. In their Beijing summary talks, both Sam Ting

Tau decays

International Nuclear Information System (INIS)

Golutvin, A.

1994-09-01

The most recent experimental results of τ physics are reviewed. The covered topics include precision measurements of semihadronic τ decay and their impact on tau branching ratio budget, the current status of the tau consistency test, a determination of Michel parameters and τ neutrino helicity, and upper limits on lepton-number violating τ decays. (orig.)

Tau reconstruction and identification algorithm

Indian Academy of Sciences (India)

CMS has developed sophisticated tau identification algorithms for tau hadronic decay modes. Production of tau lepton decaying to hadrons are studied at 7 TeV centre-of-mass energy with 2011 collision data collected by CMS detector and has been used to measure the performance of tau identification algorithms by ...

Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies

Science.gov (United States)

Avery, Lindsay B.; Wang, Mengmeng; Kavosi, Mania S.; Joyce, Alison; Kurz, Jeffrey C.; Fan, Yao-Yun; Dowty, Martin E.; Zhang, Minlei; Zhang, Yiqun; Cheng, Aili; Hua, Fei; Jones, Hannah M.; Neubert, Hendrik; Polzer, Robert J.; O'Hara, Denise M.

2016-01-01

ABSTRACT Therapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r2 = 0.83, r = 0.91, p PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic. PMID:27232760

A Protein Aggregation Inhibitor, Leuco-Methylthioninium Bis(Hydromethanesulfonate, Decreases α-Synuclein Inclusions in a Transgenic Mouse Model of Synucleinopathy

Directory of Open Access Journals (Sweden)

Karima Schwab

2018-01-01

Full Text Available α-Synuclein (α-Syn aggregation is a pathological feature of synucleinopathies, neurodegenerative disorders that include Parkinson’s disease (PD. We have tested whether N,N,N′,N′-tetramethyl-10H-phenothiazine-3,7-diaminium bis(hydromethanesulfonate (leuco-methylthioninium bis(hydromethanesulfonate; LMTM, a tau aggregation inhibitor, affects α-Syn aggregation in vitro and in vivo. Both cellular and transgenic models in which the expression of full-length human α-Syn (h-α-Syn fused with a signal sequence peptide to promote α-Syn aggregation were used. Aggregated α-Syn was observed following differentiation of N1E-115 neuroblastoma cells transfected with h-α-Syn. The appearance of aggregated α-Syn was inhibited by LMTM, with an EC50 of 1.1 μM, with minimal effect on h-α-Syn mRNA levels being observed. Two independent lines of mice (L58 and L62 transgenic for the same fusion protein accumulated neuronal h-α-Syn that, with aging, developed into fibrillary inclusions characterized by both resistance to proteinase K (PK-cleavage and their ability to bind thiazin red. There was a significant decrease in α-Syn-positive neurons in multiple brain regions following oral treatment of male and female mice with LMTM administered daily for 6 weeks at 5 and 15 mg MT/kg. The early aggregates of α-Syn and the late-stage fibrillar inclusions were both susceptible to inhibition by LMTM, a treatment that also resulted in the rescue of movement and anxiety-related traits in these mice. The results suggest that LMTM may provide a potential disease modification therapy in PD and other synucleinopathies through the inhibition of α-Syn aggregation.

Z' to tau tau - emu final state

CERN Document Server

CMS Collaboration

2015-01-01

A search for new physics beyond the standard model in the high-mass ditau final state with one tau decaying in the electron channel and one tau decaying in the muon channel is performed using proton-proton collisions at $\\sqrt{s}$ = 8 TeV recorded by the CMS experiment at the LHC. The data correspond to an integrated luminosity of 19.7 fb$^{-1}$. The data are in good agreement with the standard model prediction. An upper limit at 95$\\%$ CL on the product of cross section times branching fraction into tau pairs is calculated as a function of the resonance mass for the Sequential Standard Model $Z'$ ($Z'_{SSM}$ masses excluded up to 1300 GeV) and for the GUT-inspired $E_6$ model ($Z'_{\\psi}$ masses excluded up to 810 GeV). The results are further interpreted in terms of the Arkani-Hamed, Dimopolous, and Dvali (ADD) model, setting an exclusion limit on the parameter $\\Lambda_T$ up to 2800 GeV.

Prospects for Tau Physics

International Nuclear Information System (INIS)

Lafferty, George D.

2009-01-01

The tau lepton is a powerful tool with which to study a wide variety of physics in and beyond the Standard Model. We review the prospects for tau physics in the light of recent progress at the B factories and elsewhere, and we consider the tau physics that may come from future accelerators.

Sources of extracellular tau and its signaling.

Science.gov (United States)

Avila, Jesús; Simón, Diana; Díaz-Hernández, Miguel; Pintor, Jesús; Hernández, Félix

2014-01-01

The pathology associated with tau protein, tauopathy, has been recently analyzed in different disorders, leading to the suggestion that intracellular and extracellular tau may itself be the principal agent in the transmission and spreading of tauopathies. Tau pathology is based on an increase in the amount of tau, an increase in phosphorylated tau, and/or an increase in aggregated tau. Indeed, phosphorylated tau protein is the main component of tau aggregates, such as the neurofibrillary tangles present in the brain of Alzheimer's disease patients. It has been suggested that intracellular tau could be toxic to neurons in its phosphorylated and/or aggregated form. However, extracellular tau could also damage neurons and since neuronal death is widespread in Alzheimer's disease, mainly among cholinergic neurons, these cells may represent a possible source of extracellular tau. However, other sources of extracellular tau have been proposed that are independent of cell death. In addition, several ways have been proposed for cells to interact with, transmit, and spread extracellular tau, and to transduce signals mediated by this tau. In this work, we will discuss the role of extracellular tau in the spreading of the tau pathology.

Virtual Transgenics: Using a Molecular Biology Simulation to Impact Student Academic Achievement and Attitudes

Science.gov (United States)

Shegog, Ross; Lazarus, Melanie M.; Murray, Nancy G.; Diamond, Pamela M.; Sessions, Nathalie; Zsigmond, Eva

2012-01-01

The transgenic mouse model is useful for studying the causes and potential cures for human genetic diseases. Exposing high school biology students to laboratory experience in developing transgenic animal models is logistically prohibitive. Computer-based simulation, however, offers this potential in addition to advantages of fidelity and reach.…

Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis.

Science.gov (United States)

Musicki, Biljana; Bivalacqua, Trinity J; Champion, Hunter C; Burnett, Arthur L

2014-02-01

Sickle cell disease (SCD)-associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear. We evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide-producing enzyme NADPH oxidase activity in the sickle cell mouse penis. SCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser-1177 (positive regulatory site), eNOS interactions with heat-shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4-hydroxy-2-nonenal [HNE]) were measured by Western blot. Effect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse. Continuous treatment with sildenafil reversed (P penis. Sildenafil treatment of WT mice did not affect any of these parameters. Our findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. © 2013 International Society for Sexual Medicine.

Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer's disease.

Science.gov (United States)

Han, Kun; Jia, Ning; Li, Ji; Yang, Li; Min, Lian-Qiu

2013-09-01

The objective of this study was to investigate the effects of varying doses of caffeine on memory impairment and the expression of brain neurotrophic derived factor (BNDF) and TrkB in PS1/APP double transgenic mouse models. PS1/APP double transgenic mice were administered 0.3 ml/day of saline, 1.5 mg/day of caffeine or 0.75 mg/day of caffeine for eight weeks. A water maze test and western blotting were used to determine the memory capability and expression of hippocampal BNDF and TrkB of the mice. The results demonstrated that 0.75 mg/day and 1.5 mg/day doses of caffeine significantly increased memory capability and the expression of hippocampal BDNF and TrkB in PS1/APP mice with a dose-response effect. The results suggested that chronic caffeine treatment may reverse memory impairment in PS1/APP transgenic mice, and BDNF and its receptor TrkB, may be involved in this process.

Posttranslational inactivation of endothelial nitric oxide synthase in the transgenic sickle cell mouse penis

Science.gov (United States)

Musicki, Biljana; Champion, Hunter C.; Hsu, Lewis L.; Bivalacqua, Trinity J.; Burnett, Arthur L.

2017-01-01

INTRODUCTION Sickle cell disease (SCD)-associated priapism is characterized by endothelial nitric oxide synthase (eNOS) dysfunction in the penis. However, the mechanism of decreased eNOS function/activation in the penis in association with SCD is not known. AIMS Our hypothesis in the present study was that eNOS is functionally inactivated in the SCD penis in association with impairments in eNOS posttranslational phosphorylation and the enzyme’s interactions with its regulatory proteins. METHODS Sickle cell transgenic (sickle) mice were used as an animal model of SCD. Wild type (WT) mice served as controls. Penes were excised at baseline for molecular studies. eNOS phosphorylation on Ser-1177 (positive regulatory site) and Thr-495 (negative regulatory site), total eNOS, and phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser-1177) expressions, and eNOS interactions with heat shock protein 90 (HSP90) and caveolin-1 were measured by Western blot. Constitutive NOS catalytic activity was measured by conversion of L-[14C]arginine-to-L-[14C]citrulline in the presence of calcium. MAIN OUTCOME MEASURES Molecular mechanisms of eNOS dysfunction in the sickle mouse penis. RESULTS eNOS phosphorylated on Ser-1177, an active portion of eNOS, was decreased in the sickle mouse penis compared to WT penis. eNOS interaction with its positive protein regulator HSP90, but not with its negative protein regulator caveolin-1, and phosphorylated AKT expression, as well as constitutive NOS activity, were also decreased in the sickle mouse penis compared to WT penis. eNOS phosphorylated on Thr-495, total eNOS, HSP90, and caveolin-1 protein expressions in the penis were not affected by SCD. CONCLUSION These findings provide a molecular basis for chronically reduced eNOS function in the penis by SCD, which involves decreased eNOS phosphorylation on Ser-1177 and decreased eNOS-HSP90 interaction. PMID:21143412

Investigation of tau pair production at PETRA

International Nuclear Information System (INIS)

Kuester, H.

1983-11-01

The reaction e + e - -> tau + tau - has been measured at center of mass energies around 34 GeV. The selection is sensitive to 93% of the tau pair decays, thus making possible a high identification efficiency of proportional 70% over a large solid angle. The total cross section has been measured to Rsub(tau) = sigmasub(tautau)/sigmasub(point) = .94 +- .06(stat.) +- .06(syst.). In the differential cross section a charge asymmetry of Asub(tau) = (-(9.0 +- 6.6)% was observed, corresponding to a tau axial vector coupling to the weak neutral current of asub(tau) = -.94 +- 0.69. Moreover, final states from the decays tau -> πν, tau -> eνν, and tau -> μνν have been isolated and branching ratios into these channels have been determined. From the inclusive momentum spectra of the observed decay products (including the channel tau -> rhoν) the forward backward asymmetry of tau polarization has been determined to Asub(p,tau) = -(1 +- 22)% which corresponds to vsub(tau) = -.1 +- 2.9. Tests on factorization are discussed. (orig.) [de

Effect of 5'-flanking sequence deletions on expression of the human insulin gene in transgenic mice

DEFF Research Database (Denmark)

Fromont-Racine, M; Bucchini, D; Madsen, O

1990-01-01

Expression of the human insulin gene was examined in transgenic mouse lines carrying the gene with various lengths of DNA sequences 5' to the transcription start site (+1). Expression of the transgene was demonstrated by 1) the presence of human C-peptide in urine, 2) the presence of specific...... of the transgene was observed in cell types other than beta-islet cells....

The ε3 and ε4 alleles of human APOE differentially affect tau phosphorylation in hyperinsulinemic and pioglitazone treated mice.

Directory of Open Access Journals (Sweden)

Alvina W M To

2011-02-01

Full Text Available Impaired insulin signalling is increasingly thought to contribute to Alzheimer's disease (AD. The ε4 isoform of the APOE gene is the greatest genetic risk factor for sporadic, late onset AD, and is also associated with risk for type 2 diabetes mellitus (T2DM. Neuropathological studies reported the highest number of AD lesions in brain tissue of ε4 diabetic patients. However other studies assessing AD pathology amongst the diabetic population have produced conflicting reports and have failed to show an increase in AD-related pathology in diabetic brain. The thiazolidinediones (TZDs, peroxisome proliferator-activated receptor gamma agonists, are peripheral insulin sensitisers used to treat T2DM. The TZD, pioglitazone, improved memory and cognitive functions in mild to moderate AD patients. Since it is not yet clear how apoE isoforms influence the development of T2DM and its progression to AD, we investigated amyloid beta and tau pathology in APOE knockout mice, carrying human APOEε3 or ε4 transgenes after diet-induced insulin resistance with and without pioglitazone treatment.Male APOE knockout, APOEε3-transgenic and APOEε4-transgenic mice, together with background strain C57BL6 mice were kept on a high fat diet (HFD or low fat diet (LFD for 32 weeks, or were all fed HFD for 32 weeks and during the final 3 weeks animals were treated with pioglitazone or vehicle.All HFD animals developed hyperglycaemia with elevated plasma insulin. Tau phosphorylation was reduced at 3 epitopes (Ser396, Ser202/Thr205 and Thr231 in all HFD, compared to LFD, animals independent of APOE genotype. The introduction of pioglitazone to HFD animals led to a significant reduction in tau phosphorylation at the Ser202/Thr205 epitope in APOEε3 animals only. We found no changes in APP processing however the levels of soluble amyloid beta 40 was reduced in APOE knockout animals treated with pioglitazone.

$W\\rightarrow\\tau\

CERN Document Server

Kraus, Jana

Two measurements based on proton-proton collisions recorded with the ATLAS experiment at the LHC with $\\tau$ leptons and missing transverse energy in the final state are presented. The $W$ boson production cross section with subsequent $W\\rightarrow\\tau\

Tau imaging in neurodegenerative diseases

Energy Technology Data Exchange (ETDEWEB)

Dani, M.; Edison, P. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Brooks, D.J. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Aarhus University, Institute of Clinical Medicine, Aarhus (Denmark)

2016-06-15

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [{sup 18}F]THK523, [{sup 18}F]THK5117, [{sup 18}F]THK5105 and [{sup 18}F]THK5351, [{sup 18}F]AV1451(T807) and [{sup 11}C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. (orig.)

Calcium electrotransfer for termination of transgene expression in muscle

DEFF Research Database (Denmark)

Hojman, Pernille; Spanggaard, Iben; Olsen, Caroline Holkman

2011-01-01

Gene electrotransfer is expanding in clinical use, thus we have searched for an emergency procedure to stop transgene expression in case of serious adverse events. Calcium is cytotoxic at high intracellular levels, so we tested effects of calcium electrotransfer on transgene expression in muscle....... A clinical grade calcium solution (20 μl, 168 mM) was injected into transfected mouse or rat tibialis cranialis muscle. Ca(2+) uptake was quantified using calcium 45 ((45)Ca), and voltage and time between injection and pulsation were varied. Extinction of transgene expression was investigated by using both...... voltage pulses of 1000 V/cm. Using these parameters, in vivo imaging showed that transgene expression significantly decreased 4 hr after Ca(2+) electrotransfer and was eliminated within 24 hr. Similarly, serum erythropoietin was reduced by 46% at 4 hr and to control levels at 2 days. Histological analyses...

Polycythemia in transgenic mice expressing the human erythropoietin gene

International Nuclear Information System (INIS)

Semenza, G.L.; Traystman, M.D.; Gearhart, J.D.; Antonarakis, S.E.

1989-01-01

Erythropoietin is a glycoprotein hormone that regulates mammalian erythropoiesis. To study the expression of the human erythropoietin gene, EPO, 4 kilobases of DNA encompassing the gene with 0.4 kilobase of 5' flanking sequence and 0.7 kilobase of 3' flanking sequence was microinjected into fertilized mouse eggs. Transgenic mice were generated that are polycythemic, with increased erythrocytic indices in peripheral blood, increased numbers of erythroid precursors in hematopoietic tissue, and increased serum erythropoietin levels. Transgenic homozygotes show a greater degree of polycythemia than do heterozygotes as well as striking extramedullary erythropoiesis. Human erythropoietin RNA was found not only in fetal liver, adult liver, and kidney but also in all other transgenic tissues analyzed. Anemia induced increased human erythropoietin RNA levels in liver but not kidney. These transgenic mice represent a unique model of polycythemia due to increased erythropoietin levels

A BAC-based transgenic mouse specifically expresses an inducible Cre in the urothelium.

Directory of Open Access Journals (Sweden)

Tian Huai Shen

Full Text Available Cre-loxp mediated conditional knockout strategy has played critical roles for revealing functions of many genes essential for development, as well as the causal relationships between gene mutations and diseases in the postnatal adult mice. One key factor of this strategy is the availability of mice with tissue- or cell type-specific Cre expression. However, the success of the traditional molecular cloning approach to generate mice with tissue specific Cre expression often depends on luck. Here we provide a better alternative by using bacterial artificial chromosome (BAC-based recombineering to insert iCreERT2 cDNA at the ATG start of the Upk2 gene. The BAC-based transgenic mice express the inducible Cre specifically in the urothelium as demonstrated by mRNA expression and staining for LacZ expression after crossing with a Rosa26 reporter mouse. Taking into consideration the size of the gene of interest and neighboring genes included in a BAC, this method should be widely applicable for generation of mice with tissue specific gene expression or deletions in a more specific manner than previously reported.

Aberrant Wound Healing in an Epidermal Interleukin-4 Transgenic Mouse Model of Atopic Dermatitis

Science.gov (United States)

Zhao, Yan; Bao, Lei; Chan, Lawrence S.; DiPietro, Luisa A.; Chen, Lin

2016-01-01

Wound healing in a pre-existing Th2-dominated skin milieu was assessed by using an epidermal specific interleukin-4 (IL-4) transgenic (Tg) mouse model, which develops a pruritic inflammatory skin condition resembling human atopic dermatitis. Our results demonstrated that IL-4 Tg mice had delayed wound closure and re-epithelialization even though these mice exhibited higher degrees of epithelial cell proliferation. Wounds in IL-4 Tg mice also showed a marked enhancement in expression of inflammatory cytokines/chemokines, elevated infiltration of inflammatory cells including neutrophils, macrophages, CD3+ lymphocytes, and epidermal dendritic T lymphocytes. In addition, these mice exhibited a significantly higher level of angiogenesis as compared to wild type mice. Furthermore, wounds in IL-4 Tg mice presented with larger amounts of granulation tissue, but had less expression and deposition of collagen. Taken together, an inflamed skin condition induced by IL-4 has a pronounced negative influence on the healing process. Understanding more about the pathogenesis of wound healing in a Th2- dominated environment may help investigators explore new potential therapeutic strategies. PMID:26752054

A Precise Measurement of the Tau Lifetime

CERN Document Server

Abdallah, J; Adam, W; Adzic, P; Albrecht, T; Alderweireld, T; Alemany-Fernandez, R; Allmendinger, T; Allport, P P; Amaldi, Ugo; Amapane, N; Amato, S; Anashkin, E; Andreazza, A; Andringa, S; Anjos, N; Antilogus, P; Apel, W D; Arnoud, Y; Ask, S; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Ballestrero, A; Bambade, P; Barbier, R; Bardin, Dimitri Yuri; Barker, G J; Baroncelli, A; Battaglia, Marco; Baubillier, M; Becks, K H; Begalli, M; Behrmann, A; Ben-Haim, E; Benekos, N C; Benvenuti, Alberto C; Bérat, C; Berggren, M; Berntzon, L; Bertrand, D; Besançon, M; Besson, N; Bloch, D; Blom, M; Bluj, M; Bonesini, M; Boonekamp, M; Booth, P S L; Borisov, G; Botner, O; Bouquet, B; Bowcock, T J V; Boyko, I; Bracko, M; Brenner, R; Brodet, E; Brückman, P; Brunet, J M; Bugge, L; Buschmann, P; Calvi, M; Camporesi, T; Canale, V; Carena, F; Castro, N; Cavallo, F R; Chapkin, M M; Charpentier, P; Checchia, P; Chierici, R; Shlyapnikov, P; Chudoba, J; Chung, S U; Cieslik, K; Collins, P; Contri, R; Cosme, G; Cossutti, F; Costa, M J; Crennell, D J; Cuevas-Maestro, J; D'Hondt, J; Dalmau, J; Da Silva, T; Da Silva, W; Della Ricca, G; De Angelis, A; de Boer, Wim; De Clercq, C; De Lotto, B; De Maria, N; De Min, A; De Paula, L S; Di Ciaccio, L; Di Simone, A; Doroba, K; Drees, J; Dris, M; Eigen, G; Ekelöf, T J C; Ellert, M; Elsing, M; Espirito-Santo, M C; Fanourakis, G K; Fassouliotis, D; Feindt, M; Fernández, J; Ferrer, A; Ferro, F; Flagmeyer, U; Föth, H; Fokitis, E; Fulda-Quenzer, F; Fuster, J A; Gandelman, M; García, C; Gavillet, P; Gazis, E N; Gokieli, R; Golob, B; Gómez-Ceballos, G; Gonçalves, P; Graziani, E; Grosdidier, G; Grzelak, K; Guy, J; Haag, C; Hallgren, A; Hamacher, K; Hamilton, K; Haug, S; Hauler, F; Hedberg, V; Hennecke, M; Herr, H; Hoffman, J; Holmgren, S O; Holt, P J; Houlden, M A; Hultqvist, K; Jackson, J N; Jarlskog, G; Jarry, P; Jeans, D; Johansson, E K; Johansson, P D; Jonsson, P; Joram, C; Jungermann, L; Kapusta, F; Katsanevas, S; Katsoufis, E C; Kernel, G; Kersevan, B P; Kerzel, U; Kiiskinen, A P; King, B T; Kjaer, N J; Kluit, P; Kokkinias, P; Kourkoumelis, C; Kuznetsov, O; Krumshtein, Z; Kucharczyk, M; Lamsa, J; Leder, G; Ledroit, F; Leinonen, L; Leitner, R; Lemonne, J; Lepeltier, V; Lesiak, T; Liebig, W; Liko, D; Lipniacka, A; Lopes, J H; López, J M; Loukas, D; Lutz, P; Lyons, L; MacNaughton, J; Malek, A; Maltezos, S; Mandl, F; Marco, J; Marco, R; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Martínez-Rivero, C; Masik, J; Mastroyiannopoulos, N; Matorras, F; Matteuzzi, C; Mazzucato, F; Mazzucato, M; McNulty, R; Meroni, C; Migliore, E; Mitaroff, W A; Mjörnmark, U; Moa, T; Moch, M; Mönig, K; Monge, R; Montenegro, J; Moraes, D; Moreno, S; Morettini, P; Müller, U; Münich, K; Mulders, M; Mundim, L; Murray, W; Muryn, B; Myatt, G; Myklebust, T; Nassiakou, M; Navarria, Francesco Luigi; Nawrocki, K; Nicolaidou, R; Nikolenko, M; Oblakowska-Mucha, A; Obraztsov, V F; Olshevskii, A G; Onofre, A; Orava, R; Österberg, K; Ouraou, A; Oyanguren, A; Paganoni, M; Paiano, S; Palacios, J P; Palka, H; Papadopoulou, T D; Pape, L; Parkes, C; Parodi, F; Parzefall, U; Passeri, A; Passon, O; Peralta, L; Perepelitsa, V F; Perrotta, A; Petrolini, A; Piedra, J; Pieri, L; Pierre, F; Pimenta, M; Piotto, E; Podobnik, T; Poireau, V; Pol, M E; Polok, G; Pozdnyakov, V; Pukhaeva, N; Pullia, A; Rames, J; Read, A; Rebecchi, P; Rehn, J; Reid, D; Reinhardt, R; Renton, P B; Richard, F; Rídky, J; Rivero, M; Rodríguez, D; Romero, A; Ronchese, P; Roudeau, P; Rovelli, T; Ruhlmann-Kleider, V; Ryabtchikov, D; Sadovskii, A; Salmi, L; Salt, J; Sander, C; Savoy-Navarro, A; Schwickerath, U; Segar, A; Sekulin, R L; Siebel, M; Sissakian, A N; Smadja, G; Smirnova, O G; Sokolov, A; Sopczak, A; Sosnowski, R; Spassoff, Tz; Stanitzki, M; Stocchi, A; Strauss, J; Stugu, B; Szczekowski, M; Szeptycka, M; Szumlak, T; Tabarelli de Fatis, T; Taffard, A C; Tegenfeldt, F; Timmermans, J; Tkatchev, L G; Tobin, M; Todorovova, S; Tomé, B; Tonazzo, A; Tortosa, P; Travnicek, P; Treille, D; Tristram, G; Trochimczuk, M; Troncon, C; Turluer, M L; Tyapkin, I A; Tyapkin, P; Tzamarias, S; Uvarov, V; Valenti, G; van Dam, P; Van Eldik, J; Van Lysebetten, A; Van Remortel, N; Van Vulpen, I; Vegni, G; Veloso, F; Venus, W A; Verdier, P; Verzi, V; Vilanova, D; Vitale, L; Vrba, V; Wahlen, H; Washbrook, A J; Weiser, C; Wicke, D; Wickens, J H; Wilkinson, G; Winter, M; Witek, M; Yushchenko, O P; Zalewska-Bak, A; Zalewski, P; Zavrtanik, D; Zhuravlov, V; Zimin, N I; Zintchenko, A; Zupan, M

2004-01-01

The tau lepton lifetime has been measured with the e+e- -> tau+tau- events collected by the DELPHI detector at LEP in the years 1991-1995. Three different methods have been exploited, using both one-prong and three-prong tau decay channels. Two measurements have been made using events in which both taus decay to a single charged particle. Combining these measurements gave tau_tau (1 prong) = 291.8 +/- 2.3 (stat) +/- 1.5 (sys) fs. A third measurement using taus which decayed to three charged particles yielded tau_tau (3 prong) = 288.6 +/- 2.4 (stat) +/- 1.3 (sys) fs. These were combined with previous DELPHI results to measure the tau lifetime, using the full LEP1 data sample, to be tau_tau = 290.9 +/- 1.4 (stat) +/- 1.0 (sys) fs.

$\\tau$ decays with neutral kaons

CERN Document Server

Abbiendi, G.; Akesson, P.F.; Alexander, G.; Allison, John; Anderson, K.J.; Arcelli, S.; Asai, S.; Ashby, S.F.; Axen, D.; Azuelos, G.; Bailey, I.; Ball, A.H.; Barberio, E.; Barlow, Roger J.; Batley, J.R.; Baumann, S.; Behnke, T.; Bell, Kenneth Watson; Bella, G.; Bellerive, A.; Bentvelsen, S.; Bethke, S.; Betts, S.; Biebel, O.; Biguzzi, A.; Bloodworth, I.J.; Bock, P.; Bohme, J.; Boeriu, O.; Bonacorsi, D.; Boutemeur, M.; Braibant, S.; Bright-Thomas, P.; Brigliadori, L.; Brown, Robert M.; Burckhart, H.J.; Capiluppi, P.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, David G.; Chrisman, D.; Ciocca, C.; Clarke, P.E.L.; Clay, E.; Cohen, I.; Conboy, J.E.; Cooke, O.C.; Couchman, J.; Couyoumtzelis, C.; Coxe, R.L.; Cuffiani, M.; Dado, S.; Dallavalle, G.Marco; Dallison, S.; Davis, R.; de Roeck, A.; Dervan, P.; Desch, K.; Dienes, B.; Dixit, M.S.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Estabrooks, P.G.; Etzion, E.; Fabbri, F.; Fanfani, A.; Fanti, M.; Faust, A.A.; Feld, L.; Ferrari, P.; Fiedler, F.; Fierro, M.; Fleck, I.; Frey, A.; Furtjes, A.; Futyan, D.I.; Gagnon, P.; Gary, J.W.; Gaycken, G.; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Gingrich, D.M.; Glenzinski, D.; Goldberg, J.; Gorn, W.; Grandi, C.; Graham, K.; Gross, E.; Grunhaus, J.; Gruwe, M.; Hajdu, C.; Hanson, G.G.; Hansroul, M.; Hapke, M.; Harder, K.; Harel, A.; Hargrove, C.K.; Harin-Dirac, M.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Herten, G.; Heuer, R.D.; Hildreth, M.D.; Hill, J.C.; Hobson, P.R.; Hocker, James Andrew; Hoffman, Kara Dion; Homer, R.J.; Honma, A.K.; Horvath, D.; Hossain, K.R.; Howard, R.; Huntemeyer, P.; Igo-Kemenes, P.; Imrie, D.C.; Ishii, K.; Jacob, F.R.; Jawahery, A.; Jeremie, H.; Jimack, M.; Jones, C.R.; Jovanovic, P.; Junk, T.R.; Kanaya, N.; Kanzaki, J.; Karapetian, G.; Karlen, D.; Kartvelishvili, V.; Kawagoe, K.; Kawamoto, T.; Kayal, P.I.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Kim, D.H.; Klier, A.; Kobayashi, T.; Kobel, M.; Kokott, T.P.; Kolrep, M.; Komamiya, S.; Kowalewski, Robert V.; Kress, T.; Krieger, P.; von Krogh, J.; Kuhl, T.; Kupper, M.; Kyberd, P.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Lauber, J.; Lawson, I.; Layter, J.G.; Lellouch, D.; Letts, J.; Levinson, L.; Liebisch, R.; Lillich, J.; List, B.; Littlewood, C.; Lloyd, A.W.; Lloyd, S.L.; Loebinger, F.K.; Long, G.D.; Losty, M.J.; Lu, J.; Ludwig, J.; Macchiolo, A.; Macpherson, A.; Mader, W.; Mannelli, M.; Marcellini, S.; Marchant, T.E.; Martin, A.J.; Martin, J.P.; Martinez, G.; Mashimo, T.; Mattig, Peter; McDonald, W.John; McKenna, J.; Mckigney, E.A.; McMahon, T.J.; McPherson, R.A.; Meijers, F.; Mendez-Lorenzo, P.; Merritt, F.S.; Mes, H.; Meyer, I.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Mohr, W.; Montanari, A.; Mori, T.; Nagai, K.; Nakamura, I.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oakham, F.G.; Odorici, F.; Ogren, H.O.; Okpara, A.; Oreglia, M.J.; Orito, S.; Pasztor, G.; Pater, J.R.; Patrick, G.N.; Patt, J.; Perez-Ochoa, R.; Petzold, S.; Pfeifenschneider, P.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Poli, B.; Polok, J.; Przybycien, M.; Quadt, A.; Rembser, C.; Rick, H.; Robins, S.A.; Rodning, N.; Roney, J.M.; Rosati, S.; Roscoe, K.; Rossi, A.M.; Rozen, Y.; Runge, K.; Runolfsson, O.; Rust, D.R.; Sachs, K.; Saeki, T.; Sahr, O.; Sang, W.M.; Sarkisian, E.K.G.; Sbarra, C.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schieck, J.; Schmitt, S.; Schoning, A.; Schroder, Matthias; Schumacher, M.; Schwick, C.; Scott, W.G.; Seuster, R.; Shears, T.G.; Shen, B.C.; Shepherd-Themistocleous, C.H.; Sherwood, P.; Siroli, G.P.; Skuja, A.; Smith, A.M.; Snow, G.A.; Sobie, R.; Soldner-Rembold, S.; Spagnolo, S.; Sproston, M.; Stahl, A.; Stephens, K.; Stoll, K.; Strom, David M.; Strohmer, R.; Surrow, B.; Talbot, S.D.; Taras, P.; Tarem, S.; Teuscher, R.; Thiergen, M.; Thomas, J.; Thomson, M.A.; Torrence, E.; Towers, S.; Trefzger, T.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Van Kooten, Rick J.; Vannerem, P.; Verzocchi, M.; Voss, H.; Wackerle, F.; Waller, D.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wengler, T.; Wermes, N.; Wetterling, D.; White, J.S.; Wilson, G.W.; Wilson, J.A.; Wyatt, T.R.; Yamashita, S.; Zacek, V.; Zer-Zion, D.

2000-01-01

The branching ratio of the tau lepton to a neutral K meson is measured from a sample of approximately 200,000 tau decays recorded by the OPAL detector at centre-of-mass energies near the Z0 resonance. The measurement is based on two samples which identify one-prong tau decays with KL and KS mesons. The combined branching ratios are measured to be B(tau- -->pi- K0bar nutau) = (9.33+-0.68+-0.49)x10^-3 B(tau- -->pi- K0bar [>=1pi0] nutau) = (3.24+-0.74+-0.66)x10^-3 B(tau- -->K- K0bar [>=0pi0] nutau) = (3.30+-0.55+-0.39)x10^-3 where the first error is statistical and the second systematic.

Study of production and disintegration of tau+tau- pairs at PETRA

International Nuclear Information System (INIS)

Journe, V.

1984-06-01

The subject of this thesis is the study of the production and decay of tau + tau - pairs in e + e - collisions at total centre of mass energies of 14, 22 and 34 GeV. The experiment was carried out at the PETRA e + e - collider, using the CELLO detector. The processes studied allows firstly to test quantum electrodynamics. The measured total cross-section shows the 1/s behaviour characteristic of point-like particles. A first independent confirmation of spin 1/2 for the tau is obtained by measuring the angular distribution which is compatible with (1 + cos 2 theta). At √s = 34 GeV, the effect of electro-weak interference can clearly be seen. Experimentally a forward-backward asymmetry of -(10.2 +- 5.2)% is observed, from which a value for the axial vector coupling constant of asub(tau) = -1.1 +- .6 may be deduced (the prediction of the standard model is -1). Comparison of this value with asub(e), and asub(u) allows a check to be made of the lepton universality hypothesis. Topological branching ratio for tau decays into 1, 3, 5 charged particles have been measured and compared to predictions [fr

PET/SPECT/CT multimodal imaging in a transgenic mouse model of breast cancer

Energy Technology Data Exchange (ETDEWEB)

Boisgard, R.; Alberini, J.L.; Jego, B.; Siquier, K.; Theze, B.; Guillermet, S.; Tavitian, B. [Service Hospitalier Frederic Joliot, Institut d' Imagerie BioMedicale, CEA, 91 - Orsay (France); Inserm, U803, 91 - Orsay (France)

2008-02-15

Background. - In the therapy monitoring of breast cancer, conventional imaging methods include ultrasound, mammography, CT and MRI, which are essentially based on tumor size modifications. However these modifications represent a late consequence of the biological response and fail to differentiate scar or necrotic tissue from residual viable tumoral tissue. Therefore, a current objective is to develop tools able to predict early response to treatment. Positron Emission Tomography (PET) and Single Photon Emission Computerized Tomography (SPECT) are imaging modalities able to provide extremely sensitive quantitative molecular data and are widely used in humans and animals. Results. - Mammary epithelial cells of female transgenic mice expressing the polyoma middle T onco-protein (Py M.T.), undergo four distinct stages of tumour progression, from pre malignant to malignant stages. Stages are identifiable in the mammary tissue and can lead to the development of distant metastases Longitudinal studies by dynamic whole body acquisitions by multimodal imaging including PET, SPECT and Computed Tomography (CT) allow following the tumoral evolution in Py M.T. mice in comparison with the histopathological analysis. At four weeks of age, mammary hyperplasia was identified by histopathology, but no abnormalities were found by palpation or detected by PET with 2-deoxy-2-[{sup 18}F]fluoro-D-glucose. Such as in some human mammary cancers, the sodium iodide sym-porter (N.I.S.) in tumoral mammary epithelial cells is expressed in this mouse model. In order to investigate the expression of N.I.S. in the Py M.T. mice mammary tumours, [{sup 99m}Tc]TcO{sub 4} imaging was performed with a dedicated SPECT/CT system camera (B.I.O.S.P.A.C.E. Gamma Imager/CT). Local uptake of [{sup 99m}Tc]TcO{sub 4} was detected as early as four weeks of age. The efficacy of chemotherapy was evaluated in this mouse model using a conventional regimen (Doxorubicine, 100 mg/ kg) administered weekly from nine to

9th Transgenic Technology Meeting (TT2010) in Berlin, Germany: a meeting report.

Science.gov (United States)

Saunders, Thomas L; Sobieszczuk, Peter

2010-12-01

The first Transgenic Technology (TT) Meeting was organized in 1999 by Johannes Wilbertz, Karolinska Institute, Stockholm, Sweden as a regional meeting. The TT Meetings continued in this way, constantly gathering additional practitioners of transgenic methodologies until the breakthrough in 2005 when the 6th TT Meeting in Barcelona, Spain, hosted by Lluis Montoliu (Centro Nacional de Biotecnologia, Madrid, Spain), generated the momentum to establish the International Society for Transgenic Technologies (ISTT). Since 2006, the ISTT has continued to promote the TT Meetings and provide its membership with a forum to discuss best practices and new methods in the field. The TT2010 Meeting was held at the Max Delbrück Center for Molecular Medicine (Berlin, Germany). Participation at the TT2010 Meeting exceeded the registration capacity and set a new attendance record. Session topics included methods for the generation of rat and mouse models of human disease, fundamental and advanced topics in rodent embryonic stem cells, and the newest transgenic technologies. Short presentations from selected abstracts were of especial interest. Roundtable discussions on transgenic facility establishment and cryoarchiving of mouse lines were favorably received. Students, technical staff, and professors participated in numerous discussions and came away with practical methods and new ideas for research.

The tau-charm factory: Experimental perspectives

International Nuclear Information System (INIS)

Perl, M.L.; Schindler, R.H.

1991-09-01

This report discusses the Tau-Charm Factory Concept; D and D S Physics at the Tau-Charm Factory; τ and ν τ Physics at the Tau-Charm Factory; and Charmonium, Gluonium and Light Quark Spectroscopy at the Tau-Charm Factory

Tau deletion promotes brain insulin resistance.

Science.gov (United States)

Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie; Ahmed, Tariq; Tailleux, Anne; Dumont, Julie; Issad, Tarik; Gerhardt, Ellen; Pagesy, Patrick; Vileno, Margaux; Bournonville, Clément; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Demeyer, Dominique; Eddarkaoui, Sabiha; Vallez, Emmanuelle; Vieau, Didier; Humez, Sandrine; Faivre, Emilie; Grenier-Boley, Benjamin; Outeiro, Tiago F; Staels, Bart; Amouyel, Philippe; Balschun, Detlef; Buee, Luc; Blum, David

2017-08-07

The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients. © 2017 Marciniak et al.

Measurement of Tau Lepton Branching Fractions

Energy Technology Data Exchange (ETDEWEB)

Nicol, N.

2003-12-19

We present {tau}{sup -} lepton branching fraction measurements based on data from the TPC/Two-Gamma detector at PEP. Using a sample of {tau}{sup -} {yields} {nu}{sub {tau}}K{sup -}{pi}{sup +}{pi}{sup -} events, we examine the resonance structure of the K{sup -}{pi}{sup +}{pi}{sup -} system and obtain the first measurements of branching fractions for {tau}{sup -} {yields} {nu}{sub {tau}}K{sub 1}{sup -}(1270) and {tau}{sup -} {yields} {nu}{sub {tau}}K{sub 1}{sup -}(1400). We also describe a complete set of branching fraction measurements in which all the decays of the {tau}{sup -} lepton are separated into classes defined by the identities of the charged particles and an estimate of the number of neutrals. This is the first such global measurement with decay classes defined by the four possible charged particle species, e, {mu}, {pi}, and K.

Chronic caffeine treatment reverses memory impairment and the expression of brain BNDF and TrkB in the PS1/APP double transgenic mouse model of Alzheimer’s disease

Science.gov (United States)

HAN, KUN; JIA, NING; LI, JI; YANG, LI; MIN, LIAN-QIU

2013-01-01

The objective of this study was to investigate the effects of varying doses of caffeine on memory impairment and the expression of brain neurotrophic derived factor (BNDF) and TrkB in PS1/APP double transgenic mouse models. PS1/APP double transgenic mice were administered 0.3 ml/day of saline, 1.5 mg/day of caffeine or 0.75 mg/day of caffeine for eight weeks. A water maze test and western blotting were used to determine the memory capability and expression of hippocampal BNDF and TrkB of the mice. The results demonstrated that 0.75 mg/day and 1.5 mg/day doses of caffeine significantly increased memory capability and the expression of hippocampal BDNF and TrkB in PS1/APP mice with a dose-response effect. The results suggested that chronic caffeine treatment may reverse memory impairment in PS1/APP transgenic mice, and BDNF and its receptor TrkB, may be involved in this process. PMID:23900282

The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse

International Nuclear Information System (INIS)

Schechter, Ruben; Beju, Delia; Miller, Kenneth E.

2005-01-01

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I(-/-)). The I(-/-) exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 β (GSK-3 β) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities

The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse

Energy Technology Data Exchange (ETDEWEB)

Schechter, Ruben [William K. Warren Medical Research Institute, University of Oklahoma Medical Health Science Center, Tulsa, OK 74107 (United States); Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Science, Tulsa, OK 74107 (United States); schechter@okstate edu, E-mail: ruben; Beju, Delia [William K. Warren Medical Research Institute, University of Oklahoma Medical Health Science Center, Tulsa, OK 74107 (United States); Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Science, Tulsa, OK 74107 (United States); Miller, Kenneth E [Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Science, Tulsa, OK 74107 (United States)

2005-09-09

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I(-/-)). The I(-/-) exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 {beta} (GSK-3 {beta}) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities.

Tau mRNA 3'UTR-to-CDS ratio is increased in Alzheimer disease.

Science.gov (United States)

García-Escudero, Vega; Gargini, Ricardo; Martín-Maestro, Patricia; García, Esther; García-Escudero, Ramón; Avila, Jesús

2017-08-10

Neurons frequently show an imbalance in expression of the 3' untranslated region (3'UTR) relative to the coding DNA sequence (CDS) region of mature messenger RNAs (mRNA). The ratio varies among different cells or parts of the brain. The Map2 protein levels per cell depend on the 3'UTR-to-CDS ratio rather than the total mRNA amount, which suggests powerful regulation of protein expression by 3'UTR sequences. Here we found that MAPT (the microtubule-associated protein tau gene) 3'UTR levels are particularly high with respect to other genes; indeed, the 3'UTR-to-CDS ratio of MAPT is balanced in healthy brain in mouse and human. The tau protein accumulates in Alzheimer diseased brain. We nonetheless observed that the levels of RNA encoding MAPT/tau were diminished in these patients' brains. To explain this apparently contradictory result, we studied MAPT mRNA stoichiometry in coding and non-coding regions, and found that the 3'UTR-to-CDS ratio was higher in the hippocampus of Alzheimer disease patients, with higher tau protein but lower total mRNA levels. Our data indicate that changes in the 3'UTR-to-CDS ratio have a regulatory role in the disease. Future research should thus consider not only mRNA levels, but also the ratios between coding and non-coding regions. Copyright © 2017 Elsevier B.V. All rights reserved.

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...

Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models.

Science.gov (United States)

Butler, David; Hwang, Jeannie; Estick, Candice; Nishiyama, Akiko; Kumar, Saranya Santhosh; Baveghems, Clive; Young-Oxendine, Hollie B; Wisniewski, Meagan L; Charalambides, Ana; Bahr, Ben A

2011-01-01

Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid β peptide (Aβ) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aβ(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aβ pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1ΔE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aβ immunostaining as well as Aβ(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Aβ deposition in 20-22-month APPswe/PS1ΔE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aβ(1-38) occurs as Aβ(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Aβ truncation. Associated with Aβ clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aβ(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aβ pathology and provides proof

A transgenic mouse model for measles virus infection of the brain

Science.gov (United States)

Rall, Glenn F.; Manchester, Marianne; Daniels, Lia R.; Callahan, Eric M.; Belman, Alec R.; Oldstone, Michael B. A.

1997-01-01

In addition to the rash, fever, and upper respiratory tract congestion that are the hallmarks of acute measles virus (MV) infection, invasion of the central nervous system (CNS) can occur, establishing a persistent infection primarily in neurons. The recent identification of the human membrane glycoprotein, CD46, as the MV receptor allowed for the establishment of transgenic mice in which the CD46 gene was transcriptionally regulated by a neuron-specific promoter. Expression of the measles receptor rendered primary CD46-positive neurons permissive to infection with MV–Edmonston. Notably, viral transmission within these cultures occurred in the absence of extracellular virus, presumably via neuronal processes. No infection was seen in nontransgenic mice inoculated intracerebrally with MV–Edmonston. In contrast, scattered neurons were infected following inoculation of transgenic adults, and an impressive widespread neuronal infection was established in transgenic neonates. The neonatal infection resulted in severe CNS disease by 3–4 weeks after infection. Illness was characterized initially by awkward gait and a lack of mobility, and in later stages seizures leading to death. These results show that expression of the MV receptor on specific murine cells (neurons) in vivo is absolutely essential to confer both susceptibility to infection and neurologic disease by this human virus. The disparity in clinical findings between neonatal and adult transgenic mice indicates that differences exist between the developing and mature CNS with respect to MV infection and pathogenesis. PMID:9114047

Alterations of cholinergic markers in transgenic APPSWE/PS1DE9 and APPSWE/PS1A246E mouse models of Alzheimer´s disease

Czech Academy of Sciences Publication Activity Database

Machová, Eva; Jakubík, Jan; Michal, Pavel; Oksman, M.; Iivonen, H.; Tanila, H.; Doležal, Vladimír

2007-01-01

Roč. 102, Suppl.1 (2007), s. 133-133 ISSN 0022-3042. [Biennial meeting of the International Society for Neurochemistry /21./ and Annual meeting of the American Society for Neurochemistry /38./. 19.08.2007-24.08.2007, Cancun] R&D Projects: GA MŠk(CZ) LC554; GA AV ČR IAA500110703 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * cholinergic markers * transgenic mouse model * Alzheimer ´s disease Subject RIV: FH - Neurology

Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer's disease.

Science.gov (United States)

Ho, Shuk Wai; Tsui, Yuk Tung Chanel; Wong, Ting Ting; Cheung, Stanley Kwok-Kuen; Goggins, William B; Yi, Lau Ming; Cheng, Kwok Kin; Baum, Larry

2013-12-17

Alzheimer's disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation.

A Simple Model to Study Tau Pathology

Directory of Open Access Journals (Sweden)

Alexander L. Houck

2016-01-01

Full Text Available Tau proteins play a role in the stabilization of microtubules, but in pathological conditions, tauopathies, tau is modified by phosphorylation and can aggregate into aberrant aggregates. These aggregates could be toxic to cells, and different cell models have been used to test for compounds that might prevent these tau modifications. Here, we have used a cell model involving the overexpression of human tau in human embryonic kidney 293 cells. In human embryonic kidney 293 cells expressing tau in a stable manner, we have been able to replicate the phosphorylation of intracellular tau. This intracellular tau increases its own level of phosphorylation and aggregates, likely due to the regulatory effect of some growth factors on specific tau kinases such as GSK3. In these conditions, a change in secreted tau was observed. Reversal of phosphorylation and aggregation of tau was found by the use of lithium, a GSK3 inhibitor. Thus, we propose this as a simple cell model to study tau pathology in nonneuronal cells due to their viability and ease to work with.

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...

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...

Complex genomic rearrangement in CCS-LacZ transgenic mice.

Science.gov (United States)

Stroud, Dina Myers; Darrow, Bruce J; Kim, Sang Do; Zhang, Jie; Jongbloed, Monique R M; Rentschler, Stacey; Moskowitz, Ivan P G; Seidman, Jonathan; Fishman, Glenn I

2007-02-01

The cardiac conduction system (CCS)-lacZ insertional mouse mutant strain genetically labels the developing and mature CCS. This pattern of expression is presumed to reflect the site of transgene integration rather than regulatory elements within the transgene proper. We sought to characterize the genomic structure of the integration locus and identify nearby gene(s) that might potentially confer the observed CCS-specific transcription. We found rearrangement of chromosome 7 between regions D1 and E1 with altered transcription of multiple genes in the D1 region. Several lines of evidence suggested that regulatory elements from at least one gene, Slco3A1, influenced CCS-restricted reporter gene expression. In embryonic hearts, Slco3A1 was expressed in a spatial pattern similar to the CCS-lacZ transgene and was similarly neuregulin-responsive. At later stages, however, expression patterns of the transgene and Slco3A1 diverged, suggesting that the Slco3A1 locus may be necessary, but not sufficient to confer CCS-specific transgene expression in the CCS-lacZ line. (c) 2007 Wiley-Liss, Inc.

Positive and negative early life experiences differentially modulate long term survival and amyloid protein levels in a mouse model of Alzheimer's disease.

Science.gov (United States)

Lesuis, Sylvie L; Maurin, Herve; Borghgraef, Peter; Lucassen, Paul J; Van Leuven, Fred; Krugers, Harm J

2016-06-28

Stress has been implicated as a risk factor for the severity and progression of sporadic Alzheimer's disease (AD). Early life experiences determine stress responsivity in later life, and modulate age-dependent cognitive decline. Therefore, we examined whether early life experiences influence AD outcome in a bigenic mouse model which progressively develops combined tau and amyloid pathology (biAT mice).Mice were subjected to either early life stress (ELS) or to 'positive' early handling (EH) postnatally (from day 2 to 9). In biAT mice, ELS significantly compromised long term survival, in contrast to EH which increased life expectancy. In 4 month old mice, ELS-reared biAT mice displayed increased hippocampal Aβ levels, while these levels were reduced in EH-reared biAT mice. No effects of ELS or EH were observed on the brain levels of APP, protein tau, or PSD-95. Dendritic morphology was moderately affected after ELS and EH in the amygdala and medial prefrontal cortex, while object recognition memory and open field performance were not affected. We conclude that despite the strong transgenic background, early life experiences significantly modulate the life expectancy of biAT mice. Parallel changes in hippocampal Aβ levels were evident, without affecting cognition of young adult biAT mice.

Overexpression of mouse TTF-2 gene causes cleft palate

Science.gov (United States)

Meng, Tian; Shi, Jia-Yu; Wu, Min; Wang, Yan; Li, Ling; Liu, Yan; Zheng, Qian; Huang, Lei; Shi, Bing

2012-01-01

In humans, mutations of the gene encoding for thyroid transcription factor-2 (TTF-2 or FOXE1) result in Bamforth syndrome. Bamforth syndrome is characterized by agenesis, cleft palate, spiky hair and choanal atresia. TTF-2 null mice (TTF-2−/−) also exhibit cleft palate, suggesting its involvement in the palatogenesis. However, the molecular pathology and genetic regulation by TTF2 remain largely unknown. In the present study, the recombinant expression vector pBROAD3-TTF-2 containing the promoter of the mouse ROSA26 gene was created to form the structural gene of mouse TTF-2 and was microinjected into the male pronuclei of fertilized ova. Sequence analysis confirmed that the TTF-2 transgenic mouse model was established successfully. The transgenic mice displayed a phenotype of cleft palate. In addition, we found that TTF-2 was highly expressed in the medial edge epithelium (MEE) from the embryonic day 12.5 (E12.5) to E14.5 in TTF-2 transgenic mice. These observations suggest that overexpression of TTF-2 during palatogenesis may contribute to formation of cleft palate. PMID:22304410

Atypical PKC, PKCλ/ι, activates β-secretase and increases Aβ1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's disease.

Science.gov (United States)

Sajan, Mini P; Hansen, Barbara C; Higgs, Margaret G; Kahn, C Ron; Braun, Ursula; Leitges, Michael; Park, Collin R; Diamond, David M; Farese, Robert V

2018-01-01

Hyperinsulinemia activates brain Akt and PKC-λ/ι and increases Aβ 1-40/42 and phospho-tau in insulin-resistant animals. Here, we examined underlying mechanisms in mice, neuronal cells, and mouse hippocampal slices. Like Aβ 1-40/42 , β-secretase activity was increased in insulin-resistant mice and monkeys. In insulin-resistant mice, inhibition of hepatic PKC-λ/ι sufficient to correct hepatic abnormalities and hyperinsulinemia simultaneously reversed increases in Akt, atypical protein kinase C (aPKC), β-secretase, and Aβ 1-40/42 , and restored acute Akt activation. However, 2 aPKC inhibitors additionally blocked insulin's ability to activate brain PKC-λ/ι and thereby increase β-secretase and Aβ 1-40/42 . Furthermore, direct blockade of brain aPKC simultaneously corrected an impairment in novel object recognition in high-fat-fed insulin-resistant mice. In neuronal cells and/or mouse hippocampal slices, PKC-ι/λ activation by insulin, metformin, or expression of constitutive PKC-ι provoked increases in β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau that were blocked by various PKC-λ/ι inhibitors, but not by an Akt inhibitor. PKC-λ/ι provokes increases in brain β-secretase, Aβ 1-40/42 , and phospho-thr-231-tau. Excessive signaling via PKC-λ/ι may link hyperinsulinemia and other PKC-λ/ι activators to pathological and functional abnormalities in Alzheimer's disease. Published by Elsevier Inc.

Tau pathology in Creutzfeldt-Jakob disease revisited.

Science.gov (United States)

Kovacs, Gabor G; Rahimi, Jasmin; Ströbel, Thomas; Lutz, Mirjam I; Regelsberger, Günther; Streichenberger, Nathalie; Perret-Liaudet, Armand; Höftberger, Romana; Liberski, Pawel P; Budka, Herbert; Sikorska, Beata

2017-05-01

Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau-immunoreactive neuritic profiles. Fifty-two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains. © 2016 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Tau protein and adult hippocampal neurogenesis

Directory of Open Access Journals (Sweden)

Almudena eFuster-Matanzo

2012-07-01

Full Text Available Tau protein is a microtubule associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10 and by presence of hypherphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis.

Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation.

Science.gov (United States)

Kanno, Takeshi; Tsuchiya, Ayako; Tanaka, Akito; Nishizaki, Tomoyuki

2016-09-01

Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer's disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.

A measurement of the $\\tau$ mass and the first CPT test with $\\tau$ leptons

CERN Document Server

Abbiendi, G.; Ainsley, C.; Akesson, P.F.; Alexander, G.; Allison, John; Anderson, K.J.; Arcelli, S.; Asai, S.; Ashby, S.F.; Axen, D.; Azuelos, G.; Bailey, I.; Ball, A.H.; Barberio, E.; Barlow, Roger J.; Batley, J.R.; Baumann, S.; Behnke, T.; Bell, Kenneth Watson; Bella, G.; Bellerive, A.; Bentvelsen, S.; Bethke, S.; Biebel, O.; Bloodworth, I.J.; Bock, P.; Bohme, J.; Boeriu, O.; Bonacorsi, D.; Boutemeur, M.; Braibant, S.; Bright-Thomas, P.; Brigliadori, L.; Brown, Robert M.; Burckhart, H.J.; Cammin, J.; Capiluppi, P.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, David G.; Ciocca, C.; Clarke, P.E.L.; Clay, E.; Cohen, I.; Cooke, O.C.; Couchman, J.; Couyoumtzelis, C.; Coxe, R.L.; Cuffiani, M.; Dado, S.; Dallavalle, G.Marco; Dallison, S.; Davis, R.; Roeck, A.de; Dervan, P.; Desch, K.; Dienes, B.; Dixit, M.S.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Estabrooks, P.G.; Etzion, E.; Fabbri, F.; Fanti, M.; Faust, A.A.; Feld, L.; Ferrari, P.; Fiedler, F.; Fleck, I.; Ford, M.; Frey, A.; Furtjes, A.; Futyan, D.I.; Gagnon, P.; Gary, J.W.; Gaycken, G.; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Gingrich, D.M.; Glenzinski, D.; Goldberg, J.; Grandi, C.; Graham, K.; Gross, E.; Grunhaus, J.; Gruwe, M.; Gunther, P.O.; Hajdu, C.; Hanson, G.G.; Hansroul, M.; Hapke, M.; Harder, K.; Harel, A.; Hargrove, C.K.; Harin-Dirac, M.; Hauke, A.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Hensel, C.; Herten, G.; Heuer, R.D.; Hildreth, M.D.; Hill, J.C.; Hobson, P.R.; Hocker, James Andrew; Hoffman, Kara Dion; Homer, R.J.; Honma, A.K.; Horvath, D.; Hossain, K.R.; Howard, R.; Huntemeyer, P.; Igo-Kemenes, P.; Imrie, D.C.; Ishii, K.; Jacob, F.R.; Jawahery, A.; Jeremie, H.; Jones, C.R.; Jovanovic, P.; Junk, T.R.; Kanaya, N.; Kanzaki, J.; Karapetian, G.; Karlen, D.; Kartvelishvili, V.; Kawagoe, K.; Kawamoto, T.; Kayal, P.I.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Kim, D.H.; Klein, K.; Klier, A.; Kobayashi, T.; Kobel, M.; Kokott, T.P.; Komamiya, S.; Kowalewski, Robert V.; Kress, T.; Krieger, P.; von Krogh, J.; Kuhl, T.; Kupper, M.; Kyberd, P.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Lawson, I.; Layter, J.G.; Leins, A.; Lellouch, D.; Letts, J.; Levinson, L.; Liebisch, R.; Lillich, J.; List, B.; Littlewood, C.; Lloyd, A.W.; Lloyd, S.L.; Loebinger, F.K.; Long, G.D.; Losty, M.J.; Lu, J.; Ludwig, J.; Macchiolo, A.; Macpherson, A.; Mader, W.; Mannelli, M.; Marcellini, S.; Marchant, T.E.; Martin, A.J.; Martin, J.P.; Martinez, G.; Mashimo, T.; Mattig, Peter; McDonald, W.John; McKenna, J.; McMahon, T.J.; McPherson, R.A.; Meijers, F.; Mendez-Lorenzo, P.; Merritt, F.S.; Mes, H.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Mohr, W.; Montanari, A.; Mori, T.; Nagai, K.; Nakamura, I.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oakham, F.G.; Odorici, F.; Ogren, H.O.; Oh, A.; Okpara, A.; Oreglia, M.J.; Orito, S.; Pasztor, G.; Pater, J.R.; Patrick, G.N.; Patt, J.; Pfeifenschneider, P.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Poli, B.; Polok, J.; Pooth, O.; Przybycien, M.; Quadt, A.; Rembser, C.; Rick, H.; Robins, S.A.; Rodning, N.; Roney, J.M.; Rosati, S.; Roscoe, K.; Rossi, A.M.; Rozen, Y.; Runge, K.; Runolfsson, O.; Rust, D.R.; Sachs, K.; Saeki, T.; Sahr, O.; Sang, W.M.; Sarkisian, E.K.G.; Sbarra, C.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schmitt, S.; Schroder, Matthias; Schumacher, M.; Schwick, C.; Scott, W.G.; Seuster, R.; Shears, T.G.; Shen, B.C.; Shepherd-Themistocleous, C.H.; Sherwood, P.; Siroli, G.P.; Skuja, A.; Smith, A.M.; Snow, G.A.; Sobie, R.; Soldner-Rembold, S.; Spagnolo, S.; Sproston, M.; Stahl, A.; Stephens, K.; Stoll, K.; Strom, David M.; Strohmer, R.; Surrow, B.; Talbot, S.D.; Tarem, S.; Taylor, R.J.; Teuscher, R.; Thiergen, M.; Thomas, J.; Thomson, M.A.; Torrence, E.; Towers, S.; Trefzger, T.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Vannerem, P.; Verzocchi, M.; Voss, H.; Vossebeld, J.; Waller, D.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wengler, T.; Wermes, N.; Wetterling, D.; White, J.S.; Wilson, G.W.; Wilson, J.A.; Wyatt, T.R.; Yamashita, S.; Zacek, V.; Zer-Zion, D.

2000-01-01

We measure the mass of the tau lepton to be 1775.1+-1.6(stat)+-1.0(sys t.) MeV using tau pairs from Z0 decays. To test CPT invariance we compare the masses of the positively and negatively charged tau leptons. The relative mass difference is found to be smaller than 3.0 10^-3 at the 90% confidence level.

An upper limit on the $\\tau$ neutrino mass from three- and five-prong tau decays

CERN Document Server

Barate, R; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Nief, J Y; Pietrzyk, B; Casado, M P; Chmeissani, M; Comas, P; Crespo, J M; Delfino, M C; Fernández, E; Fernández-Bosman, M; Garrido, L; Juste, A; Martínez, M; Merino, G; Miquel, R; Mir, L M; Padilla, C; Park, I C; Pascual, A; Perlas, J A; Riu, I; Sánchez, F; Colaleo, A; Creanza, D; De Palma, M; Gelao, G; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Nuzzo, S; Ranieri, A; Raso, G; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Tricomi, A; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Abbaneo, D; Alemany, R; Becker, U; Bright-Thomas, P G; Casper, David William; Cattaneo, M; Cerutti, F; Dissertori, G; Drevermann, H; Forty, Roger W; Frank, M; Hagelberg, R; Hansen, J B; Harvey, J; Janot, P; Jost, B; Lehraus, Ivan; Mato, P; Minten, Adolf G; Moneta, L; Pacheco, A; Pusztaszeri, J F; Ranjard, F; Rolandi, Luigi; Rousseau, D; Schlatter, W D; Schmitt, M; Schneider, O; Tejessy, W; Teubert, F; Tomalin, I R; Wachsmuth, H W; Wagner, A; Ajaltouni, Ziad J; Barrès, A; Boyer, C; Falvard, A; Ferdi, C; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rosnet, P; Rossignol, J M; Fearnley, Tom; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Rensch, B; Wäänänen, A; Daskalakis, G; Kyriakis, A; Markou, C; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Rougé, A; Rumpf, M; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Boccali, T; Focardi, E; Parrini, G; Zachariadou, K; Corden, M; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Passalacqua, L; Pepé-Altarelli, M; Curtis, L; Dorris, S J; Halley, A W; Lynch, J G; O'Shea, V; Raine, C; Scarr, J M; Smith, K; Teixeira-Dias, P; Thompson, A S; Thomson, E; Thomson, F; Buchmüller, O L; Dhamotharan, S; Geweniger, C; Graefe, G; Hanke, P; Hansper, G; Hepp, V; Kluge, E E; Putzer, A; Sommer, J; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, Peter J; Girone, M; Goodsir, S M; Martin, E B; Moutoussi, A; Nash, J; Sedgbeer, J K; Spagnolo, P; Stacey, A M; Williams, M D; Ghete, V M; Girtler, P; Kneringer, E; Kuhn, D; Rudolph, G; Betteridge, A P; Bowdery, C K; Buck, P G; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Jones, R W L; Sloan, Terence; Williams, M I; Giehl, I; Greene, A M; Hoffmann, C; Jakobs, K; Kleinknecht, K; Quast, G; Renk, B; Rohne, E; Sander, H G; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Benchouk, C; Bonissent, A; Bujosa, G; Carr, J; Coyle, P; Diaconu, C A; Etienne, F; Leroy, O; Motsch, F; Payre, P; Talby, M; Sadouki, A; Thulasidas, M; Trabelsi, K; Aleppo, M; Antonelli, M; Ragusa, F; Berlich, R; Blum, Walter; Büscher, V; Dietl, H; Ganis, G; Gotzhein, C; Kroha, H; Lütjens, G; Lutz, Gerhard; Mannert, C; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Stenzel, H; Wiedenmann, W; Wolf, G; Boucrot, J; Callot, O; Chen, S; Choi, Y; Cordier, A; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Höcker, A; Jacholkowska, A; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Nikolic, I A; Schune, M H; Tournefier, E; Veillet, J J; Videau, I; Zerwas, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Palla, Fabrizio; Rizzo, G; Sanguinetti, G; Sciabà, A; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Vannini, C; Venturi, A; Verdini, P G; Blair, G A; Bryant, L M; Chambers, J T; Green, M G; Medcalf, T; Perrodo, P; Strong, J A; Von Wimmersperg-Töller, J H; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Norton, P R; Thompson, J C; Wright, A E; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Black, S N; Dann, J H; Johnson, R P; Kim, H Y; Konstantinidis, N P; Litke, A M; McNeil, M A; Taylor, G; Booth, C N; Brew, C A J; Cartwright, S L; Combley, F; Kelly, M S; Lehto, M H; Reeve, J; Thompson, L F; Affholderbach, K; Böhrer, A; Brandt, S; Cowan, G D; Grupen, Claus; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Musolino, G; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Charles, E; Elmer, P; Ferguson, D P S; Gao, Y; González, S; Greening, T C; Hayes, O J; Hu, H; Jin, S; McNamara, P A; Nachtman, J M; Nielsen, J; Orejudos, W; Pan, Y B; Saadi, Y; Scott, I J; Walsh, J; Wu Sau Lan; Wu, X; Yamartino, J M; Zobernig, G

1998-01-01

A bound on the tau neutrino mass is established using the data collected from 1991 to 1995 at Ecm = M(Z) with the ALEPH detector. Two separate limits are derived by fitting the distribution of visible energy vs invariant mass in tau+ -> pi+ pi+ pi- nu and tau+ -> pi+ pi+ pi- pi- pi+ (pi0) nu decays. The two results are combined to obtain a 95 % confidence level upper limit of 18.2 MeV/c^2 on the mass of the tau neutrino.

Treatment-as-usual (TAU) is anything but usual: a meta-analysis of CBT versus TAU for anxiety and depression.

Science.gov (United States)

Watts, Sarah E; Turnell, Adrienne; Kladnitski, Natalie; Newby, Jill M; Andrews, Gavin

2015-04-01

There were three aims of this study, the first was to examine the efficacy of CBT versus treatment-as-usual (TAU) in the treatment of anxiety and depressive disorders, the second was to examine how TAU is defined in TAU control groups for those disorders, and the third was to explore whether the type of TAU condition influences the estimate of effects of CBT. A systematic search of Cochrane Central Register of Controlled Trials, PsycINFO, and CINAHL was conducted. 48 studies of CBT for depressive or anxiety disorders (n=6926) that specified that their control group received TAU were identified. Most (n=45/48) provided an explanation of the TAU group however there was significant heterogeneity amongst TAU conditions. The meta-analysis showed medium effects favoring CBT over TAU for both anxiety (g=0.69, 95% CI 0.47-0.92, pCBT is superior to TAU and the size of the effect of CBT compared to TAU depends on the nature of the TAU condition. The term TAU is used in different ways and should be more precisely described. The four key details to be reported can be thought of as "who, what, how many, and any additional treatments?" Copyright © 2014 Elsevier B.V. All rights reserved.

Measurement of $Z\\rightarrow\\tau^+\\tau^-$ production in proton-proton collisions at $\\sqrt{s} = 8$ TeV

CERN Document Server

Aaij, Roel; LHCb Collaboration; Adinolfi, Marco; Aidala, Christine Angela; Ajaltouni, Ziad; Akar, Simon; Albicocco, Pietro; Albrecht, Johannes; Alessio, Federico; Alexander, Michael; Alfonso Albero, Alejandro; Ali, Suvayu; Alkhazov, Georgy; Alvarez Cartelle, Paula; Alves Jr, Antonio Augusto; Amato, Sandra; Amerio, Silvia; Amhis, Yasmine; An, Liupan; Anderlini, Lucio; Andreassi, Guido; Andreotti, Mirco; Andrews, Jason; Appleby, Robert; Archilli, Flavio; d'Argent, Philippe; Arnau Romeu, Joan; Artamonov, Alexander; Artuso, Marina; Arzymatov, Kenenbek; Aslanides, Elie; Atzeni, Michele; Bachmann, Sebastian; Back, John; Baker, Sophie; Balagura, Vladislav; Baldini, Wander; Baranov, Alexander; Barlow, Roger; Barsuk, Sergey; Barter, William; Baryshnikov, Fedor; Batozskaya, Varvara; Batsukh, Baasansuren; Battista, Vincenzo; Bay, Aurelio; Beddow, John; Bedeschi, Franco; Bediaga, Ignacio; Beiter, Andrew; Bel, Lennaert; Beliy, Nikita; Bellee, Violaine; Belloli, Nicoletta; Belous, Konstantin; Belyaev, Ivan; Ben-Haim, Eli; Bencivenni, Giovanni; Benson, Sean; Beranek, Sarah; Berezhnoy, Alexander; Bernet, Roland; Berninghoff, Daniel; Bertholet, Emilie; Bertolin, Alessandro; Betancourt, Christopher; Betti, Federico; Bettler, Marc-Olivier; van Beuzekom, Martinus; Bezshyiko, Iaroslava; Bhasin, Srishti; Bhom, Jihyun; Bian, Lingzhu; Bifani, Simone; Billoir, Pierre; Birnkraut, Alex; Bizzeti, Andrea; Bjørn, Mikkel; Blago, Michele Piero; Blake, Thomas; Blanc, Frederic; Blusk, Steven; Bobulska, Dana; Bocci, Valerio; Boente Garcia, Oscar; Boettcher, Thomas; Bondar, Alexander; Bondar, Nikolay; Borghi, Silvia; Borisyak, Maxim; Borsato, Martino; Bossu, Francesco; Boubdir, Meriem; Bowcock, Themistocles; Bozzi, Concezio; Braun, Svende; Brodski, Michael; Brodzicka, Jolanta; Brundu, Davide; Buchanan, Emma; Buonaura, Annarita; Burr, Christopher; Bursche, Albert; Buytaert, Jan; Byczynski, Wiktor; Cadeddu, Sandro; Cai, Hao; Calabrese, Roberto; Calladine, Ryan; Calvi, Marta; Calvo Gomez, Miriam; Camboni, Alessandro; Campana, Pierluigi; Campora Perez, Daniel Hugo; Capriotti, Lorenzo; Carbone, Angelo; Carboni, Giovanni; Cardinale, Roberta; Cardini, Alessandro; Carniti, Paolo; Carson, Laurence; Carvalho Akiba, Kazuyoshi; Casse, Gianluigi; Cassina, Lorenzo; Cattaneo, Marco; Cavallero, Giovanni; Cenci, Riccardo; Chamont, David; Chapman, Matthew George; Charles, Matthew; Charpentier, Philippe; Chatzikonstantinidis, Georgios; Chefdeville, Maximilien; Chekalina, Viktoriia; Chen, Chen; Chen, Shanzhen; Chitic, Stefan-Gabriel; Chobanova, Veronika; Chrzaszcz, Marcin; Chubykin, Alexsei; Ciambrone, Paolo; Cid Vidal, Xabier; Ciezarek, Gregory; Clarke, Peter; Clemencic, Marco; Cliff, Harry; Closier, Joel; Coco, Victor; Cogan, Julien; Cogneras, Eric; Cojocariu, Lucian; Collins, Paula; Colombo, Tommaso; Comerma-Montells, Albert; Contu, Andrea; Coombs, George; Coquereau, Samuel; Corti, Gloria; Corvo, Marco; Costa Sobral, Cayo Mar; Couturier, Benjamin; Cowan, Greig; Craik, Daniel Charles; Crocombe, Andrew; Cruz Torres, Melissa Maria; Currie, Robert; D'Ambrosio, Carmelo; Da Cunha Marinho, Franciole; Da Silva, Cesar Luiz; Dall'Occo, Elena; Dalseno, Jeremy; Danilina, Anna; Davis, Adam; De Aguiar Francisco, Oscar; De Bruyn, Kristof; De Capua, Stefano; De Cian, Michel; De Miranda, Jussara; De Paula, Leandro; De Serio, Marilisa; De Simone, Patrizia; Dean, Cameron Thomas; Decamp, Daniel; Del Buono, Luigi; Delaney, Blaise; Dembinski, Hans Peter; Demmer, Moritz; Dendek, Adam; Derkach, Denis; Deschamps, Olivier; Desse, Fabrice; Dettori, Francesco; Dey, Biplab; Di Canto, Angelo; Di Nezza, Pasquale; Didenko, Sergey; Dijkstra, Hans; Dordei, Francesca; Dorigo, Mirco; Dosil Suárez, Alvaro; Douglas, Lauren; Dovbnya, Anatoliy; Dreimanis, Karlis; Dufour, Laurent; Dujany, Giulio; Durante, Paolo; Durham, John Matthew; Dutta, Deepanwita; Dzhelyadin, Rustem; Dziewiecki, Michal; Dziurda, Agnieszka; Dzyuba, Alexey; Easo, Sajan; Egede, Ulrik; Egorychev, Victor; Eidelman, Semen; Eisenhardt, Stephan; Eitschberger, Ulrich; Ekelhof, Robert; Eklund, Lars; Ely, Scott; Ene, Alexandru; Escher, Stephan; Esen, Sevda; Evans, Timothy; Falabella, Antonio; Farley, Nathanael; Farry, Stephen; Fazzini, Davide; Federici, Luca; Fernandez, Gerard; Fernandez Declara, Placido; Fernandez Prieto, Antonio; Ferrari, Fabio; Ferreira Lopes, Lino; Ferreira Rodrigues, Fernando; Ferro-Luzzi, Massimiliano; Filippov, Sergey; Fini, Rosa Anna; Fiorini, Massimiliano; Firlej, Miroslaw; Fitzpatrick, Conor; Fiutowski, Tomasz; Fleuret, Frederic; Fontana, Marianna; Fontanelli, Flavio; Forty, Roger; Franco Lima, Vinicius; Frank, Markus; Frei, Christoph; Fu, Jinlin; Funk, Wolfgang; Färber, Christian; Féo Pereira Rivello Carvalho, Mauricio; Gabriel, Emmy; Gallas Torreira, Abraham; Galli, Domenico; Gallorini, Stefano; Gambetta, Silvia; Gandelman, Miriam; Gandini, Paolo; Gao, Yuanning; Garcia Martin, Luis Miguel; Garcia Plana, Beatriz; García Pardiñas, Julián; Garra Tico, Jordi; Garrido, Lluis; Gascon, David; Gaspar, Clara; Gavardi, Laura; Gazzoni, Giulio; Gerick, David; Gersabeck, Evelina; 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Mancinelli, Giampiero; Marangotto, Daniele; Maratas, Jan; Marchand, Jean François; Marconi, Umberto; Marin Benito, Carla; Marinangeli, Matthieu; Marino, Pietro; Marks, Jörg; Martellotti, Giuseppe; Martin, Morgan; Martinelli, Maurizio; Martinez Santos, Diego; Martinez Vidal, Fernando; Massafferri, André; Matev, Rosen; Mathad, Abhijit; Mathe, Zoltan; Matteuzzi, Clara; Mauri, Andrea; Maurice, Emilie; Maurin, Brice; Mazurov, Alexander; McCann, Michael; McNab, Andrew; McNulty, Ronan; Mead, James Vincent; Meadows, Brian; Meaux, Cedric; Meier, Frank; Meinert, Nis; Melnychuk, Dmytro; Merk, Marcel; Merli, Andrea; Michielin, Emanuele; Milanes, Diego Alejandro; Millard, Edward James; Minard, Marie-Noelle; Minzoni, Luca; Mitzel, Dominik Stefan; Mogini, Andrea; Molina Rodriguez, Josue; Mombächer, Titus; Monroy, Igancio Alberto; Monteil, Stephane; Morandin, Mauro; Morello, Gianfranco; Morello, Michael Joseph; Morgunova, Olga; Moron, Jakub; Morris, Adam Benjamin; Mountain, Raymond; Muheim, Franz; Mulder, Mick; 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Ricciardi, Stefania; Richards, Sophie; Rinnert, Kurt; Robbe, Patrick; Robert, Arnaud; Rodrigues, Ana Barbara; Rodrigues, Eduardo; Rodriguez Lopez, Jairo Alexis; Roehrken, Markus; Rogozhnikov, Alexey; Roiser, Stefan; Rollings, Alexandra Paige; Romanovskiy, Vladimir; Romero Vidal, Antonio; Rotondo, Marcello; Rudolph, Matthew Scott; Ruf, Thomas; Ruiz Vidal, Joan; Saborido Silva, Juan Jose; Sagidova, Naylya; Saitta, Biagio; Salustino Guimaraes, Valdir; Sanchez Gras, Cristina; Sanchez Mayordomo, Carlos; Sanmartin Sedes, Brais; Santacesaria, Roberta; Santamarina Rios, Cibran; Santimaria, Marco; Santovetti, Emanuele; Sarpis, Gediminas; Sarti, Alessio; Satriano, Celestina; Satta, Alessia; Saur, Miroslav; Savrina, Darya; Schael, Stefan; Schellenberg, Margarete; Schiller, Manuel; Schindler, Heinrich; Schmelling, Michael; Schmelzer, Timon; Schmidt, Burkhard; Schneider, Olivier; Schopper, Andreas; Schreiner, HF; Schubiger, Maxime; Schune, Marie Helene; Schwemmer, Rainer; Sciascia, Barbara; Sciubba, Adalberto; Semennikov, Alexander; Sepulveda, Eduardo Enrique; Sergi, Antonino; Serra, Nicola; Serrano, Justine; Sestini, Lorenzo; Seyfert, Paul; Shapkin, Mikhail; Shcheglov, Yury; Shears, Tara; Shekhtman, Lev; Shevchenko, Vladimir; Shmanin, Evgenii; Siddi, Benedetto Gianluca; Silva Coutinho, Rafael; Silva de Oliveira, Luiz Gustavo; Simi, Gabriele; Simone, Saverio; Skidmore, Nicola; Skwarnicki, Tomasz; Smeaton, John Gordon; Smith, Eluned; Smith, Iwan Thomas; Smith, Mark; Soares, Marcelo; Soares Lavra, Lais; Sokoloff, Michael; Soler, Paul; Souza De Paula, Bruno; Spaan, Bernhard; Spradlin, Patrick; Stagni, Federico; Stahl, Marian; Stahl, Sascha; Stefko, Pavol; Stefkova, Slavomira; Steinkamp, Olaf; Stemmle, Simon; Stenyakin, Oleg; Stepanova, Margarita; Stevens, Holger; Stone, Sheldon; Storaci, Barbara; Stracka, Simone; Stramaglia, Maria Elena; Straticiuc, Mihai; Straumann, Ulrich; Strokov, Sergey; Sun, Jiayin; Sun, Liang; Swientek, Krzysztof; Syropoulos, Vasileios; Szumlak, Tomasz; Szymanski, Maciej Pawel; T'Jampens, Stephane; Tang, Zhipeng; Tayduganov, Andrey; Tekampe, Tobias; Tellarini, Giulia; Teubert, Frederic; Thomas, Eric; van Tilburg, Jeroen; Tilley, Matthew James; Tisserand, Vincent; Tolk, Siim; Tomassetti, Luca; Tonelli, Diego; Tou, Da Yu; Tourinho Jadallah Aoude, Rafael; Tournefier, Edwige; Tourneur, Stephane; Traill, Murdo; Tran, Minh Tâm; Trisovic, Ana; Tsaregorodtsev, Andrei; Tully, Alison; Tuning, Niels; Ukleja, Artur; Usachov, Andrii; Ustyuzhanin, Andrey; Uwer, Ulrich; Vacca, Claudia; Vagner, Alexander; Vagnoni, Vincenzo; Valassi, Andrea; Valat, Sebastien; Valenti, Giovanni; Vazquez Gomez, Ricardo; Vazquez Regueiro, Pablo; Vecchi, Stefania; van Veghel, Maarten; Velthuis, Jaap; Veltri, Michele; Veneziano, Giovanni; Venkateswaran, Aravindhan; Verlage, Tobias Anton; Vernet, Maxime; Vesterinen, Mika; Viana Barbosa, Joao Vitor; Vieira, Daniel; Vieites Diaz, Maria; Viemann, Harald; Vilasis-Cardona, Xavier; Vitkovskiy, Arseniy; Vitti, Marcela; Volkov, Vladimir; Vollhardt, Achim; Voneki, Balazs; Vorobyev, Alexey; Vorobyev, Vitaly; de Vries, Jacco; Vázquez Sierra, Carlos; Waldi, Roland; Walsh, John; Wang, Jianchun; Wang, Mengzhen; Wang, Yilong; Wang, Zhenzi; Ward, David; Wark, Heather Mckenzie; Watson, Nigel; Websdale, David; Weiden, Andreas; Weisser, Constantin; Whitehead, Mark; Wicht, Jean; Wilkinson, Guy; Wilkinson, Michael; Williams, Ifan; Williams, Mark Richard James; Williams, Mike; Williams, Timothy; Wilson, Fergus; Wimberley, Jack; Winn, Michael Andreas; Wishahi, Julian; Wislicki, Wojciech; Witek, Mariusz; Wormser, Guy; Wotton, Stephen; Wyllie, Kenneth; Xiao, Dong; Xie, Yuehong; Xu, Ao; Xu, Menglin; Xu, Qingnian; Xu, Zehua; Xu, Zhirui; Yang, Zhenwei; Yang, Zishuo; Yao, Yuezhe; Yeomans, Lauren Emma; Yin, Hang; Yu, Jiesheng; Yuan, Xuhao; Yushchenko, Oleg; Zarebski, Kristian Alexander; Zavertyaev, Mikhail; Zhang, Dongliang; Zhang, Liming; Zhang, Wen Chao; Zhang, Yanxi; Zhelezov, Alexey; Zheng, Yangheng; Zhu, Xianglei; Zhukov, Valery; Zonneveld, Jennifer Brigitta; Zucchelli, Stefano

2018-01-01

A measurement of the $Z\\rightarrow\\tau^+\\tau^-$ production cross-section is presented using data, corresponding to an integrated luminosity of 2 fb$^{-1}$, from $pp$ collisions at $\\sqrt{s}=8$ TeV collected by the LHCb experiment. The $\\tau^+\\tau^-$ candidates are reconstructed in final states with the first tau lepton decaying leptonically, and the second decaying either leptonically or to one or three charged hadrons. The production cross-section is measured for $Z$ bosons with invariant mass between 60 and 120 GeV/$c^2$, which decay to tau leptons with transverse momenta greater than 20 GeV/$c$ and pseudorapidities between 2.0 and 4.5. The cross-section is determined to be $\\sigma_{pp\\rightarrow{}Z\\rightarrow{}\\tau^+\\tau^-} = 95.8 \\pm 2.1 \\pm 4.6 \\pm 0.2 \\pm 1.1 \\mathrm{pb}$, where the first uncertainty is statistical, the second is systematic, the third is due to the LHC beam energy uncertainty, and the fourth to the integrated luminosity uncertainty. This result is compatible with NNLO Standard mo...

Lentiviral transgenic microRNA-based shRNA suppressed mouse cytochromosome P450 3A (CYP3A expression in a dose-dependent and inheritable manner.

Directory of Open Access Journals (Sweden)

Yong Wang

Full Text Available Cytochomosome P450 enzymes (CYP are heme-containing monooxygenases responsible for oxidative metabolism of many exogenous and endogenous compounds including drugs. The species difference of CYP limits the extent to which data obtained from animals can be translated to humans in pharmacodynamics or pharmacokinetics studies. Transgenic expression of human CYP in animals lacking or with largely reduced endogenous CYP counterparts is recognized as an ideal strategy to correct CYP species difference. CYP3A is the most abundant CYP subfamily both in human and mammals. In this study, we designed a microRNA-based shRNA (miR-shRNA simultaneously targeting four members of mouse CYP3A subfamily (CYP3A11, CYP3A16, CYP3A41 and CYP3A44, and transgenic mice expressing the designed miR-shRNA were generated by lentiviral transgenesis. Results showed that the CYP3A expression level in transgenic mice was markedly reduced compared to that in wild type or unrelated miR-shRNA transgenic mice, and was inversely correlated to the miR-shRNA expression level. The CYP3A expression levels in transgenic offspring of different generations were also remarkably lower compared to those of controls, and moreover the inhibition rate of CYP3A expression remained comparable over generations. The ratio of the targeted CYP3A transcriptional levels was comparable between knockdown and control mice of the same gender as detected by RT-PCR DGGE analysis. These data suggested that transgenic miR-shRNA suppressed CYP3A expression in a dose-dependent and inheritable manner, and transcriptional levels of the targeted CYP3As were suppressed to a similar extent. The observed knockdown efficacy was further confirmed by enzymatic activity analysis, and data showed that CYP3A activities in transgenic mice were markedly reduced compared to those in wild-type or unrelated miR-shRNA transgenic controls (1.11±0.71 vs 5.85±1.74, 5.9±2.4; P<0.01. This work laid down a foundation to further knock

Tau leptonic branching ratios

CERN Document Server

Buskulic, Damir; De Bonis, I; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Odier, P; Pietrzyk, B; Ariztizabal, F; Chmeissani, M; Crespo, J M; Efthymiopoulos, I; Fernández, E; Fernández-Bosman, M; Gaitan, V; Garrido, L; Martínez, M; Orteu, S; Pacheco, A; Padilla, C; Palla, Fabrizio; Pascual, A; Perlas, J A; Sánchez, F; Teubert, F; Colaleo, A; Creanza, D; De Palma, M; Farilla, A; Gelao, G; Girone, M; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Natali, S; Nuzzo, S; Ranieri, A; Raso, G; Romano, F; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Bonvicini, G; Cattaneo, M; Comas, P; Coyle, P; Drevermann, H; Engelhardt, A; Forty, Roger W; Frank, M; Hagelberg, R; Harvey, J; Jacobsen, R; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Markou, C; Martin, E B; Mato, P; Minten, Adolf G; Miquel, R; Oest, T; Palazzi, P; Pater, J R; Pusztaszeri, J F; Ranjard, F; Rensing, P E; Rolandi, Luigi; Schlatter, W D; Schmelling, M; Schneider, O; Tejessy, W; Tomalin, I R; Venturi, A; Wachsmuth, H W; Wiedenmann, W; Wildish, T; Witzeling, W; Wotschack, J; Ajaltouni, Ziad J; Bardadin-Otwinowska, Maria; Barrès, A; Boyer, C; Falvard, A; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rossignol, J M; Saadi, F; Fearnley, Tom; Hansen, J B; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Kyriakis, A; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Zachariadou, K; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Passalacqua, L; Rougé, A; Rumpf, M; Tanaka, R; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Focardi, E; Parrini, G; Corden, M; Delfino, M C; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Pepé-Altarelli, M; Dorris, S J; Halley, A W; ten Have, I; Knowles, I G; Lynch, J G; Morton, W T; O'Shea, V; Raine, C; Reeves, P; Scarr, J M; Smith, K; Smith, M G; Thompson, A S; Thomson, F; Thorn, S; Turnbull, R M; Becker, U; Braun, O; Geweniger, C; Graefe, G; Hanke, P; Hepp, V; Kluge, E E; Putzer, A; Rensch, B; Schmidt, M; Sommer, J; Stenzel, H; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Colling, D J; Dornan, Peter J; Konstantinidis, N P; Moneta, L; Moutoussi, A; Nash, J; San Martin, G; Sedgbeer, J K; Stacey, A M; Dissertori, G; Girtler, P; Kuhn, D; Rudolph, G; Bowdery, C K; Brodbeck, T J; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Sloan, Terence; Whelan, E P; Williams, M I; Galla, A; Greene, A M; Kleinknecht, K; Quast, G; Raab, J; Renk, B; Sander, H G; Wanke, R; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Bencheikh, A M; Benchouk, C; Bonissent, A; Bujosa, G; Calvet, D; Carr, J; Diaconu, C A; Etienne, F; Thulasidas, M; Nicod, D; Payre, P; Rousseau, D; Talby, M; Abt, I; Assmann, R W; Bauer, C; Blum, Walter; Brown, D; Dietl, H; Dydak, Friedrich; Ganis, G; Gotzhein, C; Jakobs, K; Kroha, H; Lütjens, G; Lutz, Gerhard; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Saint-Denis, R; Wolf, G; Alemany, R; Boucrot, J; Callot, O; Cordier, A; Courault, F; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Jacquet, M; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Musolino, G; Nikolic, I A; Park, H J; Park, I C; Schune, M H; Simion, S; Veillet, J J; Videau, I; Abbaneo, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Rizzo, G; Sanguinetti, G; Sciabà, A; Spagnolo, P; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Triggiani, G; Vannini, C; Verdini, P G; Walsh, J; Betteridge, A P; Blair, G A; Bryant, L M; Cerutti, F; Gao, Y; Green, M G; Johnson, D L; Medcalf, T; Mir, L M; Perrodo, P; Strong, J A; Bertin, V; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Edwards, M; Maley, P; Norton, P R; Thompson, J C; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Marx, B; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Johnson, R P; Kim, H Y; Litke, A M; McNeil, M A; Taylor, G; Beddall, A; Booth, C N; Boswell, R; Cartwright, S L; Combley, F; Dawson, I; Köksal, A; Letho, M; Newton, W M; Rankin, C; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Feigl, E; Grupen, Claus; Lutters, G; Minguet-Rodríguez, J A; Rivera, F; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Ragusa, F; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Bellantoni, L; Elmer, P; Feng, Z; Ferguson, D P S; Gao, Y S; González, S; Grahl, J; Harton, J L; Hayes, O J; Hu, H; McNamara, P A; Nachtman, J M; Orejudos, W; Pan, Y B; Saadi, Y; Schmitt, M; Scott, I J; Sharma, V; Turk, J; Walsh, A M; Wu Sau Lan; Wu, X; Yamartino, J M; Zheng, M; Zobernig, G

1996-01-01

A sample of 62249 \\tau-pair events is selected from data taken with the ALEPH detector in 1991, 1992 and 1993. The measurement of the branching fractions for \\tau decays into electrons and muons is presented with emphasis on the study of systematic effects from selection, particle identification and decay classification. Combined with the most recent ALEPH determination of the \\tau lifetime, these results provide a relative measurement of the leptonic couplings in the weak charged current for transverse W bosons.

Associations between [18F]AV1451 tau PET and CSF measures of tau pathology in a clinical sample.

Science.gov (United States)

La Joie, Renaud; Bejanin, Alexandre; Fagan, Anne M; Ayakta, Nagehan; Baker, Suzanne L; Bourakova, Viktoriya; Boxer, Adam L; Cha, Jungho; Karydas, Anna; Jerome, Gina; Maass, Anne; Mensing, Ashley; Miller, Zachary A; O'Neil, James P; Pham, Julie; Rosen, Howard J; Tsai, Richard; Visani, Adrienne V; Miller, Bruce L; Jagust, William J; Rabinovici, Gil D

2018-01-23

To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent β-amyloid (Aβ) and tau ([ 18 F]AV1451) PET and lumbar puncture. CSF biomarkers (Aβ 42 , total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aβ-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. [ 18 F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aβ-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [ 18 F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau ( r = 0.75 vs 0.57 for t-tau and -0.49 for Aβ 42 ). When restricted to Aβ-positive patients with AD, [ 18 F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aβ 42 ( r = 0.02). On voxelwise analysis, [ 18 F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [ 18 F]AV1451-PET, but not CSF biomarkers. [ 18 F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. This study provides Class III evidence that, in a clinical sample of patients with a variety

One-prong $\\tau$ decays with kaons

CERN Document Server

Barate, R.; Ghez, Philippe; Goy, C.; Lees, J.P.; Merle, E.; Minard, M.N.; Pietrzyk, B.; Alemany, R.; Casado, M.P.; Chmeissani, M.; Crespo, J.M.; Fernandez, E.; Fernandez-Bosman, M.; Garrido, L.; Grauges, E.; Juste, A.; Martinez, M.; Merino, G.; Miquel, R.; Mir, L.M.; Pacheco, A.; Park, I.C.; Riu, I.; Colaleo, A.; Creanza, D.; De Palma, M.; Gelao, G.; Iaselli, G.; Maggi, G.; Maggi, M.; Nuzzo, S.; Ranieri, A.; Raso, G.; Ruggieri, F.; Selvaggi, G.; Silvestris, L.; Tempesta, P.; Tricomi, A.; Zito, G.; Huang, X.; Lin, J.; Ouyang, Q.; Wang, T.; Xie, Y.; Xu, R.; Xue, S.; Zhang, J.; Zhang, L.; Zhao, W.; Abbaneo, D.; Becker, U.; Boix, G.; Cattaneo, M.; Ciulli, V.; Dissertori, G.; Drevermann, H.; Forty, R.W.; Frank, M.; Halley, A.W.; Hansen, J.B.; Harvey, John; Janot, P.; Jost, B.; Lehraus, I.; Leroy, O.; Mato, P.; Minten, A.; Moutoussi, A.; Ranjard, F.; Rolandi, Gigi; Rousseau, D.; Schlatter, D.; Schmitt, M.; Schneider, O.; Tejessy, W.; Teubert, F.; Tomalin, I.R.; Tournefier, E.; Wright, A.E.; Ajaltouni, Z.; Badaud, F.; Chazelle, G.; Deschamps, O.; Falvard, A.; Ferdi, C.; Gay, P.; Guicheney, C.; Henrard, P.; Jousset, J.; Michel, B.; Monteil, S.; Montret, J.C.; Pallin, D.; Perret, P.; Podlyski, F.; Hansen, J.D.; Hansen, J.R.; Hansen, P.H.; Nilsson, B.S.; Rensch, B.; Waananen, A.; Daskalakis, G.; Kyriakis, A.; Markou, C.; Simopoulou, E.; Siotis, I.; Vayaki, A.; Blondel, A.; Bonneaud, G.; Brient, J.C.; Rouge, A.; Rumpf, M.; Swynghedauw, M.; Verderi, M.; Videau, H.; Focardi, E.; Parrini, G.; Zachariadou, K.; Cavanaugh, R.; Corden, M.; Georgiopoulos, C.; Antonelli, A.; Bencivenni, G.; Bologna, G.; Bossi, F.; Campana, P.; Capon, G.; Cerutti, F.; Chiarella, V.; Laurelli, P.; Mannocchi, G.; Murtas, F.; Murtas, G.P.; Passalacqua, L.; Pepe-Altarelli, M.; Curtis, L.; Lynch, J.G.; Negus, P.; O'Shea, V.; Raine, C.; Teixeira-Dias, P.; Thompson, A.S.; Buchmuller, O.; Dhamotharan, S.; Geweniger, C.; Hanke, P.; Hansper, G.; Hepp, V.; Kluge, E.E.; Putzer, A.; Sommer, J.; Tittel, K.; Werner, S.; Wunsch, M.; Beuselinck, R.; Binnie, D.M.; Cameron, W.; Dornan, P.J.; Girone, M.; Goodsir, S.; Martin, E.B.; Marinelli, N.; Sedgbeer, J.K.; Spagnolo, P.; Thomson, Evelyn J.; Williams, M.D.; Ghete, V.M.; Girtler, P.; Kneringer, E.; Kuhn, D.; Rudolph, G.; Betteridge, A.P.; Bowdery, C.K.; Buck, P.G.; Colrain, P.; Crawford, G.; Finch, A.J.; Foster, F.; Hughes, G.; Jones, R.W.L.; Robertson, N.A.; Williams, M.I.; Giehl, I.; Hoffmann, C.; Jakobs, K.; Kleinknecht, K.; Quast, G.; Renk, B.; Rohne, E.; Sander, H.G.; van Gemmeren, P.; Wachsmuth, H.; Zeitnitz, C.; Aubert, J.J.; Benchouk, C.; Bonissent, A.; Carr, J.; Coyle, P.; Etienne, F.; Motsch, F.; Payre, P.; Talby, M.; Thulasidas, M.; Aleppo, M.; Antonelli, M.; Ragusa, F.; Berlich, R.; Buescher, Volker; Dietl, H.; Ganis, G.; Huttmann, K.; Lutjens, G.; Mannert, C.; Manner, W.; Moser, H.G.; Schael, S.; Settles, R.; Seywerd, H.; Stenzel, H.; Wiedenmann, W.; Wolf, G.; Azzurri, P.; Boucrot, J.; Callot, O.; Chen, S.; Cordier, A.; Davier, M.; Duflot, L.; Grivaz, J.F.; Heusse, P.; Hocker, Andreas; Jacholkowska, A.; Kim, D.W.; Le Diberder, F.; Lefrancois, J.; Lutz, A.M.; Schune, M.H.; Veillet, J.J.; Videau, I.; Zerwas, D.; Bagliesi, Giuseppe; Bettarini, S.; Boccali, T.; Bozzi, C.; Calderini, G.; Dell'Orso, R.; Ferrante, I.; Foa, L.; Giassi, A.; Gregorio, A.; Ligabue, F.; Lusiani, A.; Marrocchesi, P.S.; Messineo, A.; Palla, F.; Rizzo, G.; Sanguinetti, G.; Sciaba, A.; Sguazzoni, G.; Tenchini, R.; Vannini, C.; Venturi, A.; Verdini, P.G.; Blair, G.A.; Cowan, G.; Green, M.G.; Medcalf, T.; Strong, J.A.; von Wimmersperg-Toeller, J.H.; Botterill, D.R.; Clifft, R.W.; Edgecock, T.R.; Norton, P.R.; Thompson, J.C.; Bloch-Devaux, Brigitte; Colas, P.; Emery, S.; Kozanecki, W.; Lancon, E.; Lemaire, M.C.; Locci, E.; Perez, P.; Rander, J.; Renardy, J.F.; Roussarie, A.; Schuller, J.P.; Schwindling, J.; Trabelsi, A.; Vallage, B.; Black, S.N.; Dann, J.H.; Johnson, R.P.; Kim, H.Y.; Konstantinidis, N.; Litke, A.M.; McNeil, M.A.; Taylor, G.; Booth, C.N.; Cartwright, S.; Combley, F.; Kelly, M.S.; Lehto, M.; Thompson, L.F.; Affholderbach, K.; Boehrer, Armin; Brandt, S.; Grupen, C.; Prange, G.; Giannini, G.; Gobbo, B.; Rothberg, J.; Wasserbaech, S.; Armstrong, S.R.; Charles, E.; Elmer, P.; Ferguson, D.P.S.; Gao, Y.; Gonzalez, S.; Greening, T.C.; Hayes, O.J.; Hu, H.; Jin, S.; McNamara, P.A., III; Nachtman, J.M.; Nielsen, J.; Orejudos, W.; Pan, Y.B.; Saadi, Y.; Scott, I.J.; Walsh, J.; Wu, Sau Lan; Wu, X.; Zobernig, G.

1999-01-01

One-prong $\\tau$ decays into final states involving kaons are studied with about 161k $\\tau^+\\tau^-$ events collected by the ALEPH detector from 1991 to 1995. Charged kaons are identified by dE/dx measurement, while $K^0_L$'s are detected through their interaction in calorimeters. Branching ratios are measured for the inclusive mode, $B(\\tau^-\\rightarrow K^-X\

RANK/RANKL/OPG Signalization Implication in Periodontitis: New Evidence from a RANK Transgenic Mouse Model

Directory of Open Access Journals (Sweden)

Bouchra Sojod

2017-05-01

Full Text Available Periodontitis is based on a complex inflammatory over-response combined with possible genetic predisposition factors. The RANKL/RANK/OPG signaling pathway is implicated in bone resorption through its key function in osteoclast differentiation and activation, as well as in the inflammatory response. This central element of osteo-immunology has been suggested to be perturbed in several diseases, including periodontitis, as it is a predisposing factor for this disease. The aim of the present study was to validate this hypothesis using a transgenic mouse line, which over-expresses RANK (RTg and develops a periodontitis-like phenotype at 5 months of age. RTg mice exhibited severe alveolar bone loss, an increased number of TRAP positive cells, and disorganization of periodontal ligaments. This phenotype was more pronounced in females. We also observed dental root resorption lacunas. Hyperplasia of the gingival epithelium, including Malassez epithelial rests, was visible as early as 25 days, preceding any other symptoms. These results demonstrate that perturbations of the RANKL/RANK/OPG system constitute a core element of periodontitis, and more globally, osteo-immune diseases.

RANK/RANKL/OPG Signalization Implication in Periodontitis: New Evidence from a RANK Transgenic Mouse Model

Science.gov (United States)

Sojod, Bouchra; Chateau, Danielle; Mueller, Christopher G.; Babajko, Sylvie; Berdal, Ariane; Lézot, Frédéric; Castaneda, Beatriz

2017-01-01

Periodontitis is based on a complex inflammatory over-response combined with possible genetic predisposition factors. The RANKL/RANK/OPG signaling pathway is implicated in bone resorption through its key function in osteoclast differentiation and activation, as well as in the inflammatory response. This central element of osteo-immunology has been suggested to be perturbed in several diseases, including periodontitis, as it is a predisposing factor for this disease. The aim of the present study was to validate this hypothesis using a transgenic mouse line, which over-expresses RANK (RTg) and develops a periodontitis-like phenotype at 5 months of age. RTg mice exhibited severe alveolar bone loss, an increased number of TRAP positive cells, and disorganization of periodontal ligaments. This phenotype was more pronounced in females. We also observed dental root resorption lacunas. Hyperplasia of the gingival epithelium, including Malassez epithelial rests, was visible as early as 25 days, preceding any other symptoms. These results demonstrate that perturbations of the RANKL/RANK/OPG system constitute a core element of periodontitis, and more globally, osteo-immune diseases. PMID:28596739

Measurement of the $\\mathrm{Z}\\gamma^{*} \\to \\tau\\tau$ cross section in pp collisions at $\\sqrt{s} = $ 13 TeV and validation of $\\tau$ lepton analysis techniques

CERN Document Server

Sirunyan, Albert M; CMS Collaboration; Adam, Wolfgang; Ambrogi, Federico; Asilar, Ece; Bergauer, Thomas; Brandstetter, Johannes; Brondolin, Erica; Dragicevic, Marko; Erö, Janos; Escalante Del Valle, Alberto; Flechl, Martin; Friedl, Markus; Fruehwirth, Rudolf; Ghete, Vasile Mihai; Grossmann, Johannes; Hrubec, Josef; Jeitler, Manfred; König, Axel; Krammer, Natascha; Krätschmer, Ilse; Liko, Dietrich; Madlener, Thomas; Mikulec, Ivan; Pree, Elias; Rad, Navid; Rohringer, Herbert; Schieck, Jochen; Schöfbeck, Robert; Spanring, Markus; Spitzbart, Daniel; Taurok, Anton; Waltenberger, Wolfgang; Wittmann, Johannes; Wulz, Claudia-Elisabeth; Zarucki, Mateusz; Chekhovsky, Vladimir; Mossolov, Vladimir; Suarez Gonzalez, Juan; De Wolf, Eddi A; Di Croce, Davide; Janssen, Xavier; Lauwers, Jasper; Van De Klundert, Merijn; Van Haevermaet, Hans; Van Mechelen, Pierre; Van Remortel, Nick; Abu Zeid, Shimaa; Blekman, Freya; D'Hondt, Jorgen; De Bruyn, Isabelle; De Clercq, Jarne; Deroover, Kevin; Flouris, Giannis; Lontkovskyi, Denys; Lowette, Steven; Marchesini, Ivan; Moortgat, Seth; Moreels, Lieselotte; Python, Quentin; Skovpen, Kirill; Tavernier, Stefaan; Van Doninck, Walter; Van Mulders, Petra; Van Parijs, Isis; Beghin, Diego; Bilin, Bugra; Brun, Hugues; Clerbaux, Barbara; De Lentdecker, Gilles; Delannoy, Hugo; Dorney, Brian; Fasanella, Giuseppe; Favart, Laurent; Goldouzian, Reza; Grebenyuk, Anastasia; Kalsi, Amandeep Kaur; Lenzi, Thomas; Luetic, Jelena; Maerschalk, Thierry; Marinov, Andrey; Seva, Tomislav; Starling, Elizabeth; Vander Velde, Catherine; Vanlaer, Pascal; Vannerom, David; Yonamine, Ryo; Zenoni, Florian; Cornelis, Tom; Dobur, Didar; Fagot, Alexis; Gul, Muhammad; Khvastunov, Illia; Poyraz, Deniz; Roskas, Christos; Salva Diblen, Sinem; Trocino, Daniele; Tytgat, Michael; Verbeke, Willem; Zaganidis, Nicolas; Bakhshiansohi, Hamed; Bondu, Olivier; Brochet, Sébastien; Bruno, Giacomo; Caputo, Claudio; Caudron, Adrien; David, Pieter; De Visscher, Simon; Delaere, Christophe; Delcourt, Martin; Francois, Brieuc; Giammanco, Andrea; Komm, Matthias; Krintiras, Georgios; Lemaitre, Vincent; Magitteri, Alessio; Mertens, Alexandre; Musich, Marco; Piotrzkowski, Krzysztof; Quertenmont, Loic; Saggio, Alessia; Vidal Marono, Miguel; Wertz, Sébastien; Zobec, Joze; Aldá Júnior, Walter Luiz; Alves, Fábio Lúcio; Alves, Gilvan; Brito, Lucas; Correia Silva, Gilson; Hensel, Carsten; Moraes, Arthur; Pol, Maria Elena; Rebello Teles, Patricia; Belchior Batista Das Chagas, Ewerton; Carvalho, Wagner; Chinellato, Jose; Coelho, Eduardo; Melo Da Costa, Eliza; Da Silveira, Gustavo Gil; De Jesus Damiao, Dilson; Fonseca De Souza, Sandro; Huertas Guativa, Lina Milena; Malbouisson, Helena; Melo De Almeida, Miqueias; Mora Herrera, Clemencia; Mundim, Luiz; Nogima, Helio; Sanchez Rosas, Luis Junior; Santoro, Alberto; Sznajder, Andre; Thiel, Mauricio; Tonelli Manganote, Edmilson José; Torres Da Silva De Araujo, Felipe; Vilela Pereira, Antonio; Ahuja, Sudha; Bernardes, Cesar Augusto; Tomei, Thiago; De Moraes Gregores, Eduardo; Mercadante, Pedro G; Novaes, Sergio F; Padula, Sandra; Romero Abad, David; Ruiz Vargas, José Cupertino; Aleksandrov, Aleksandar; Hadjiiska, Roumyana; Iaydjiev, Plamen; Misheva, Milena; Rodozov, Mircho; Shopova, Mariana; Sultanov, Georgi; Dimitrov, Anton; Litov, Leander; Pavlov, Borislav; Petkov, Peicho; Fang, Wenxing; Gao, Xuyang; Yuan, Li; Ahmad, Muhammad; Bian, Jian-Guo; Chen, Guo-Ming; Chen, He-Sheng; Chen, Mingshui; Chen, Ye; Jiang, Chun-Hua; Leggat, Duncan; Liao, Hongbo; Liu, Zhenan; Romeo, Francesco; Shaheen, Sarmad Masood; Spiezia, Aniello; Tao, Junquan; Wang, Chunjie; Wang, Zheng; Yazgan, Efe; Yu, Taozhe; Zhang, Huaqiao; Zhao, Jingzhou; Ban, Yong; Chen, Geng; Li, Jing; Li, Qiang; Liu, Shuai; Mao, Yajun; Qian, Si-Jin; Wang, Dayong; Xu, Zijun; Zhang, Fengwangdong; Wang, Yi; Avila, Carlos; Cabrera, Andrés; Carrillo Montoya, Camilo Andres; Chaparro Sierra, Luisa Fernanda; Florez, Carlos; González Hernández, Carlos Felipe; Ruiz Alvarez, José David; Segura Delgado, Manuel Alejandro; Courbon, Benoit; Godinovic, Nikola; Lelas, Damir; Puljak, Ivica; Ribeiro Cipriano, Pedro M; Sculac, Toni; Antunovic, Zeljko; Kovac, Marko; Brigljevic, Vuko; Ferencek, Dinko; Kadija, Kreso; Mesic, Benjamin; Starodumov, Andrei; Susa, Tatjana; Ather, Mohsan Waseem; Attikis, Alexandros; Mavromanolakis, Georgios; Mousa, Jehad; Nicolaou, Charalambos; Ptochos, Fotios; Razis, Panos A; Rykaczewski, Hans; Finger, Miroslav; Finger Jr, Michael; Carrera Jarrin, Edgar; Abdalla, Hassan; El-khateeb, Esraa; Khalil, Shaaban; Bhowmik, Sandeep; Dewanjee, Ram Krishna; Kadastik, Mario; Perrini, Lucia; Raidal, Martti; Tiko, Andres; Veelken, Christian; Eerola, Paula; Kirschenmann, Henning; Pekkanen, Juska; Voutilainen, Mikko; Havukainen, Joona; Heikkilä, Jaana Kristiina; Jarvinen, Terhi; Karimäki, Veikko; Kinnunen, Ritva; Lampén, Tapio; Lassila-Perini, Kati; Laurila, Santeri; Lehti, Sami; Lindén, Tomas; Luukka, Panja-Riina; Mäenpää, Teppo; Siikonen, Hannu; Tuominen, Eija; Tuominiemi, Jorma; Tuuva, Tuure; Besancon, Marc; Couderc, Fabrice; Dejardin, Marc; Denegri, Daniel; Faure, Jean-Louis; Ferri, Federico; Ganjour, Serguei; Ghosh, Saranya; Givernaud, Alain; Gras, Philippe; Hamel de Monchenault, Gautier; Jarry, Patrick; Kucher, Inna; Leloup, Clément; Locci, Elizabeth; Machet, Martina; Malcles, Julie; Negro, Giulia; Rander, John; Rosowsky, André; Sahin, Mehmet Özgür; Titov, Maksym; Abdulsalam, Abdulla; Amendola, Chiara; Antropov, Iurii; Baffioni, Stephanie; Beaudette, Florian; Busson, Philippe; Cadamuro, Luca; Charlot, Claude; Granier de Cassagnac, Raphael; Jo, Mihee; Lisniak, Stanislav; Lobanov, Artur; Martin Blanco, Javier; Nguyen, Matthew; Ochando, Christophe; Ortona, Giacomo; Paganini, Pascal; Pigard, Philipp; Salerno, Roberto; Sauvan, Jean-Baptiste; Sirois, Yves; Stahl Leiton, Andre Govinda; Strebler, Thomas; Yilmaz, Yetkin; Zabi, Alexandre; Zghiche, Amina; Agram, Jean-Laurent; Andrea, Jeremy; Bloch, Daniel; Brom, Jean-Marie; Buttignol, Michael; Chabert, Eric Christian; Chanon, Nicolas; Collard, Caroline; Conte, Eric; Coubez, Xavier; Drouhin, Frédéric; Fontaine, Jean-Charles; Gelé, Denis; Goerlach, Ulrich; Jansová, Markéta; Juillot, Pierre; Le Bihan, Anne-Catherine; Tonon, Nicolas; Van Hove, Pierre; Gadrat, Sébastien; Beauceron, Stephanie; Bernet, Colin; Boudoul, Gaelle; Chierici, Roberto; Contardo, Didier; Depasse, Pierre; El Mamouni, Houmani; Fay, Jean; Finco, Linda; Gascon, Susan; Gouzevitch, Maxime; Grenier, Gérald; Ille, Bernard; Lagarde, Francois; Laktineh, Imad Baptiste; Lethuillier, Morgan; Mirabito, Laurent; Pequegnot, Anne-Laure; Perries, Stephane; Popov, Andrey; Sordini, Viola; Vander Donckt, Muriel; Viret, Sébastien; Zhang, Sijing; Toriashvili, Tengizi; Tsamalaidze, Zviad; Autermann, Christian; Feld, Lutz; Kiesel, Maximilian Knut; Klein, Katja; Lipinski, Martin; Preuten, Marius; Schomakers, Christian; Schulz, Johannes; Teroerde, Marius; Wittmer, Bruno; Zhukov, Valery; Albert, Andreas; Duchardt, Deborah; Endres, Matthias; Erdmann, Martin; Erdweg, Sören; Esch, Thomas; Fischer, Robert; Güth, Andreas; Hamer, Matthias; Hebbeker, Thomas; Heidemann, Carsten; Hoepfner, Kerstin; Knutzen, Simon; Merschmeyer, Markus; Meyer, Arnd; Millet, Philipp; Mukherjee, Swagata; Pook, Tobias; Radziej, Markus; Reithler, Hans; Rieger, Marcel; Scheuch, Florian; Teyssier, Daniel; Thüer, Sebastian; Flügge, Günter; Kargoll, Bastian; Kress, Thomas; Künsken, Andreas; Müller, Thomas; Nehrkorn, Alexander; Nowack, Andreas; Pistone, Claudia; Pooth, Oliver; Stahl, Achim; Aldaya Martin, Maria; Arndt, Till; Asawatangtrakuldee, Chayanit; Beernaert, Kelly; Behnke, Olaf; Behrens, Ulf; Bermúdez Martínez, Armando; Bin Anuar, Afiq Aizuddin; Borras, Kerstin; Botta, Valeria; Campbell, Alan; Connor, Patrick; Contreras-Campana, Christian; Costanza, Francesco; Diez Pardos, Carmen; Eckerlin, Guenter; Eckstein, Doris; Eichhorn, Thomas; Eren, Engin; Gallo, Elisabetta; Garay Garcia, Jasone; Geiser, Achim; Grados Luyando, Juan Manuel; Grohsjean, Alexander; Gunnellini, Paolo; Guthoff, Moritz; Harb, Ali; Hauk, Johannes; Hempel, Maria; Jung, Hannes; Kasemann, Matthias; Keaveney, James; Kleinwort, Claus; Korol, Ievgen; Krücker, Dirk; Lange, Wolfgang; Lelek, Aleksandra; Lenz, Teresa; Leonard, Jessica; Lipka, Katerina; Lohmann, Wolfgang; Mankel, Rainer; Melzer-Pellmann, Isabell-Alissandra; Meyer, Andreas Bernhard; Missiroli, Marino; Mittag, Gregor; Mnich, Joachim; Mussgiller, Andreas; Ntomari, Eleni; Pitzl, Daniel; Raspereza, Alexei; Savitskyi, Mykola; Saxena, Pooja; Shevchenko, Rostyslav; Stefaniuk, Nazar; Van Onsem, Gerrit Patrick; Walsh, Roberval; Wen, Yiwen; Wichmann, Katarzyna; Wissing, Christoph; Zenaiev, Oleksandr; Aggleton, Robin; Bein, Samuel; Blobel, Volker; Centis Vignali, Matteo; Dreyer, Torben; Garutti, Erika; Gonzalez, Daniel; Haller, Johannes; Hinzmann, Andreas; Hoffmann, Malte; Karavdina, Anastasia; Klanner, Robert; Kogler, Roman; Kovalchuk, Nataliia; Kurz, Simon; Lapsien, Tobias; Marconi, Daniele; Meyer, Mareike; Niedziela, Marek; Nowatschin, Dominik; Pantaleo, Felice; Peiffer, Thomas; Perieanu, Adrian; Scharf, Christian; Schleper, Peter; Schmidt, Alexander; Schumann, Svenja; Schwandt, Joern; Sonneveld, Jory; Stadie, Hartmut; Steinbrück, Georg; Stober, Fred-Markus Helmut; Stöver, Marc; Tholen, Heiner; Troendle, Daniel; Usai, Emanuele; Vanhoefer, Annika; Vormwald, Benedikt; Akbiyik, Melike; Barth, Christian; Baselga, Marta; Baur, Sebastian; Butz, Erik; Caspart, René; Chwalek, Thorsten; Colombo, Fabio; De Boer, Wim; Dierlamm, Alexander; Faltermann, Nils; Freund, Benedikt; Friese, Raphael; Giffels, Manuel; Harrendorf, Marco Alexander; Hartmann, Frank; Heindl, Stefan Michael; Husemann, Ulrich; Kassel, Florian; Kudella, Simon; Mildner, Hannes; Mozer, Matthias Ulrich; Müller, Thomas; Plagge, Michael; Quast, Gunter; Rabbertz, Klaus; Schröder, Matthias; Shvetsov, Ivan; Sieber, Georg; Simonis, Hans-Jürgen; Ulrich, Ralf; Wayand, Stefan; Weber, Marc; Weiler, Thomas; Williamson, Shawn; Wöhrmann, Clemens; Wolf, Roger; Anagnostou, Georgios; Daskalakis, Georgios; Geralis, Theodoros; Kyriakis, Aristotelis; Loukas, Demetrios; Topsis-Giotis, Iasonas; Karathanasis, George; Kesisoglou, Stilianos; Panagiotou, Apostolos; Saoulidou, Niki; Kousouris, Konstantinos; Evangelou, Ioannis; Foudas, Costas; Gianneios, Paraskevas; Katsoulis, Panagiotis; Kokkas, Panagiotis; Mallios, Stavros; Manthos, Nikolaos; Papadopoulos, Ioannis; Paradas, Evangelos; Strologas, John; Triantis, Frixos A; Tsitsonis, Dimitrios; Csanad, Mate; Filipovic, Nicolas; Pasztor, Gabriella; Surányi, Olivér; Veres, Gabor Istvan; Bencze, Gyorgy; Hajdu, Csaba; Horvath, Dezso; Hunyadi, Ádám; Sikler, Ferenc; Veszpremi, Viktor; Vesztergombi, Gyorgy; Beni, Noemi; Czellar, Sandor; Karancsi, János; Makovec, Alajos; Molnar, Jozsef; Szillasi, Zoltan; Bartók, Márton; Raics, Peter; Trocsanyi, Zoltan Laszlo; Ujvari, Balazs; Choudhury, Somnath; Komaragiri, Jyothsna Rani; Bahinipati, Seema; Mal, Prolay; Mandal, Koushik; Nayak, Aruna; Sahoo, Deepak Kumar; Sahoo, Niladribihari; Swain, Sanjay Kumar; Bansal, Sunil; Beri, Suman Bala; Bhatnagar, Vipin; Chawla, Ridhi; Dhingra, Nitish; Kaur, Anterpreet; Kaur, Manjit; Kaur, Sandeep; Kumar, Ramandeep; Kumari, Priyanka; Mehta, Ankita; Singh, Jasbir; Walia, Genius; Kumar, Ashok; Shah, Aashaq; Bhardwaj, Ashutosh; Chauhan, Sushil; Choudhary, Brajesh C; Garg, Rocky Bala; Keshri, Sumit; Kumar, Ajay; Malhotra, Shivali; Naimuddin, Md; Ranjan, Kirti; Sharma, Ramkrishna; Bhardwaj, Rishika; Bhattacharya, Rajarshi; Bhattacharya, Satyaki; Bhawandeep, Bhawandeep; Dey, Sourav; Dutt, Suneel; Dutta, Suchandra; Ghosh, Shamik; Majumdar, Nayana; Modak, Atanu; Mondal, Kuntal; Mukhopadhyay, Supratik; Nandan, Saswati; Purohit, Arnab; Roy, Ashim; Roy Chowdhury, Suvankar; Sarkar, Subir; Sharan, Manoj; Thakur, Shalini; Behera, Prafulla Kumar; Chudasama, Ruchi; Dutta, Dipanwita; Jha, Vishwajeet; Kumar, Vineet; Mohanty, Ajit Kumar; Netrakanti, Pawan Kumar; Pant, Lalit Mohan; Shukla, Prashant; Topkar, Anita; Aziz, Tariq; Dugad, Shashikant; Mahakud, Bibhuprasad; Mitra, Soureek; Mohanty, Gagan Bihari; Sur, Nairit; Sutar, Bajrang; Banerjee, Sudeshna; Bhattacharya, Soham; Chatterjee, Suman; Das, Pallabi; Guchait, Monoranjan; Jain, Sandhya; Kumar, Sanjeev; Maity, Manas; Majumder, Gobinda; Mazumdar, Kajari; Sarkar, Tanmay; Wickramage, Nadeesha; Chauhan, Shubhanshu; Dube, Sourabh; Hegde, Vinay; Kapoor, Anshul; Kothekar, Kunal; Pandey, Shubham; Rane, Aditee; Sharma, Seema; Chenarani, Shirin; Eskandari Tadavani, Esmaeel; Etesami, Seyed Mohsen; Khakzad, Mohsen; Mohammadi Najafabadi, Mojtaba; Naseri, Mohsen; Paktinat Mehdiabadi, Saeid; Rezaei Hosseinabadi, Ferdos; Safarzadeh, Batool; Zeinali, Maryam; Felcini, Marta; Grunewald, Martin; Abbrescia, Marcello; Calabria, Cesare; Colaleo, Anna; Creanza, Donato; Cristella, Leonardo; De Filippis, Nicola; De Palma, Mauro; Errico, Filippo; Fiore, Luigi; Iaselli, Giuseppe; Lezki, Samet; Maggi, Giorgio; Maggi, Marcello; Miniello, Giorgia; My, Salvatore; Nuzzo, Salvatore; Pompili, Alexis; Pugliese, Gabriella; Radogna, Raffaella; Ranieri, Antonio; Selvaggi, Giovanna; Sharma, Archana; Silvestris, Lucia; Venditti, Rosamaria; Verwilligen, Piet; Abbiendi, Giovanni; Battilana, Carlo; Bonacorsi, Daniele; Borgonovi, Lisa; Braibant-Giacomelli, Sylvie; Campanini, Renato; Capiluppi, Paolo; Castro, Andrea; Cavallo, Francesca Romana; Chhibra, Simranjit Singh; Codispoti, Giuseppe; Cuffiani, Marco; Dallavalle, Gaetano-Marco; Fabbri, Fabrizio; Fanfani, Alessandra; Fasanella, Daniele; Giacomelli, Paolo; Grandi, Claudio; Guiducci, Luigi; Marcellini, Stefano; Masetti, Gianni; Montanari, Alessandro; Navarria, Francesco; Perrotta, Andrea; Rossi, Antonio; Rovelli, Tiziano; Siroli, Gian Piero; Tosi, Nicolò; Albergo, Sebastiano; Costa, Salvatore; Di Mattia, Alessandro; Giordano, Ferdinando; Potenza, Renato; Tricomi, Alessia; Tuve, Cristina; Barbagli, Giuseppe; Chatterjee, Kalyanmoy; Ciulli, Vitaliano; Civinini, Carlo; D'Alessandro, Raffaello; Focardi, Ettore; Lenzi, Piergiulio; Meschini, Marco; Paoletti, Simone; Russo, Lorenzo; Sguazzoni, Giacomo; Strom, Derek; Viliani, Lorenzo; Benussi, Luigi; Bianco, Stefano; Fabbri, Franco; Piccolo, Davide; Primavera, Federica; Calvelli, Valerio; Ferro, Fabrizio; Ravera, Fabio; Robutti, Enrico; Tosi, Silvano; Benaglia, Andrea; Beschi, Andrea; Brianza, Luca; Brivio, Francesco; Ciriolo, Vincenzo; Dinardo, Mauro Emanuele; Fiorendi, Sara; Gennai, Simone; Ghezzi, Alessio; Govoni, Pietro; Malberti, Martina; Malvezzi, Sandra; Manzoni, Riccardo Andrea; Menasce, Dario; Moroni, Luigi; Paganoni, Marco; Pauwels, Kristof; Pedrini, Daniele; Pigazzini, Simone; Ragazzi, Stefano; Tabarelli de Fatis, Tommaso; Buontempo, Salvatore; Cavallo, Nicola; Di Guida, Salvatore; Fabozzi, Francesco; Fienga, Francesco; Iorio, Alberto Orso Maria; Khan, Wajid Ali; Lista, Luca; Meola, Sabino; Paolucci, Pierluigi; Sciacca, Crisostomo; Thyssen, Filip; Azzi, Patrizia; Bacchetta, Nicola; Bellato, Marco; Benato, Lisa; Bisello, Dario; Boletti, Alessio; Carvalho Antunes De Oliveira, Alexandra; Checchia, Paolo; Dall'Osso, Martino; De Castro Manzano, Pablo; Dorigo, Tommaso; Dosselli, Umberto; Gasparini, Fabrizio; Gasparini, Ugo; Lacaprara, Stefano; Lujan, Paul; Margoni, Martino; Meneguzzo, Anna Teresa; Pozzobon, Nicola; Ronchese, Paolo; Rossin, Roberto; Simonetto, Franco; Torassa, Ezio; Zanetti, Marco; Zotto, Pierluigi; Zumerle, Gianni; Braghieri, Alessandro; Magnani, Alice; Montagna, Paolo; Ratti, Sergio P; Re, Valerio; Ressegotti, Martina; Riccardi, Cristina; Salvini, Paola; Vai, Ilaria; Vitulo, Paolo; Alunni Solestizi, Luisa; Biasini, Maurizio; Bilei, Gian Mario; Cecchi, Claudia; Ciangottini, Diego; Fanò, Livio; Lariccia, Paolo; Leonardi, Roberto; Manoni, Elisa; Mantovani, Giancarlo; Mariani, Valentina; Menichelli, Mauro; Rossi, Alessandro; Santocchia, Attilio; Spiga, Daniele; Androsov, Konstantin; Azzurri, Paolo; Bagliesi, Giuseppe; Boccali, Tommaso; Borrello, Laura; Castaldi, Rino; Ciocci, Maria Agnese; Dell'Orso, Roberto; Fedi, Giacomo; Giannini, Leonardo; Giassi, Alessandro; Grippo, Maria Teresa; Ligabue, Franco; Lomtadze, Teimuraz; Manca, Elisabetta; Mandorli, Giulio; Messineo, Alberto; Palla, Fabrizio; Rizzi, Andrea; Savoy-Navarro, Aurore; Spagnolo, Paolo; Tenchini, Roberto; Tonelli, Guido; Venturi, Andrea; Verdini, Piero Giorgio; Barone, Luciano; Cavallari, Francesca; Cipriani, Marco; Daci, Nadir; Del Re, Daniele; Di Marco, Emanuele; Diemoz, Marcella; Gelli, Simone; Longo, Egidio; Margaroli, Fabrizio; Marzocchi, Badder; Meridiani, Paolo; Organtini, Giovanni; Paramatti, Riccardo; Preiato, Federico; Rahatlou, Shahram; Rovelli, Chiara; Santanastasio, Francesco; Amapane, Nicola; Arcidiacono, Roberta; Argiro, Stefano; Arneodo, Michele; Bartosik, Nazar; Bellan, Riccardo; Biino, Cristina; Cartiglia, Nicolo; Cenna, Francesca; Costa, Marco; Covarelli, Roberto; Degano, Alessandro; Demaria, Natale; Kiani, Bilal; Mariotti, Chiara; Maselli, Silvia; Migliore, Ernesto; Monaco, Vincenzo; Monteil, Ennio; Monteno, Marco; Obertino, Maria Margherita; Pacher, Luca; Pastrone, Nadia; Pelliccioni, Mario; Pinna Angioni, Gian Luca; Romero, Alessandra; Ruspa, Marta; Sacchi, Roberto; Shchelina, Ksenia; Sola, Valentina; Solano, Ada; Staiano, Amedeo; Traczyk, Piotr; Belforte, Stefano; Casarsa, Massimo; Cossutti, Fabio; Della Ricca, Giuseppe; Zanetti, Anna; Kim, Dong Hee; Kim, Gui Nyun; Kim, Min Suk; Lee, Jeongeun; Lee, Sangeun; Lee, Seh Wook; Moon, Chang-Seong; Oh, Young Do; Sekmen, Sezen; Son, Dong-Chul; Yang, Yu Chul; Kim, Hyunchul; Moon, Dong Ho; Oh, Geonhee; Brochero Cifuentes, Javier Andres; Goh, Junghwan; Kim, Tae Jeong; Cho, Sungwoong; Choi, Suyong; Go, Yeonju; Gyun, Dooyeon; Ha, Seungkyu; Hong, Byung-Sik; Jo, Youngkwon; Kim, Yongsun; Lee, Kisoo; Lee, Kyong Sei; Lee, Songkyo; Lim, Jaehoon; Park, Sung Keun; Roh, Youn; Almond, John; Kim, Junho; Kim, Jae Sung; Lee, Haneol; Lee, Kyeongpil; Nam, Kyungwook; Oh, Sung Bin; Radburn-Smith, Benjamin Charles; Seo, Seon-hee; Yang, Unki; Yoo, Hwi Dong; Yu, Geum Bong; Kim, Hyunyong; Kim, Ji Hyun; Lee, Jason Sang Hun; Park, Inkyu; Choi, Young-Il; Hwang, Chanwook; Lee, Jongseok; Yu, Intae; Dudenas, Vytautas; Juodagalvis, Andrius; Vaitkus, Juozas; Ahmed, Ijaz; Ibrahim, Zainol Abidin; Md Ali, Mohd Adli Bin; Mohamad Idris, Faridah; Wan Abdullah, Wan Ahmad Tajuddin; Yusli, Mohd Nizam; Zolkapli, Zukhaimira; Reyes-Almanza, Rogelio; Ramirez-Sanchez, Gabriel; Duran-Osuna, Cecilia; Castilla-Valdez, Heriberto; De La Cruz-Burelo, Eduard; Heredia-De La Cruz, Ivan; Rabadán-Trejo, Raúl Iraq; Lopez-Fernandez, Ricardo; Mejia Guisao, Jhovanny; Sánchez Hernández, Alberto; Carrillo Moreno, Salvador; Oropeza Barrera, Cristina; Vazquez Valencia, Fabiola; Eysermans, Jan; Pedraza, Isabel; Salazar Ibarguen, Humberto Antonio; Uribe Estrada, Cecilia; Morelos Pineda, Antonio; Krofcheck, David; Butler, Philip H; Ahmad, Ashfaq; Ahmad, Muhammad; Hassan, Qamar; Hoorani, Hafeez R; Saddique, Asif; Shah, Mehar Ali; Shoaib, Muhammad; Waqas, Muhammad; Bialkowska, Helena; Bluj, Michal; Boimska, Bozena; Frueboes, Tomasz; Górski, Maciej; Kazana, Malgorzata; Nawrocki, Krzysztof; Szleper, Michal; Zalewski, Piotr; Bunkowski, Karol; Byszuk, Adrian; Doroba, Krzysztof; Kalinowski, Artur; Konecki, Marcin; Krolikowski, Jan; Misiura, Maciej; Olszewski, Michal; Pyskir, Andrzej; Walczak, Marek; Bargassa, Pedrame; Beirão Da Cruz E Silva, Cristóvão; Di Francesco, Agostino; Faccioli, Pietro; Galinhas, Bruno; Gallinaro, Michele; Hollar, Jonathan; Leonardo, Nuno; Lloret Iglesias, Lara; Nemallapudi, Mythra Varun; Seixas, Joao; Strong, Giles; Toldaiev, Oleksii; Vadruccio, Daniele; Varela, Joao; Alexakhin, Vadim; Golunov, Alexander; Golutvin, Igor; Gorbounov, Nikolai; Kamenev, Alexey; Karjavin, Vladimir; Lanev, Alexander; Malakhov, Alexander; Matveev, Viktor; Moisenz, Petr; Palichik, Vladimir; Perelygin, Victor; Savina, Maria; Shmatov, Sergey; Shulha, Siarhei; Skatchkov, Nikolai; Smirnov, Vitaly; Voytishin, Nikolay; Zarubin, Anatoli; Ivanov, Yury; Kim, Victor; Kuznetsova, Ekaterina; Levchenko, Petr; Murzin, Victor; Oreshkin, Vadim; Smirnov, Igor; Sosnov, Dmitry; Sulimov, Valentin; Uvarov, Lev; Vavilov, Sergey; Vorobyev, Alexey; Andreev, Yuri; Dermenev, Alexander; Gninenko, Sergei; Golubev, Nikolai; Karneyeu, Anton; Kirsanov, Mikhail; Krasnikov, Nikolai; Pashenkov, Anatoli; Tlisov, Danila; Toropin, Alexander; Epshteyn, Vladimir; Gavrilov, Vladimir; Lychkovskaya, Natalia; Popov, Vladimir; Pozdnyakov, Ivan; Safronov, Grigory; Spiridonov, Alexander; Stepennov, Anton; Stolin, Viatcheslav; Toms, Maria; Vlasov, Evgueni; Zhokin, Alexander; Aushev, Tagir; Bylinkin, Alexander; Chadeeva, Marina; Markin, Oleg; Parygin, Pavel; Philippov, Dmitry; Polikarpov, Sergey; Rusinov, Vladimir; Andreev, Vladimir; Azarkin, Maksim; Dremin, Igor; Kirakosyan, Martin; Rusakov, Sergey V; Terkulov, Adel; Baskakov, Alexey; Belyaev, Andrey; Boos, Edouard; Bunichev, Viacheslav; Dubinin, Mikhail; Dudko, Lev; Gribushin, Andrey; Klyukhin, Vyacheslav; Kodolova, Olga; Lokhtin, Igor; Miagkov, Igor; Obraztsov, Stepan; Perfilov, Maxim; Petrushanko, Sergey; Savrin, Viktor; Blinov, Vladimir; Shtol, Dmitry; Skovpen, Yuri; Azhgirey, Igor; Bayshev, Igor; Bitioukov, Sergei; Elumakhov, Dmitry; Godizov, Anton; Kachanov, Vassili; Kalinin, Alexey; Konstantinov, Dmitri; Mandrik, Petr; Petrov, Vladimir; Ryutin, Roman; Sobol, Andrei; Troshin, Sergey; Tyurin, Nikolay; Uzunian, Andrey; Volkov, Alexey; Adzic, Petar; Cirkovic, Predrag; Devetak, Damir; Dordevic, Milos; Milosevic, Jovan; Rekovic, Vladimir; Alcaraz Maestre, Juan; Bachiller, Irene; Barrio Luna, Mar; Cerrada, Marcos; Colino, Nicanor; De La Cruz, Begona; Delgado Peris, Antonio; Fernandez Bedoya, Cristina; Fernández Ramos, Juan Pablo; Flix, Jose; Fouz, Maria Cruz; Gonzalez Lopez, Oscar; Goy Lopez, Silvia; Hernandez, Jose M; Josa, Maria Isabel; Moran, Dermot; Pérez-Calero Yzquierdo, Antonio María; Puerta Pelayo, Jesus; Redondo, Ignacio; Romero, Luciano; Senghi Soares, Mara; Triossi, Andrea; Álvarez Fernández, Adrian; Albajar, Carmen; de Trocóniz, Jorge F; Cuevas, Javier; Erice, Carlos; Fernandez Menendez, Javier; Gonzalez Caballero, Isidro; González Fernández, Juan Rodrigo; Palencia Cortezon, Enrique; Sanchez Cruz, Sergio; Vischia, Pietro; Vizan Garcia, Jesus Manuel; Cabrillo, Iban Jose; Calderon, Alicia; Chazin Quero, Barbara; Curras, Esteban; Duarte Campderros, Jordi; Fernandez, Marcos; Garcia-Ferrero, Juan; Gomez, Gervasio; Lopez Virto, Amparo; Marco, Jesus; Martinez Rivero, Celso; Martinez Ruiz del Arbol, Pablo; Matorras, Francisco; Piedra Gomez, Jonatan; Rodrigo, Teresa; Ruiz-Jimeno, Alberto; Scodellaro, Luca; Trevisani, Nicolò; Vila, Ivan; Vilar Cortabitarte, Rocio; Abbaneo, Duccio; Akgun, Bora; Auffray, Etiennette; Baillon, Paul; Ball, Austin; Barney, David; Bendavid, Joshua; Bianco, Michele; Bloch, Philippe; Bocci, Andrea; Botta, Cristina; Camporesi, Tiziano; Castello, Roberto; Cepeda, Maria; Cerminara, Gianluca; Chapon, Emilien; Chen, Yi; D'Enterria, David; Dabrowski, Anne; Daponte, Vincenzo; David Tinoco Mendes, Andre; De Gruttola, Michele; De Roeck, Albert; Deelen, Nikkie; Dobson, Marc; Du Pree, Tristan; Dünser, Marc; Dupont, Niels; Elliott-Peisert, Anna; Everaerts, Pieter; Fallavollita, Francesco; Franzoni, Giovanni; Fulcher, Jonathan; Funk, Wolfgang; Gigi, Dominique; Gilbert, Andrew; Gill, Karl; Glege, Frank; Gulhan, Doga; Harris, Philip; Hegeman, Jeroen; Innocente, Vincenzo; Jafari, Abideh; Janot, Patrick; Karacheban, Olena; Kieseler, Jan; Knünz, Valentin; Kornmayer, Andreas; Kortelainen, Matti J; Krammer, Manfred; Lange, Clemens; Lecoq, Paul; Lourenco, Carlos; Lucchini, Marco Toliman; Malgeri, Luca; Mannelli, Marcello; Martelli, Arabella; Meijers, Frans; Merlin, Jeremie Alexandre; Mersi, Stefano; Meschi, Emilio; Milenovic, Predrag; Moortgat, Filip; Mulders, Martijn; Neugebauer, Hannes; Ngadiuba, Jennifer; Orfanelli, Styliani; Orsini, Luciano; Pape, Luc; Perez, Emmanuel; Peruzzi, Marco; Petrilli, Achille; Petrucciani, Giovanni; Pfeiffer, Andreas; Pierini, Maurizio; Rabady, Dinyar; Racz, Attila; Reis, Thomas; Rolandi, Gigi; Rovere, Marco; Sakulin, Hannes; Schäfer, Christoph; Schwick, Christoph; Seidel, Markus; Selvaggi, Michele; Sharma, Archana; Silva, Pedro; Sphicas, Paraskevas; Stakia, Anna; Steggemann, Jan; Stoye, Markus; Tosi, Mia; Treille, Daniel; Tsirou, Andromachi; Veckalns, Viesturs; Verweij, Marta; Zeuner, Wolfram Dietrich; Bertl, Willi; Caminada, Lea; Deiters, Konrad; Erdmann, Wolfram; Horisberger, Roland; Ingram, Quentin; Kaestli, Hans-Christian; Kotlinski, Danek; Langenegger, Urs; Rohe, Tilman; Wiederkehr, Stephan Albert; Backhaus, Malte; Bäni, Lukas; Berger, Pirmin; Bianchini, Lorenzo; Casal, Bruno; Dissertori, Günther; Dittmar, Michael; Donegà, Mauro; Dorfer, Christian; Grab, Christoph; Heidegger, Constantin; Hits, Dmitry; Hoss, Jan; Kasieczka, Gregor; Klijnsma, Thomas; Lustermann, Werner; Mangano, Boris; Marionneau, Matthieu; Meinhard, Maren Tabea; Meister, Daniel; Micheli, Francesco; Musella, Pasquale; Nessi-Tedaldi, Francesca; Pandolfi, Francesco; Pata, Joosep; Pauss, Felicitas; Perrin, Gaël; Perrozzi, Luca; Quittnat, Milena; Reichmann, Michael; Sanz Becerra, Diego Alejandro; Schönenberger, Myriam; Shchutska, Lesya; Tavolaro, Vittorio Raoul; Theofilatos, Konstantinos; Vesterbacka Olsson, Minna Leonora; Wallny, Rainer; Zhu, De Hua; Aarrestad, Thea Klaeboe; Amsler, Claude; Canelli, Maria Florencia; De Cosa, Annapaola; Del Burgo, Riccardo; Donato, Silvio; Galloni, Camilla; Hreus, Tomas; Kilminster, Benjamin; Pinna, Deborah; Rauco, Giorgia; Robmann, Peter; Salerno, Daniel; Schweiger, Korbinian; Seitz, Claudia; Takahashi, Yuta; Zucchetta, Alberto; Candelise, Vieri; Chang, Yu-Hsiang; Cheng, Kai-yu; Doan, Thi Hien; Jain, Shilpi; Khurana, Raman; Kuo, Chia-Ming; Lin, Willis; Pozdnyakov, Andrey; Yu, Shin-Shan; Kumar, Arun; Chang, Paoti; Chao, Yuan; Chen, Kai-Feng; Chen, Po-Hsun; Fiori, Francesco; Hou, George Wei-Shu; Hsiung, Yee; Liu, Yueh-Feng; Lu, Rong-Shyang; Paganis, Efstathios; Psallidas, Andreas; Steen, Arnaud; Tsai, Jui-fa; Asavapibhop, Burin; Kovitanggoon, Kittikul; Singh, Gurpreet; Srimanobhas, Norraphat; Bat, Ayse; Boran, Fatma; Cerci, Salim; Damarseckin, Serdal; Demiroglu, Zuhal Seyma; Dozen, Candan; Dumanoglu, Isa; Girgis, Semiray; Gokbulut, Gul; Guler, Yalcin; Hos, Ilknur; Kangal, Evrim Ersin; Kara, Ozgun; Kayis Topaksu, Aysel; Kiminsu, Ugur; Oglakci, Mehmet; Onengut, Gulsen; Ozdemir, Kadri; Sunar Cerci, Deniz; Tali, Bayram; Tok, Ufuk Guney; Turkcapar, Semra; Zorbakir, Ibrahim Soner; Zorbilmez, Caglar; Karapinar, Guler; Ocalan, Kadir; Yalvac, Metin; Zeyrek, Mehmet; Gülmez, Erhan; Kaya, Mithat; Kaya, Ozlem; Tekten, Sevgi; Yetkin, Elif Asli; Agaras, Merve Nazlim; Atay, Serhat; Cakir, Altan; Cankocak, Kerem; Komurcu, Yildiray; Grynyov, Boris; Levchuk, Leonid; Ball, Fionn; Beck, Lana; Brooke, James John; Burns, Douglas; Clement, Emyr; Cussans, David; Davignon, Olivier; Flacher, Henning; Goldstein, Joel; Heath, Greg P; Heath, Helen F; Kreczko, Lukasz; Newbold, Dave M; Paramesvaran, Sudarshan; Sakuma, Tai; Seif El Nasr-storey, Sarah; Smith, Dominic; Smith, Vincent J; Bell, Ken W; Belyaev, Alexander; Brew, Christopher; Brown, Robert M; Calligaris, Luigi; Cieri, Davide; Cockerill, David JA; Coughlan, John A; Harder, Kristian; Harper, Sam; Linacre, Jacob; Olaiya, Emmanuel; Petyt, David; Shepherd-Themistocleous, Claire; Thea, Alessandro; Tomalin, Ian R; Williams, Thomas; Womersley, William John; Auzinger, Georg; Bainbridge, Robert; Borg, Johan; Breeze, Shane; Buchmuller, Oliver; Bundock, Aaron; Casasso, Stefano; Citron, Matthew; Colling, David; Corpe, Louie; Dauncey, Paul; Davies, Gavin; De Wit, Adinda; Della Negra, Michel; Di Maria, Riccardo; Elwood, Adam; Haddad, Yacine; Hall, Geoffrey; Iles, Gregory; James, Thomas; Lane, Rebecca; Laner, Christian; Lyons, Louis; Magnan, Anne-Marie; Malik, Sarah; Mastrolorenzo, Luca; Matsushita, Takashi; Nash, Jordan; Nikitenko, Alexander; Palladino, Vito; Pesaresi, Mark; Raymond, David Mark; Richards, Alexander; Rose, Andrew; Scott, Edward; Seez, Christopher; Shtipliyski, Antoni; Summers, Sioni; Tapper, Alexander; Uchida, Kirika; Vazquez Acosta, Monica; Virdee, Tejinder; Wardle, Nicholas; Winterbottom, Daniel; Wright, Jack; Zenz, Seth Conrad; Cole, Joanne; Hobson, Peter R; Khan, Akram; Kyberd, Paul; Reid, Ivan; Teodorescu, Liliana; Zahid, Sema; Borzou, Ahmad; Call, Kenneth; Dittmann, Jay; Hatakeyama, Kenichi; Liu, Hongxuan; Pastika, Nathaniel; Smith, Caleb; Bartek, Rachel; Dominguez, Aaron; Buccilli, Andrew; Cooper, Seth; Henderson, Conor; Rumerio, Paolo; West, Christopher; Arcaro, Daniel; Avetisyan, Aram; Bose, Tulika; Gastler, Daniel; Rankin, Dylan; Richardson, Clint; Rohlf, James; Sulak, Lawrence; Zou, David; Benelli, Gabriele; Cutts, David; Hadley, Mary; Hakala, John; Heintz, Ulrich; Hogan, Julie Managan; Kwok, Ka Hei Martin; Laird, Edward; Landsberg, Greg; Lee, Jangbae; Mao, Zaixing; Narain, Meenakshi; Pazzini, Jacopo; Piperov, Stefan; Sagir, Sinan; Syarif, Rizki; Yu, David; Band, Reyer; Brainerd, Christopher; Breedon, Richard; Burns, Dustin; Calderon De La Barca Sanchez, Manuel; Chertok, Maxwell; Conway, John; Conway, Rylan; Cox, Peter Timothy; Erbacher, Robin; Flores, Chad; Funk, Garrett; Ko, Winston; Lander, Richard; Mclean, Christine; Mulhearn, Michael; Pellett, Dave; Pilot, Justin; Shalhout, Shalhout; Shi, Mengyao; Smith, John; Stolp, Dustin; Tos, Kyle; Tripathi, Mani; Wang, Zhangqier; Bachtis, Michail; Bravo, Cameron; Cousins, Robert; Dasgupta, Abhigyan; Florent, Alice; Hauser, Jay; Ignatenko, Mikhail; Mccoll, Nickolas; Regnard, Simon; Saltzberg, David; Schnaible, Christian; Valuev, Vyacheslav; Bouvier, Elvire; Burt, Kira; Clare, Robert; Ellison, John Anthony; Gary, J William; Ghiasi Shirazi, Seyyed Mohammad Amin; Hanson, Gail; Heilman, Jesse; Karapostoli, Georgia; Kennedy, Elizabeth; Lacroix, Florent; Long, Owen Rosser; Olmedo Negrete, Manuel; Paneva, Mirena Ivova; Si, Weinan; Wang, Long; Wei, Hua; Wimpenny, Stephen; Yates, Brent; Branson, James G; Cittolin, Sergio; Derdzinski, Mark; Gerosa, Raffaele; Gilbert, Dylan; Hashemi, Bobak; Holzner, André; Klein, Daniel; Kole, Gouranga; Krutelyov, Vyacheslav; Letts, James; Masciovecchio, Mario; Olivito, Dominick; Padhi, Sanjay; Pieri, Marco; Sani, Matteo; Sharma, Vivek; Simon, Sean; Tadel, Matevz; Vartak, Adish; Wasserbaech, Steven; Wood, John; Würthwein, Frank; Yagil, Avraham; Zevi Della Porta, Giovanni; Amin, Nick; Bhandari, Rohan; Bradmiller-Feld, John; Campagnari, Claudio; Dishaw, Adam; Dutta, Valentina; Franco Sevilla, Manuel; Gouskos, Loukas; Heller, Ryan; Incandela, Joe; Ovcharova, Ana; Qu, Huilin; Richman, Jeffrey; Stuart, David; Suarez, Indara; Yoo, Jaehyeok; Anderson, Dustin; Bornheim, Adolf; Bunn, Julian; Lawhorn, Jay Mathew; Newman, Harvey B; Nguyen, Thong; Pena, Cristian; Spiropulu, Maria; Vlimant, Jean-Roch; Wilkinson, Richard; Xie, Si; Zhang, Zhicai; Zhu, Ren-Yuan; Andrews, Michael Benjamin; Ferguson, Thomas; Mudholkar, Tanmay; Paulini, Manfred; Russ, James; Sun, Menglei; Vogel, Helmut; Vorobiev, Igor; Weinberg, Marc; Cumalat, John Perry; Ford, William T; Jensen, Frank; Johnson, Andrew; Krohn, Michael; Leontsinis, Stefanos; Mulholland, Troy; Stenson, Kevin; Ulmer, Keith; Wagner, Stephen Robert; Alexander, James; Chaves, Jorge; Chu, Jennifer; Dittmer, Susan; Mcdermott, Kevin; Mirman, Nathan; Patterson, Juliet Ritchie; Quach, Dan; Rinkevicius, Aurelijus; Ryd, Anders; Skinnari, Louise; Soffi, Livia; Tan, Shao Min; Tao, Zhengcheng; Thom, Julia; Tucker, Jordan; Wittich, Peter; Zientek, Margaret; Abdullin, Salavat; Albrow, Michael; Alyari, Maral; Apollinari, Giorgio; Apresyan, Artur; Apyan, Aram; Banerjee, Sunanda; Bauerdick, Lothar AT; Beretvas, Andrew; Berryhill, Jeffrey; Bhat, Pushpalatha C; Bolla, Gino; Burkett, Kevin; Butler, Joel Nathan; Canepa, Anadi; Cerati, Giuseppe Benedetto; Cheung, Harry; Chlebana, Frank; Cremonesi, Matteo; Duarte, Javier; Elvira, Victor Daniel; Freeman, Jim; Gecse, Zoltan; Gottschalk, Erik; Gray, Lindsey; Green, Dan; Grünendahl, Stefan; Gutsche, Oliver; Hanlon, Jim; Harris, Robert M; Hasegawa, Satoshi; Hirschauer, James; Hu, Zhen; Jayatilaka, Bodhitha; Jindariani, Sergo; Johnson, Marvin; Joshi, Umesh; Klima, Boaz; Kreis, Benjamin; Lammel, Stephan; Lincoln, Don; Lipton, Ron; Liu, Miaoyuan; Liu, Tiehui; Lopes De Sá, Rafael; Lykken, Joseph; Maeshima, Kaori; Magini, Nicolo; Marraffino, John Michael; Mason, David; McBride, Patricia; Merkel, Petra; Mrenna, Stephen; Nahn, Steve; O'Dell, Vivian; Pedro, Kevin; Prokofyev, Oleg; Rakness, Gregory; Ristori, Luciano; Schneider, Basil; Sexton-Kennedy, Elizabeth; Soha, Aron; Spalding, William J; Spiegel, Leonard; Stoynev, Stoyan; Strait, James; Strobbe, Nadja; Taylor, Lucas; Tkaczyk, Slawek; Tran, Nhan Viet; Uplegger, Lorenzo; Vaandering, Eric Wayne; Vernieri, Caterina; Verzocchi, Marco; Vidal, Richard; Wang, Michael; Weber, Hannsjoerg Artur; Whitbeck, Andrew; Wu, Weimin; Acosta, Darin; Avery, Paul; Bortignon, Pierluigi; Bourilkov, Dimitri; Brinkerhoff, Andrew; Carnes, Andrew; Carver, Matthew; Curry, David; Field, Richard D; Furic, Ivan-Kresimir; Gleyzer, Sergei V; Joshi, Bhargav Madhusudan; Konigsberg, Jacobo; Korytov, Andrey; Kotov, Khristian; Ma, Peisen; Matchev, Konstantin; Mei, Hualin; Mitselmakher, Guenakh; Shi, Kun; Sperka, David; Terentyev, Nikolay; Thomas, Laurent; Wang, Jian; Wang, Sean-Jiun; Yelton, John; Joshi, Yagya Raj; Linn, Stephan; Markowitz, Pete; Rodriguez, Jorge Luis; Ackert, Andrew; Adams, Todd; Askew, Andrew; Hagopian, Sharon; Hagopian, Vasken; Johnson, Kurtis F; Kolberg, Ted; Martinez, German; Perry, Thomas; Prosper, Harrison; Saha, Anirban; Santra, Arka; Sharma, Varun; Yohay, Rachel; Baarmand, Marc M; Bhopatkar, Vallary; Colafranceschi, Stefano; Hohlmann, Marcus; Noonan, Daniel; Roy, Titas; Yumiceva, Francisco; Adams, Mark Raymond; Apanasevich, Leonard; Berry, Douglas; Betts, Russell Richard; Cavanaugh, Richard; Chen, Xuan; Evdokimov, Olga; Gerber, Cecilia Elena; Hangal, Dhanush Anil; Hofman, David Jonathan; Jung, Kurt; Kamin, Jason; Sandoval Gonzalez, Irving Daniel; Tonjes, Marguerite; Trauger, Hallie; Varelas, Nikos; Wang, Hui; Wu, Zhenbin; Zhang, Jingyu; Bilki, Burak; Clarida, Warren; Dilsiz, Kamuran; Durgut, Süleyman; Gandrajula, Reddy Pratap; Haytmyradov, Maksat; Khristenko, Viktor; Merlo, Jean-Pierre; Mermerkaya, Hamit; Mestvirishvili, Alexi; Moeller, Anthony; Nachtman, Jane; Ogul, Hasan; Onel, Yasar; Ozok, Ferhat; Penzo, Aldo; Snyder, Christina; Tiras, Emrah; Wetzel, James; Yi, Kai; Blumenfeld, Barry; Cocoros, Alice; Eminizer, Nicholas; Fehling, David; Feng, Lei; Gritsan, Andrei; Maksimovic, Petar; Roskes, Jeffrey; Sarica, Ulascan; Swartz, Morris; Xiao, Meng; You, Can; Al-bataineh, Ayman; Baringer, Philip; Bean, Alice; Boren, Samuel; Bowen, James; Castle, James; Khalil, Sadia; Kropivnitskaya, Anna; Majumder, Devdatta; Mcbrayer, William; Murray, Michael; Rogan, Christopher; Royon, Christophe; Sanders, Stephen; Schmitz, Erich; Tapia Takaki, Daniel; Wang, Quan; Ivanov, Andrew; Kaadze, Ketino; Maravin, Yurii; Mohammadi, Abdollah; Saini, Lovedeep Kaur; Skhirtladze, Nikoloz; Rebassoo, Finn; Wright, Douglas; Baden, Drew; Baron, Owen; Belloni, Alberto; Eno, Sarah Catherine; Feng, Yongbin; Ferraioli, Charles; Hadley, Nicholas John; Jabeen, Shabnam; Jeng, Geng-Yuan; Kellogg, Richard G; Kunkle, Joshua; Mignerey, Alice; Ricci-Tam, Francesca; Shin, Young Ho; Skuja, Andris; Tonwar, Suresh C; Abercrombie, Daniel; Allen, Brandon; Azzolini, Virginia; Barbieri, Richard; Baty, Austin; Bauer, Gerry; Bi, Ran; Brandt, Stephanie; Busza, Wit; Cali, Ivan Amos; D'Alfonso, Mariarosaria; Demiragli, Zeynep; Gomez Ceballos, Guillelmo; Goncharov, Maxim; Hsu, Dylan; Hu, Miao; Iiyama, Yutaro; Innocenti, Gian Michele; Klute, Markus; Kovalskyi, Dmytro; Lee, Yen-Jie; Levin, Andrew; Luckey, Paul David; Maier, Benedikt; Marini, Andrea Carlo; Mcginn, Christopher; Mironov, Camelia; Narayanan, Siddharth; Niu, Xinmei; Paus, Christoph; Roland, Christof; Roland, Gunther; Salfeld-Nebgen, Jakob; Stephans, George; Sumorok, Konstanty; Tatar, Kaya; Velicanu, Dragos; Wang, Jing; Wang, Ta-Wei; Wyslouch, Bolek; Benvenuti, Alberto; Chatterjee, Rajdeep Mohan; Evans, Andrew; Hansen, Peter; Hiltbrand, Joshua; Kalafut, Sean; Kubota, Yuichi; Lesko, Zachary; Mans, Jeremy; Nourbakhsh, Shervin; Ruckstuhl, Nicole; Rusack, Roger; Turkewitz, Jared; Wadud, Mohammad Abrar; Acosta, John Gabriel; Oliveros, Sandra; Avdeeva, Ekaterina; Bloom, Kenneth; Claes, Daniel R; Fangmeier, Caleb; Golf, Frank; Gonzalez Suarez, Rebeca; Kamalieddin, Rami; Kravchenko, Ilya; Monroy, Jose; Siado, Joaquin Emilo; Snow, Gregory R; Stieger, Benjamin; Dolen, James; Godshalk, Andrew; Harrington, Charles; Iashvili, Ia; Nguyen, Duong; Parker, Ashley; Rappoccio, Salvatore; Roozbahani, Bahareh; Alverson, George; Barberis, Emanuela; Freer, Chad; Hortiangtham, Apichart; Massironi, Andrea; Morse, David Michael; Orimoto, Toyoko; Teixeira De Lima, Rafael; Wamorkar, Tanvi; Wang, Bingran; Wisecarver, Andrew; Wood, Darien; Bhattacharya, Saptaparna; Charaf, Otman; Hahn, Kristan Allan; Mucia, Nicholas; Odell, Nathaniel; Schmitt, Michael Henry; Sung, Kevin; Trovato, Marco; Velasco, Mayda; Bucci, Rachael; Dev, Nabarun; Hildreth, Michael; Hurtado Anampa, Kenyi; Jessop, Colin; Karmgard, Daniel John; Kellams, Nathan; Lannon, Kevin; Li, Wenzhao; Loukas, Nikitas; Marinelli, Nancy; Meng, Fanbo; Mueller, Charles; Musienko, Yuri; Planer, Michael; Reinsvold, Allison; Ruchti, Randy; Siddireddy, Prasanna; Smith, Geoffrey; Taroni, Silvia; Wayne, Mitchell; Wightman, Andrew; Wolf, Matthias; Woodard, Anna; Alimena, Juliette; Antonelli, Louis; Bylsma, Ben; Durkin, Lloyd Stanley; Flowers, Sean; Francis, Brian; Hart, Andrew; Hill, Christopher; Ji, Weifeng; Ling, Ta-Yung; Liu, Bingxuan; Luo, Wuming; Winer, Brian L; Wulsin, Howard Wells; Cooperstein, Stephane; Driga, Olga; Elmer, Peter; Hardenbrook, Joshua; Hebda, Philip; Higginbotham, Samuel; Kalogeropoulos, Alexis; Lange, David; Luo, Jingyu; Marlow, Daniel; Mei, Kelvin; Ojalvo, Isabel; Olsen, James; Palmer, Christopher; Piroué, Pierre; Stickland, David; Tully, Christopher; Malik, Sudhir; Norberg, Scarlet; Barker, Anthony; Barnes, Virgil E; Das, Souvik; Folgueras, Santiago; Gutay, Laszlo; Jones, Matthew; Jung, Andreas Werner; Khatiwada, Ajeeta; Miller, David Harry; Neumeister, Norbert; Peng, Cheng-Chieh; Qiu, Hao; Schulte, Jan-Frederik; Sun, Jian; Wang, Fuqiang; Xiao, Rui; Xie, Wei; Cheng, Tongguang; Parashar, Neeti; Stupak, John; Chen, Zhenyu; Ecklund, Karl Matthew; Freed, Sarah; Geurts, Frank JM; Guilbaud, Maxime; Kilpatrick, Matthew; Li, Wei; Michlin, Benjamin; Padley, Brian Paul; Roberts, Jay; Rorie, Jamal; Shi, Wei; Tu, Zhoudunming; Zabel, James; Zhang, Aobo; Bodek, Arie; de Barbaro, Pawel; Demina, Regina; Duh, Yi-ting; Ferbel, Thomas; Galanti, Mario; Garcia-Bellido, Aran; Han, Jiyeon; Hindrichs, Otto; Khukhunaishvili, Aleko; Lo, Kin Ho; Tan, Ping; Verzetti, Mauro; Ciesielski, Robert; Goulianos, Konstantin; Mesropian, Christina; Agapitos, Antonis; Chou, John Paul; Gershtein, Yuri; Gómez Espinosa, Tirso Alejandro; Halkiadakis, Eva; Heindl, Maximilian; Hughes, Elliot; Kaplan, Steven; Kunnawalkam Elayavalli, Raghav; Kyriacou, Savvas; Lath, Amitabh; Montalvo, Roy; Nash, Kevin; Osherson, Marc; Saka, Halil; Salur, Sevil; Schnetzer, Steve; Sheffield, David; Somalwar, Sunil; Stone, Robert; Thomas, Scott; Thomassen, Peter; Walker, Matthew; Delannoy, Andrés G; Heideman, Joseph; Riley, Grant; Rose, Keith; Spanier, Stefan; Thapa, Krishna; Bouhali, Othmane; Castaneda Hernandez, Alfredo; Celik, Ali; Dalchenko, Mykhailo; De Mattia, Marco; Delgado, Andrea; Dildick, Sven; Eusebi, Ricardo; Gilmore, Jason; Huang, Tao; Kamon, Teruki; Mueller, Ryan; Pakhotin, Yuriy; Patel, Rishi; Perloff, Alexx; Perniè, Luca; Rathjens, Denis; Safonov, Alexei; Tatarinov, Aysen; Akchurin, Nural; Damgov, Jordan; De Guio, Federico; Dudero, Phillip Russell; Faulkner, James; Gurpinar, Emine; Kunori, Shuichi; Lamichhane, Kamal; Lee, Sung Won; Libeiro, Terence; Mengke, Tielige; Muthumuni, Samila; Peltola, Timo; Undleeb, Sonaina; Volobouev, Igor; Wang, Zhixing; Greene, Senta; Gurrola, Alfredo; Janjam, Ravi; Johns, Willard; Maguire, Charles; Melo, Andrew; Ni, Hong; Padeken, Klaas; Sheldon, Paul; Tuo, Shengquan; Velkovska, Julia; Xu, Qiao; Arenton, Michael Wayne; Barria, Patrizia; Cox, Bradley; Hirosky, Robert; Joyce, Matthew; Ledovskoy, Alexander; Li, Hengne; Neu, Christopher; Sinthuprasith, Tutanon; Wang, Yanchu; Wolfe, Evan; Xia, Fan; Harr, Robert; Karchin, Paul Edmund; Poudyal, Nabin; Sturdy, Jared; Thapa, Prakash; Zaleski, Shawn; Brodski, Michael; Buchanan, James; Caillol, Cécile; Carlsmith, Duncan; Dasu, Sridhara; Dodd, Laura; Duric, Senka; Gomber, Bhawna; Grothe, Monika; Herndon, Matthew; Hervé, Alain; Hussain, Usama; Klabbers, Pamela; Lanaro, Armando; Levine, Aaron; Long, Kenneth; Loveless, Richard; Ruggles, Tyler; Savin, Alexander; Smith, Nicholas; Smith, Wesley H; Taylor, Devin; Woods, Nathaniel

2018-01-01

A measurement is presented of the $\\mathrm{Z}/\\gamma^{*} \\to \\tau\\tau$ cross section in pp collisions at $\\sqrt{s} = $ 13 TeV, using data recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 2.3 fb$^{-1}$. The product of the inclusive cross section and branching fraction is measured to be $\\sigma(\\mathrm{pp} \\to \\mathrm{Z}/\\gamma^{*}\\text{+X}) \\, \\mathcal{B}(\\mathrm{Z}/\\gamma^{*} \\to \\tau\\tau) = $ 1848 $\\pm$ 12 (stat) $\\pm$ 67 (syst+lumi) pb, in agreement with the standard model expectation, computed at next-to-next-to-leading order accuracy in perturbative quantum chromodynamics. The measurement is used to validate new analysis techniques relevant for future measurements of $\\tau$ lepton production. The measurement also provides the reconstruction efficiency and energy scale for $\\tau$ decays to hadrons+$\

Measurement of the $\\mathrm{Z}\\gamma^{*} \\to \\tau\\tau$ cross section in pp collisions at $\\sqrt{s} = $ 13 TeV and validation of $\\tau$ lepton analysis techniques

Energy Technology Data Exchange (ETDEWEB)

Sirunyan, Albert M; et al.

2018-01-10

A measurement is presented of the $\\mathrm{Z}/\\gamma^{*} \\to \\tau\\tau$ cross section in pp collisions at $\\sqrt{s} = $ 13 TeV, using data recorded by the CMS experiment at the LHC, corresponding to an integrated luminosity of 2.3 fb$^{-1}$. The product of the inclusive cross section and branching fraction is measured to be $\\sigma(\\mathrm{pp} \\to \\mathrm{Z}/\\gamma^{*}\\text{+X}) \\, \\mathcal{B}(\\mathrm{Z}/\\gamma^{*} \\to \\tau\\tau) = $ 1848 $\\pm$ 12 (stat) $\\pm$ 67 (syst+lumi) pb, in agreement with the standard model expectation, computed at next-to-next-to-leading order accuracy in perturbative quantum chromodynamics. The measurement is used to validate new analysis techniques relevant for future measurements of $\\tau$ lepton production. The measurement also provides the reconstruction efficiency and energy scale for $\\tau$ decays to hadrons+$\

A Mouse Model for Human Anal Cancer

Science.gov (United States)

Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

2010-01-01

Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncogenic properties including but not limited to their capacity to inactivate the cellular tumor suppressors p53 and pRb, respectively. Both E6 and E7 were found to be functionally expressed in the anal epithelia of K14E6/K14E7 transgenic mice. To assess the susceptibility of these mice to anal cancer, mice were treated topically with dimethylbenz[a]anthracene (DMBA), a chemical carcinogen that is known to induce squamous cell carcinomas in other sites. Nearly 50% of DMBA-treated HPV16 E6/E7 transgenic mice showed overt signs of tumors; whereas, none of the like treated non-transgenic mice showed tumors. Histopathological analyses confirmed that the HPV16 transgenic mice were increased in their susceptibility to anal cancers and precancerous lesions. Biomarker analyses demonstrated that these mouse anal cancers exhibit properties that are similar to those observed in HPV-positive precursors to human anal cancer. This is the first mouse model for investigating the contributions of viral and cellular factors in anal carcinogenesis, and should provide a platform for assessing new therapeutic modalities for treating and/or preventing this type of cancer. PMID:20947489

$K^{0}_{S}$ production in $\\tau$ decays

CERN Document Server

Barate, R; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Nief, J Y; Pietrzyk, B; Boix, G; Casado, M P; Chmeissani, M; Crespo, J M; Delfino, M C; Fernández, E; Fernández-Bosman, M; Garrido, L; Graugès-Pous, E; Juste, A; Martínez, M; Merino, G; Miquel, R; Mir, L M; Park, I C; Pascual, A; Perlas, J A; Riu, I; Sánchez, F; Colaleo, A; Creanza, D; De Palma, M; Gelao, G; Iaselli, Giuseppe; Maggi, G; Maggi, M; Nuzzo, S; Ranieri, A; Raso, G; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Tricomi, A; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Abbaneo, D; Alemany, R; Becker, U; Bright-Thomas, P G; Casper, David William; Cattaneo, M; Cerutti, F; Ciulli, V; Dissertori, G; Drevermann, H; Forty, Roger W; Frank, M; Hagelberg, R; Hansen, J B; Harvey, J; Janot, P; Jost, B; Lehraus, Ivan; Mato, P; Minten, Adolf G; Moneta, L; Pacheco, A; Pusztaszeri, J F; Ranjard, F; Rolandi, Luigi; Rousseau, D; Schlatter, W D; Schmitt, M; Schneider, O; Tejessy, W; Teubert, F; Tomalin, I R; Wachsmuth, H W; Wagner, A; Ajaltouni, Ziad J; Badaud, F; Chazelle, G; Deschamps, O; Falvard, A; Ferdi, C; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rosnet, P; Fearnley, Tom; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Rensch, B; Wäänänen, A; Daskalakis, G; Kyriakis, A; Markou, C; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Rougé, A; Rumpf, M; Valassi, Andrea; Verderi, M; Videau, H L; Boccali, T; Focardi, E; Parrini, G; Zachariadou, K; Corden, M; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Passalacqua, L; Pepé-Altarelli, M; Curtis, L; Dorris, S J; Halley, A W; Lynch, J G; Negus, P; O'Shea, V; Raine, C; Scarr, J M; Smith, K; Teixeira-Dias, P; Thompson, A S; Thomson, E; Thomson, F; Buchmüller, O L; Dhamotharan, S; Geweniger, C; Graefe, G; Hanke, P; Hansper, G; Hepp, V; Kluge, E E; Putzer, A; Sommer, J; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, Peter J; Girone, M; Goodsir, S M; Martin, E B; Marinelli, N; Moutoussi, A; Nash, J; Sedgbeer, J K; Spagnolo, P; Williams, M D; Ghete, V M; Girtler, P; Kneringer, E; Kuhn, D; Rudolph, G; Betteridge, A P; Bowdery, C K; Buck, P G; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Jones, R W L; Williams, M I; Giehl, I; Greene, A M; Hoffmann, C; Jakobs, K; Kleinknecht, K; Quast, G; Renk, B; Rohne, E; Sander, H G; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Benchouk, C; Bonissent, A; Bujosa, G; Carr, J; Coyle, P; Etienne, F; Leroy, O; Motsch, F; Payre, P; Talby, M; Sadouki, A; Thulasidas, M; Trabelsi, K; Aleppo, M; Antonelli, M; Ragusa, F; Berlich, R; Blum, Walter; Büscher, V; Dietl, H; Ganis, G; Gotzhein, C; Kroha, H; Lütjens, G; Lutz, Gerhard; Mannert, C; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Stenzel, H; Wiedenmann, W; Wolf, G; Boucrot, J; Callot, O; Chen, S; Choi, Y; Cordier, A; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Höcker, A; Jacholkowska, A; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Nikolic, I A; Schune, M H; Tournefier, E; Veillet, J J; Videau, I; Zerwas, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Palla, Fabrizio; Rizzo, G; Sanguinetti, G; Sciabà, A; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Vannini, C; Venturi, A; Verdini, P G; Blair, G A; Bryant, L M; Chambers, J T; Green, M G; Medcalf, T; Perrodo, P; Strong, J A; Von Wimmersperg-Töller, J H; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Norton, P R; Thompson, J C; Wright, A E; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Black, S N; Dann, J H; Johnson, R P; Kim, H Y; Konstantinidis, N P; Litke, A M; McNeil, M A; Taylor, G; Booth, C N; Brew, C A J; Cartwright, S L; Combley, F; Kelly, M S; Lehto, M H; Reeve, J; Thompson, L F; Affholderbach, K; Böhrer, A; Brandt, S; Cowan, G D; Grupen, Claus; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Musolino, G; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Charles, E; Elmer, P; Ferguson, D P S; Gao, Y; González, S; Greening, T C; Hayes, O J; Hu, H; Jin, S; McNamara, P A; Nachtman, J M; Nielsen, J; Orejudos, W; Pan, Y B; Saadi, Y; Scott, I J; Walsh, J; Wu Sau Lan; Wu, X; Yamartino, J M; Zobernig, G

1998-01-01

From a sample of about 160k $\\mbox{Z}\\!\\!\\to\\!\\!\\tau^+\\tau^-$ candidates collected with the ALEPH detector at LEP between 1991 and 1995, $\\tau$ lepton decays involving $K^0_S\\!\\to\\!\\pi^+\\pi^-$ are studied. The $K^0_SK^0_L$ associated production in $\\tau$ decays is also investigated. The branching ratios are measured for the inclusive decay $B(\\tau^-\\!\\!\\to\\!\\!K^0_SX^-\

Tau reduction diminishes spatial learning and memory deficits after mild repetitive traumatic brain injury in mice.

Directory of Open Access Journals (Sweden)

Jason S Cheng

Full Text Available OBJECTIVE: Because reduction of the microtubule-associated protein Tau has beneficial effects in mouse models of Alzheimer's disease and epilepsy, we wanted to determine whether this strategy can also improve the outcome of mild traumatic brain injury (TBI. METHODS: We adapted a mild frontal impact model of TBI for wildtype C57Bl/6J mice and characterized the behavioral deficits it causes in these animals. The Barnes maze, Y maze, contextual and cued fear conditioning, elevated plus maze, open field, balance beam, and forced swim test were used to assess different behavioral functions. Magnetic resonance imaging (MRI, 7 Tesla and histological analysis of brain sections were used to look for neuropathological alterations. We also compared the functional effects of this TBI model and of controlled cortical impact in mice with two, one or no Tau alleles. RESULTS: Repeated (2-hit, but not single (1-hit, mild frontal impact impaired spatial learning and memory in wildtype mice as determined by testing of mice in the Barnes maze one month after the injury. Locomotor activity, anxiety, depression and fear related behaviors did not differ between injured and sham-injured mice. MRI imaging did not reveal focal injury or mass lesions shortly after the injury. Complete ablation or partial reduction of tau prevented deficits in spatial learning and memory after repeated mild frontal impact. Complete tau ablation also showed a trend towards protection after a single controlled cortical impact. Complete or partial reduction of tau also reduced the level of axonopathy in the corpus callosum after repeated mild frontal impact. INTERPRETATION: Tau promotes or enables the development of learning and memory deficits and of axonopathy after mild TBI, and tau reduction counteracts these adverse effects.

MHC class I phenotype and function of human beta 2-microglobulin transgenic murine lymphocytes

DEFF Research Database (Denmark)

Bjerager, L; Pedersen, L O; Bregenholt, S

1996-01-01

. Based on data from cellular binding studies, Scatchard analyses and flow cytometry, it is concluded that exogenous h beta 2m does not bind to hybrid MHC class I (MHC-I) molecules composed of mouse heavy chain/h beta 2m molecules expressed on lymphocytes of transgenic mice. Immunoprecipitation and SDS......-PAGE analysis of metabolically labelled normal C57BL/6 lymph node cells showed binding of exogenous h beta 2m to MHC-I, in particular, to the H-2Db molecule through an exchange with endogenous mouse beta 2m. In contrast to normal H-2Db molecules, hybrid H-2Db expressed on the surface of transgenic lymphocytes...... binds radiolabelled peptide in the absence of exogenous added h beta 2m suggesting that a stable fraction of hybrid H-2Db molecules is empty or contain peptides with very low affinity. In a one-way allogenic mixed lymphocyte culture, transgenic splenocytes were found to be far less stimulatory than...

Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) in transgenic mouse models of frontotemporal lobar degeneration and Alzheimer’s disease

Science.gov (United States)

2013-01-01

Alzheimer’s disease (AD), the most common dementia, is characterized by potentially neurotoxic aggregation of Aβ peptide and tau protein, and their deposition as amyloid plaques and neurofibrillary tangles (NFTs). Tau aggregation also occurs in other common neurodegenerative diseases. Frontotemporal dementia (FTD) can be caused by tau mutations that increase the susceptibility of tau to hyperphosphorylation and aggregation, which may cause neuronal dysfunction and deposition of NFTs. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a potent inhibitor of heat shock protein 90 (Hsp90), a cytosolic chaperone implicated in the proper folding and functions of a repertoire of client proteins. 17-AAG binds to Hsp90 and enhances degradation of Hsp90 client protein. We sought to determine whether 17-AAG can reduce Aβ and tau pathology in the brains of AD and FTD model mice expressing Aβ or P301L mutant tau, respectively. Mice were randomized to receive 25, 5, or 0 mg/kg 17-AAG thrice weekly from age eight to 11 months. Analysis was performed by rotarod test on motor function, on the area occupied by plaques in hippocampus or NFTs in medulla tissue sections, and on mortality. A high dose of 17-AAG tended to decrease NFTs in male mice (p = 0.08). Further studies are required to confirm the effect of 17-AAG in diseases of tau aggregation. PMID:24344631

Resistance to organophosphorus agent toxicity in transgenic mice expressing the G117H mutant of human butyrylcholinesterase

International Nuclear Information System (INIS)

Wang Yuxia; Ticu Boeck, Andreea; Duysen, Ellen G.; Van Keuren, Margaret; Saunders, Thomas L.; Lockridge, Oksana

2004-01-01

Organophosphorus toxicants (OP) include chemical nerve agents and pesticides. The goal of this work was to find out whether an animal could be made resistant to OP toxicity by genetic engineering. The human butyrylcholinesterase (BChE) mutant G117H was chosen for study because it has the unusual ability to hydrolyze OP as well as acetylcholine, and it is resistant to inhibition by OP. Human G117H BChE, under the control of the ROSA26 promoter, was expressed in all tissues of transgenic mice. A stable transgenic mouse line expressed 0.5 μg/ml of human G117H BChE in plasma as well as 2 μg/ml of wild-type mouse BChE. Intestine, kidneys, stomach, lungs, heart, spleen, liver, brain, and muscle expressed 0.6-0.15 μg/g of G117H BChE. Transgenic mice were normal in behavior and fertility. The LD50 dose of echothiophate for wild-type mice was 0.1 mg/kg sc. This dose caused severe cholinergic signs of toxicity and lethality in wild-type mice, but caused no deaths and only mild toxicity in transgenic animals. The mechanism of protection was investigated by measuring acetylcholinesterase (AChE) and BChE activity. It was found that AChE and endogenous BChE were inhibited to the same extent in echothiophate-treated wild type and transgenic mice. This led to the hypothesis that protection against echothiophate toxicity was not explained by hydrolysis of echothiophate. In conclusion, the transgenic G117H BChE mouse demonstrates the factors required to achieve protection from OP toxicity in a vertebrate animal

Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?

Directory of Open Access Journals (Sweden)

Castillo-Carranza DL

2013-12-01

Full Text Available Diana L Castillo-Carranza,1,2 Marcos J Guerrero-Muñoz,1,2 Rakez Kayed1–31Mitchell Center for Neurodegenerative Diseases, 2Departments of Neurology, Neuroscience, and Cell Biology, 3Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USAAbstract: Alzheimer's disease (AD is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions.Keywords: immunotherapy, Alzheimer's disease, β-amyloid, tau

Tau flavored dark matter and its impact on tau Yukawa coupling

Energy Technology Data Exchange (ETDEWEB)

Chao, Wei [Center for Advanced Quantum Studies, Department of Physics, Beijing Normal University, Beijing, 100875 China (China); Guo, Huai-Ke; Li, Hao-Lin, E-mail: chao@physics.umass.edu, E-mail: huaike@physics.umass.edu, E-mail: haolinli@physics.umass.edu [Amherst Center for Fundamental Interactions, Department of Physics, University of Massachusetts-Amherst, 710 N Pleasant St., Amherst, MA, 01003 (United States)

2017-02-01

In this paper we perform a systematic study of the tau flavored dark matter (DM) model by introducing two kinds of mediators (a scalar doublet and a charged scalar singlet). The electromagnetic properties of the DM, as well as their implications in DM direct detections, are analyzed in detail. The model turns out contributing a significant radiative correction to the tau lepton mass, in addition to loosing the tension between the measured DM relic density and constraints of DM direct detections. The loop corrections can be O(10%) of the total tau mass. Signal rates of the Higgs measurements from the LHC in the h →τ τ and h → γ γ channels, relative to the Standard Model expectations, can be explained in this model.

Measurement of the $Z\\rightarrow\\tau^+\\tau^-$ production in proton-proton collisions at $\\sqrt{s} = 8$ TeV

CERN Document Server

LHCb Collaboration

2018-01-01

A measurement of the $Z\\rightarrow\\tau^+\\tau^-$ production cross-section is presented using data, corresponding to an integrated luminosity of 2 fb$^{-1}$, from $pp$ collisions at $\\sqrt{s}=8$ TeV collected by the LHCb experiment. The $\\tau^+\\tau^-$ candidates are reconstructed in final states with the first tau lepton decaying leptonically, and the second decaying either leptonically or to one or three charged hadrons. The production cross-section is measured for $Z$ bosons with invariant mass between 60 and 120 GeV/$c^2$, which decay to tau leptons with transverse momenta greater than 20 GeV/$c$ and pseudorapidities between 2.0 and 4.5. The cross-section is determined to be $\\sigma_{pp\\rightarrow{}Z\\rightarrow{}\\tau^+\\tau^-} = 95.8 \\pm 2.1 \\pm 4.6 \\pm 0.2 \\pm 1.1 \\mathrm{pb}$, where the first uncertainty is statistical, the second is systematic, the third is due to the LHC beam energy uncertainty, and the fourth to the integrated luminosity uncertainty. This result is compatible with NNLO Standard mo...

Positron Emission Tomography of (64)Cu-DOTA-Rituximab in a Transgenic Mouse Model Expressing Human CD20 for Clinical Translation to Image NHL

DEFF Research Database (Denmark)

Natarajan, Arutselvan; Gowrishankar, Gayatri; Nielsen, Carsten Haagen

2012-01-01

PURPOSE: This study aims to evaluate (64)Cu-DOTA-rituximab (PETRIT) in a preclinical transgenic mouse model expressing human CD20 for potential clinical translation. PROCEDURES: (64)Cu was chelated to DOTA-rituximab. Multiple radiolabeling, quality assurance, and imaging experiments were performed....... The human CD20 antigen was expressed in B cells of transgenic mice (CD20TM). The mice groups studied were: (a) control (nude mice, n¿=¿3) that received 7.4 MBq/dose, (b) with pre-dose (CD20TM, n¿=¿6) received 2 mg/kg pre-dose of cold rituximab prior to PETRIT of 7.4 MBq/dose, and (c) without pre-dose (CD20......TM, n¿=¿6) PETRIT alone received 7.4 MBq/dose. Small animal PET was used to image mice at various time points (0, 1, 2, 4, 24, 48, and 72 h). The OLINDA/EXM software was used to determine the human equivalent dose for individual organs. RESULTS: PETRIT was obtained with a specific activity of 545...

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

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.

Near-atomic model of microtubule-tau interactions.

Science.gov (United States)

Kellogg, Elizabeth H; Hejab, Nisreen M A; Poepsel, Simon; Downing, Kenneth H; DiMaio, Frank; Nogales, Eva

2018-06-15

Tau is a developmentally regulated axonal protein that stabilizes and bundles microtubules (MTs). Its hyperphosphorylation is thought to cause detachment from MTs and subsequent aggregation into fibrils implicated in Alzheimer's disease. It is unclear which tau residues are crucial for tau-MT interactions, where tau binds on MTs, and how it stabilizes them. We used cryo-electron microscopy to visualize different tau constructs on MTs and computational approaches to generate atomic models of tau-tubulin interactions. The conserved tubulin-binding repeats within tau adopt similar extended structures along the crest of the protofilament, stabilizing the interface between tubulin dimers. Our structures explain the effect of phosphorylation on MT affinity and lead to a model of tau repeats binding in tandem along protofilaments, tethering together tubulin dimers and stabilizing polymerization interfaces. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Study of Calorimeter Calibration with Tau's in CMS.

CERN Document Server

Denegri, Daniel; Nikitenko, Alexander

1997-01-01

We propose to calibrate in situ the CMS calorimetry using the single, isolated pions from tau-> pi nu in W -> tau nu and Z, gamma^* -> tau tau processes applying the p/E method. In case of pions non-interacting in the ECAL the method is straightforward, but for pions interacting in the ECAL care is needed to suppress and keep under control pi+- pi0's from tau's or QCS jets, which could vitiate the method. This can be achieved exploiting the ECAL granularity and tracker-calorimetry special matching. The momentum of the isolated high pt pion can be directly compared to the calorimeter measurement. Triggering of the W -> tau nu events is envisaged with a special tau-jet trigger combined with a missing transverse energy trigger. The Z gamma^* -> tau tau events could be triggered by lepton + tau-jet and double tau-jet trigger. The event rate for pt of pion > 15 GeV is e nough to calibrate each HCAL cell at a 1% precision after collection of 10^4 pb-1 of data.

Spin analysis of the process e{sup +}e{sup -}{yields}{tau}{sup +}{tau}{sup -} at LEP

Energy Technology Data Exchange (ETDEWEB)

Garcia-Abia, P [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). Inst. fuer Hochenergiephysik

1998-06-01

Using the data collected by the four experiments at LEP during 1990-1994, a precise measurement of the {tau} longitudinal polarisation (P{sub {tau}}) has been performed, as well as the measurement of the transverse-transverse (C{sub TT}) and transverse-normal (C{sub TN}) {tau} spin correlations. From the P{sub {tau}} measurement, assuming lepton universality of the neutral currents, the effective weak mixing angle has been determined to be sin{sup 2}{theta}{sub W}=0.2325{+-}0.0006. The measured results are consistent with the standard model predictions. (orig.). 10 refs.

Tau regulates the subcellular localization of calmodulin

Energy Technology Data Exchange (ETDEWEB)

Barreda, Elena Gomez de [Centro de Biologia Molecular ' Severo Ochoa' , CSIC/UAM, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain); Avila, Jesus, E-mail: javila@cbm.uam.es [Centro de Biologia Molecular ' Severo Ochoa' , CSIC/UAM, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid (Spain); CIBER de Enfermedades Neurodegenerativas, 28031 Madrid (Spain)

2011-05-13

Highlights: {yields} In this work we have tried to explain how a cytoplasmic protein could regulate a cell nuclear function. We have tested the role of a cytoplasmic protein (tau) in regulating the expression of calbindin gene. We found that calmodulin, a tau-binding protein with nuclear and cytoplasmic localization, increases its nuclear localization in the absence of tau. Since nuclear calmodulin regulates calbindin expression, a decrease in nuclear calmodulin, due to the presence of tau that retains it at the cytoplasm, results in a change in calbindin expression. -- Abstract: Lack of tau expression in neuronal cells results in a change in the expression of few genes. However, little is known about how tau regulates gene expression. Here we show that the presence of tau could alter the subcellular localization of calmodulin, a protein that could be located at the cytoplasm or in the nucleus. Nuclear calmodulin binds to co-transcription factors, regulating the expression of genes like calbindin. In this work, we have found that in neurons containing tau, a higher proportion of calmodulin is present in the cytoplasm compared with neurons lacking tau and that an increase in cytoplasmic calmodulin correlates with a higher expression of calbindin.

Tau regulates the subcellular localization of calmodulin

International Nuclear Information System (INIS)

Barreda, Elena Gomez de; Avila, Jesus

2011-01-01

Highlights: → In this work we have tried to explain how a cytoplasmic protein could regulate a cell nuclear function. We have tested the role of a cytoplasmic protein (tau) in regulating the expression of calbindin gene. We found that calmodulin, a tau-binding protein with nuclear and cytoplasmic localization, increases its nuclear localization in the absence of tau. Since nuclear calmodulin regulates calbindin expression, a decrease in nuclear calmodulin, due to the presence of tau that retains it at the cytoplasm, results in a change in calbindin expression. -- Abstract: Lack of tau expression in neuronal cells results in a change in the expression of few genes. However, little is known about how tau regulates gene expression. Here we show that the presence of tau could alter the subcellular localization of calmodulin, a protein that could be located at the cytoplasm or in the nucleus. Nuclear calmodulin binds to co-transcription factors, regulating the expression of genes like calbindin. In this work, we have found that in neurons containing tau, a higher proportion of calmodulin is present in the cytoplasm compared with neurons lacking tau and that an increase in cytoplasmic calmodulin correlates with a higher expression of calbindin.

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.

Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer’s disease

Directory of Open Access Journals (Sweden)

Darrell Sawmiller

2017-04-01

Full Text Available Alzheimer’s disease (AD, a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ plaques and neurofibrillary tangles (NFT. A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II, containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis in 5XFAD transgenic mice. Animals were fed Nutra II for 12 weeks, starting at 3 months of age, after which behavioral and neuropathological endpoints were determined. The data from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II also protected mitochondrial function in 5XFAD mice brain, as evidenced by declined ROS levels and membrane hyperpolarization, together with elevated ATP levels and respiratory states. Interestingly, while Nutra II treatment only slightly reduced soluble Aβ42 levels, this formulation significantly impacted tau metabolism, as shown by reduced total and phosphorylated tau levels of 5XFAD mouse brain. Taken together, these preclinical findings confirm that mitochondrial function may be a key treatment target for AD and that Nutra II should be further investigated as a potential candidate for AD therapy.

Identification of age- and disease-related alterations in circulating miRNAs in a mouse model of Alzheimer's disease

Directory of Open Access Journals (Sweden)

Sylvia eGarza-Manero

2015-02-01

Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-β peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs, a class of small non-coding RNAs of 22-25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD. We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in

A precise measurement of the $\\tau$ lepton lifetime

CERN Document Server

Abreu, P; Adye, T; Agasi, E; Ajinenko, I; Aleksan, Roy; Alekseev, G D; Allport, P P; Almehed, S; Alvsvaag, S J; Amaldi, Ugo; Amato, S; Andreazza, A; Andrieux, M L; Antilogus, P; Apel, W D; Arnoud, Y; Åsman, B; Augustin, J E; Augustinus, A; Baillon, Paul; Bambade, P; Barão, F; Barate, R; Bardin, Dimitri Yuri; Barker, G J; Baroncelli, A; Bärring, O; Barrio, J A; Bartl, Walter; Bates, M J; Battaglia, Marco; Baubillier, M; Baudot, J; Becks, K H; Begalli, M; Beillière, P; Belokopytov, Yu A; Benvenuti, Alberto C; Berggren, M; Bertrand, D; Bianchi, F; Bigi, M; Bilenky, S M; Billoir, P; Bloch, D; Blume, M; Blyth, S; Bocci, V; Bolognese, T; Bonesini, M; Bonivento, W; Booth, P S L; Borisov, G; Bosio, C; Bosworth, S; Botner, O; Bouquet, B; Bourdarios, C; Bowcock, T J V; Bozzo, M; Branchini, P; Brand, K D; Brenke, T; Brenner, R A; Bricman, C; Brillault, L; Brown, R C A; Brückman, P; Brunet, J M; Bugge, L; Buran, T; Burgsmüller, T; Buschmann, P; Buys, A; Caccia, M; Calvi, M; Camacho-Rozas, A J; Camporesi, T; Canale, V; Canepa, M; Cankocak, K; Cao, F; Carena, F; Carrilho, P; Carroll, L; Caso, Carlo; Castillo-Gimenez, M V; Cattai, A; Cavallo, F R; Cerrito, L; Chabaud, V; Charpentier, P; Chaussard, L; Chauveau, J; Checchia, P; Chelkov, G A; Chierici, R; Chliapnikov, P V; Chochula, P; Chorowicz, V; Cindro, V; Collins, P; Contreras, J L; Contri, R; Cortina, E; Cosme, G; Cossutti, F; Crawley, H B; Crennell, D J; Crosetti, G; Cuevas-Maestro, J; Czellar, S; Dahl-Jensen, Erik; Dahm, J; D'Almagne, B; Dam, M; Damgaard, G; Dauncey, P D; Davenport, Martyn; Da Silva, W; Defoix, C; Deghorain, A; Della Ricca, G; Delpierre, P A; Demaria, N; De Angelis, A; De Boeck, H; de Boer, Wim; De Brabandere, S; De Clercq, C; La Vaissière, C de; De Lotto, B; De Min, A; De Paula, L S; De Saint-Jean, C; Dijkstra, H; Di Ciaccio, Lucia; Djama, F; Dolbeau, J; Dönszelmann, M; Doroba, K; Dracos, M; Drees, J; Drees, K A; Dris, M; Dufour, Y; Dupont, F; Edsall, D M; Ehret, R; Eigen, G; Ekelöf, T J C; Ekspong, Gösta; Elsing, M; Engel, J P; Ershaidat, N; Erzen, B; Espirito-Santo, M C; Falk, E; Fassouliotis, D; Feindt, Michael; Ferrer, A; Filippas-Tassos, A; Firestone, A; Fischer, P A; Föth, H; Fokitis, E; Fontanelli, F; Formenti, F; Franek, B J; Frenkiel, P; Fries, D E C; Frodesen, A G; Frühwirth, R; Fulda-Quenzer, F; Fuster, J A; Galloni, A; Gamba, D; Gandelman, M; García, C; García, J; Gaspar, C; Gasparini, U; Gavillet, P; Gazis, E N; Gelé, D; Gerber, J P; Gerdyukov, L N; Gibbs, M; Gokieli, R; Golob, B; Gopal, Gian P; Gorn, L; Górski, M; Guz, Yu; Gracco, Valerio; Graziani, E; Grosdidier, G; Grzelak, K; Gumenyuk, S A; Gunnarsson, P; Günther, M; Guy, J; Hahn, F; Hahn, S; Hallgren, A; Hamacher, K; Hao, W; Harris, F J; Hedberg, V; Henriques, R P; Hernández, J J; Herquet, P; Herr, H; Hessing, T L; Higón, E; Hilke, Hans Jürgen; Hill, T S; Holmgren, S O; Holt, P J; Holthuizen, D J; Hoorelbeke, S; Houlden, M A; Hrubec, Josef; Huet, K; Hultqvist, K; Jackson, J N; Jacobsson, R; Jalocha, P; Janik, R; Jarlskog, G; Jarry, P; Jean-Marie, B; Johansson, E K; Jönsson, L B; Jönsson, P E; Joram, Christian; Juillot, P; Kaiser, M; Kapusta, F; Karafasoulis, K; Karlsson, M; Karvelas, E; Katsanevas, S; Katsoufis, E C; Keränen, R; Khokhlov, Yu A; Khomenko, B A; Khovanskii, N N; King, B J; Kjaer, N J; Klein, H; Klovning, A; Kluit, P M; Köne, B; Kokkinias, P; Koratzinos, M; Korcyl, K; Kostyukhin, V; Kourkoumelis, C; Kuznetsov, O; Kramer, P H; Krammer, Manfred; Kreuter, C; Królikowski, J; Kronkvist, I J; Krumshtein, Z; Krupinski, W; Kubinec, P; Kucewicz, W; Kurvinen, K L; Lacasta, C; Laktineh, I; Lamblot, S; Lamsa, J; Lanceri, L; Lane, D W; Langefeld, P; Last, I; Laugier, J P; Lauhakangas, R; Leder, Gerhard; Ledroit, F; Lefébure, V; Legan, C K; Leitner, R; Lemoigne, Y; Lemonne, J; Lenzen, Georg; Lepeltier, V; Lesiak, T; Liko, D; Lindner, R; Lipniacka, A; Lippi, I; Lörstad, B; Lokajícek, M; Loken, J G; López, J M; López-Fernandez, A; López-Aguera, M A; Loukas, D; Lutz, P; Lyons, L; MacNaughton, J N; Maehlum, G; Maio, A; Malychev, V; Mandl, F; Maocun, C; Marco, J; Maréchal, B; Margoni, M; Marin, J C; Mariotti, C; Markou, A; Maron, T; Martínez-Rivero, C; Martínez-Vidal, F; Martí i García, S; Matorras, F; Matteuzzi, C; Matthiae, Giorgio; Mazzucato, M; McCubbin, M L; McKay, R; McNulty, R; Medbo, J; Meroni, C; Meyer, S; Meyer, W T; Myagkov, A; Michelotto, M; Migliore, E; Mirabito, L; Mitaroff, Winfried A; Mjörnmark, U; Moa, T; Møller, R; Mönig, K; Monge, M R; Morettini, P; Müller, H; Mundim, L M; Murray, W J; Muryn, B; Myatt, Gerald; Naraghi, F; Navarria, Francesco Luigi; Navas, S; Negri, P; Némécek, S; Neumann, W; Nicolaidou, R; Nielsen, B S; Nieuwenhuizen, M; Nikolaenko, V; Niss, P; Nomerotski, A; Normand, Ainsley; Oberschulte-Beckmann, W; Obraztsov, V F; Olshevskii, A G; Onofre, A; Orava, Risto; Österberg, K; Ouraou, A; Paganini, P; Paganoni, M; Pagès, P; Palka, H; Papadopoulou, T D; Papageorgiou, K; Pape, L; Parkes, C; Parodi, F; Passeri, A; Pegoraro, M; Peralta, L; Pernegger, H; Pernicka, Manfred; Perrotta, A; Petridou, C; Petrolini, A; Petrovykh, M; Phillips, H T; Piana, G; Pierre, F; Pimenta, M; Pindo, M; Plaszczynski, S; Podobrin, O; Pol, M E; Polok, G; Poropat, P; Pozdnyakov, V; Prest, M; Privitera, P; Pukhaeva, N; Radojicic, D; Ragazzi, S; Rahmani, H; Rames, J; Ratoff, P N; Read, A L; Reale, M; Rebecchi, P; Redaelli, N G; Regler, Meinhard; Reid, D; Renton, P B; Resvanis, L K; Richard, F; Richardson, J; Rídky, J; Rinaudo, G; Ripp, I; Romero, A; Roncagliolo, I; Ronchese, P; Roos, L; Rosenberg, E I; Rosso, E; Roudeau, Patrick; Rovelli, T; Rückstuhl, W; Ruhlmann-Kleider, V; Ruiz, A; Saarikko, H; Sacquin, Yu; Sadovskii, A; Sajot, G; Salt, J; Sánchez, J; Sannino, M; Schimmelpfennig, M; Schneider, H; Schwickerath, U; Schyns, M A E; Sciolla, G; Scuri, F; Seager, P; Sedykh, Yu; Segar, A M; Seitz, A; Sekulin, R L; Shellard, R C; Siccama, I; Siegrist, P; Simonetti, S; Simonetto, F; Sissakian, A N; Sitár, B; Skaali, T B; Smadja, G; Smirnov, N; Smirnova, O G; Smith, G R; Solovyanov, O; Sosnowski, R; Souza-Santos, D; Spiriti, E; Sponholz, P; Squarcia, S; Stanescu, C; Stapnes, Steinar; Stavitski, I; Stichelbaut, F; Stocchi, A; Strauss, J; Strub, R; Stugu, B; Szczekowski, M; Szeptycka, M; Tabarelli de Fatis, T; Tavernet, J P; Chikilev, O G; Tilquin, A; Timmermans, J; Tkatchev, L G; Todorov, T; Toet, D Z; Tomaradze, A G; Tomé, B; Tortora, L; Tranströmer, G; Treille, D; Trischuk, W; Tristram, G; Trombini, A; Troncon, C; Tsirou, A L; Turluer, M L; Tyapkin, I A; Tyndel, M; Tzamarias, S; Überschär, B; Ullaland, O; Uvarov, V; Valenti, G; Vallazza, E; Van der Velde, C; van Apeldoorn, G W; van Dam, P; Van Doninck, W K; Van Eldik, J; Vassilopoulos, N; Vegni, G; Ventura, L; Venus, W A; Verbeure, F; Verlato, M; Vertogradov, L S; Vilanova, D; Vincent, P; Vitale, L; Vlasov, E; Vodopyanov, A S; Vrba, V; Wahlen, H; Walck, C; Waldner, F; Weierstall, M; Weilhammer, Peter; Weiser, C; Wetherell, Alan M; Wicke, D; Wickens, J H; Wielers, M; Wilkinson, G R; Williams, W S C; Winter, M; Witek, M; Woschnagg, K; Yip, K; Yushchenko, O P; Zach, F; Zacharatou-Jarlskog, C; Zalewska-Bak, A; Zalewski, Piotr; Zavrtanik, D; Zevgolatakos, E; Zimin, N I; Zito, M; Zontar, D; Zuberi, R; Zucchelli, G C; Zumerle, G

1996-01-01

The tau lepton lifetime has been measured using three different methods with the DELPHI detector. Two measurements of one-prong decays are combined, accounting for correlations, giving a result of \\tau_\\tau = 291.8 \\pm 3.3 \\mbox{ (stat.)} \\pm 2.0 \\mbox{(sys.) fs} while the decay length distribution of three-prong decays gives the result \\tau_{\\tau} = 286.7 \\pm 4.9 \\mbox{ (stat.)} \\pm 3.3 \\mbox{ (sys.) fs}. Combining the results presented here with previous DELPHI measurements, we get \\tau_{\\tau} = 291.4 \\pm 3.0 fs and find that the ratio of the coupling constant for tau decay relative to that for muon decay is 0.990 \\pm 0.009, compatible with lepton universality.

The adaptive immune system promotes initiation of prostate carcinogenesis in a human c-Myc transgenic mouse model.

Science.gov (United States)

Melis, Monique H M; Nevedomskaya, Ekaterina; van Burgsteden, Johan; Cioni, Bianca; van Zeeburg, Hester J T; Song, Ji-Ying; Zevenhoven, John; Hawinkels, Lukas J A C; de Visser, Karin E; Bergman, Andries M

2017-11-07

Increasing evidence from epidemiological and pathological studies suggests a role of the immune system in the initiation and progression of multiple cancers, including prostate cancer. Reports on the contribution of the adaptive immune system are contradictive, since both suppression and acceleration of disease development have been reported. This study addresses the functional role of lymphocytes in prostate cancer development using a genetically engineered mouse model (GEMM) of human c-Myc driven prostate cancer (Hi-Myc mice) combined with B and T cell deficiency (RAG1 -/- mice). From a pre-cancerous stage on, Hi-Myc mice showed higher accumulation of immune cells in their prostates then wild-type mice, of which macrophages were the most abundant. The onset of invasive adenocarcinoma was delayed in Hi-MycRAG1 -/- compared to Hi-Myc mice and associated with decreased infiltration of leukocytes into the prostate. In addition, lower levels of the cytokines CXCL2, CCL5 and TGF-β1 were detected in Hi-MycRAG1 -/- compared to Hi-Myc mouse prostates. These results from a GEMM of prostate cancer provide new insights into the promoting role of the adaptive immune system in prostate cancer development. Our findings indicate that the endogenous adaptive immune system does not protect against de novo prostate carcinogenesis in Hi-Myc transgenic mice, but rather accelerates the formation of invasive adenocarcinomas. This may have implications for the development of novel treatment strategies.

...tau and charm

International Nuclear Information System (INIS)

Anon.

1993-01-01

The Standard Model of particle physics has six quarks, grouped in three pairs (up/down, charm/strange, top/beauty), each pair being partnered with a lepton and its corresponding neutrino - respectively electron, muon, and tau. Probing the Standard Model in depth to see what makes it work means peering into all quark/lepton corners. While B physics, with its potential at proton and electron-positron machines, is being pushed hard (see previous article), other physicists underline the need for complementary information from other sectors. Essential experimental tools for exploring out-of-the-ordinary particles are a Tau-Charm Factory and a Beauty Factory. These machines address similar basic questions in the Standard Model, but in complementary ways: the Beauty Factory is optimized for beauty particles and CP violation in B decays; and the TCF is optimized for the tau lepton, charm particles, and the spectroscopy of hidden charm states and light hadrons. In early June about 100 physicists - theorists, experimentalists and accelerator physicists - from Europe and beyond gathered in Marbella, Spain, for the 3rd Workshop on the Tau-Charm Factory (TCF). The workshop aimed to reassess the TCF physics potential in the light of recent progress, to develop further the designs of the machine and the detector, and to discuss the experimental programme

Possible Tau Appearance Experiment with Atmospheric Neutrinos

Energy Technology Data Exchange (ETDEWEB)

Stanev, Todor

1999-12-27

We suggest an experimental measurement that could detect the appearance of tau neutrinos due to {nu}{sub {mu}}{yields}{nu}{sub {tau}} oscillations of atmospheric neutrinos by measuring the energy spectra of neutrino induced showers. {tau} neutrinos deposit a large fraction of their energy in showers generated by {nu}{sub {tau}} charge current interactions and the subsequent {tau} -lepton decay. The appearance of {nu}{sub {tau}} will enhance the spectrum of neutrino induced showers in energy ranges corresponding to the neutrino oscillation parameters. A shower rate lower than the ''no oscillation'' prediction is an indication for {nu}{sub {mu}}{yields}{nu}{sub s} oscillations. (c) 1999 The American Physical Society.

Tau Polarization Measurement in the L3 Detector; Medida de la polarizacion del Tau en el detector L3

Energy Technology Data Exchange (ETDEWEB)

Garcia, P

1996-06-01

The Polarization asymmetry (A{sub p}) measurement can be obtained from the energy spectra of the tau lepton (tau) decay products. This measurement provides a precise determination of the weak mixing angel (sin``2 tilde char theta{sub w}), one of the Standard Model fundamental parameters. Tau leptons are produced at LEP in e``+e``-yields tilde char f interactions at a center of mass energy of the order of the Z boson mass. In order to get A{sub p} we have calculated the analytical formulae of the tau decay products energy spectra, including radiative corrections, for all of the one prong tau decay channels. We have also extended this analytical formalism to the detector level, including the selection criteria effects and the detector resolution (calibration) in the analytical expressions. Detailed studies have been performed concerning our measurement using this formalism. From the data collected with the L3 detector between 1991 and 1994, which corresponds to an integrated luminosity of 118.8 pb``1 at a center of mass energy of the order of the Z mass, we have identified and selected the following tau decay channel samples: tau yields e nu tilde char nu, tau yields mu nu tilde char nu, tau yields pi/K nu y tau yields p/K*nu. From the analysis of these samples we get the tau polarization asymmetry measurement: A{sub p}=0.143+-0.014+-0.010, which corresponds to a value of sin``2 tilde char theta{sub w}=0.2320+-0.0018+-0.0013. (Author) 24 refs

Updated measurement of the $\\tau$ lepton lifetime

CERN Document Server

Barate, R; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Nief, J Y; Pietrzyk, B; Casado, M P; Chmeissani, M; Comas, P; Crespo, J M; Delfino, M C; Fernández, E; Fernández-Bosman, M; Garrido, L; Juste, A; Martínez, M; Merino, G; Miquel, R; Mir, L M; Padilla, C; Park, I C; Pascual, A; Perlas, J A; Riu, I; Sánchez, F; Teubert, F; Colaleo, A; Creanza, D; De Palma, M; Gelao, G; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Nuzzo, S; Ranieri, A; Raso, G; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Tricomi, A; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Abbaneo, D; Alemany, R; Becker, U; Bazarko, A O; Bright-Thomas, P G; Cattaneo, M; Cerutti, F; Dissertori, G; Drevermann, H; Forty, Roger W; Frank, M; Hagelberg, R; Hansen, J B; Harvey, J; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Mato, P; Minten, Adolf G; Moneta, L; Pacheco, A; Pusztaszeri, J F; Ranjard, F; Rizzo, G; Rolandi, Luigi; Rousseau, D; Schlatter, W D; Schmitt, M; Schneider, O; Tejessy, W; Tomalin, I R; Wachsmuth, H W; Wagner, A; Ajaltouni, Ziad J; Barrès, A; Boyer, C; Falvard, A; Ferdi, C; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Montret, J C; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rosnet, P; Rossignol, J M; Fearnley, Tom; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Rensch, B; Wäänänen, A; Daskalakis, G; Kyriakis, A; Markou, C; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Rougé, A; Rumpf, M; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Focardi, E; Parrini, G; Zachariadou, K; Corden, M; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Casper, David William; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Passalacqua, L; Pepé-Altarelli, M; Curtis, L; Dorris, S J; Halley, A W; Knowles, I G; Lynch, J G; O'Shea, V; Raine, C; Scarr, J M; Smith, K; Teixeira-Dias, P; Thompson, A S; Thomson, E; Thomson, F; Turnbull, R M; Buchmüller, O L; Dhamotharan, S; Geweniger, C; Graefe, G; Hanke, P; Hansper, G; Hepp, V; Kluge, E E; Putzer, A; Sommer, J; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Dornan, Peter J; Girone, M; Goodsir, S M; Martin, E B; Moutoussi, A; Nash, J; Sedgbeer, J K; Spagnolo, P; Stacey, A M; Williams, M D; Ghete, V M; Girtler, P; Kuhn, D; Rudolph, G; Betteridge, A P; Bowdery, C K; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Jones, R W L; Sloan, Terence; Williams, M I; Galla, A; Giehl, I; Greene, A M; Hoffmann, C; Jakobs, K; Kleinknecht, K; Quast, G; Renk, B; Rohne, E; Sander, H G; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Benchouk, C; Bonissent, A; Bujosa, G; Carr, J; Coyle, P; Diaconu, C A; Etienne, F; Konstantinidis, N P; Leroy, O; Motsch, F; Payre, P; Talby, M; Sadouki, A; Thulasidas, M; Trabelsi, K; Aleppo, M; Antonelli, M; Ragusa, F; Berlich, R; Blum, Walter; Büscher, V; Dietl, H; Ganis, G; Gotzhein, C; Kroha, H; Lütjens, G; Lutz, Gerhard; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Saint-Denis, R; Stenzel, H; Wiedenmann, W; Wolf, G; Boucrot, J; Callot, O; Chen, S; Choi, Y; Cordier, A; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Höcker, A; Jacholkowska, A; Jacquet, M; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Nikolic, I A; Schune, M H; Simion, S; Tournefier, E; Veillet, J J; Videau, I; Zerwas, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Palla, Fabrizio; Sanguinetti, G; Sciabà, A; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Vannini, C; Venturi, A; Verdini, P G; Blair, G A; Bryant, L M; Chambers, J T; Gao, Y; Green, M G; Medcalf, T; Perrodo, P; Strong, J A; Von Wimmersperg-Töller, J H; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Norton, P R; Thompson, J C; Wright, A E; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Black, S N; Dann, J H; Johnson, R P; Kim, H Y; Litke, A M; McNeil, M A; Taylor, G; Booth, C N; Boswell, R; Brew, C A J; Cartwright, S L; Combley, F; Kelly, M S; Lehto, M H; Newton, W M; Reeve, J; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Grupen, Claus; Lutters, G; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Musolino, G; Pütz, J; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Charles, E; Elmer, P; Ferguson, D P S; González, S; Greening, T C; Hayes, O J; Hu, H; Jin, S; McNamara, P A; Nachtman, J M; Nielsen, J; Orejudos, W; Pan, Y B; Saadi, Y; Scott, I J; Walsh, J; Wu Sau Lan; Wu, X; Yamartino, J M; Zobernig, G

1997-01-01

A new measurement of the mean lifetime of the tau lepton is presented. Three different analysis methods are applied to a sample of 90000 tau pairs, collected in 1993 and 1994 with the ALEPH detector at LEP. The average of this measurement and those previously published by ALEPH is tau_tau = 290.1 +- 1.5 +- 1.1 fs.

TBI-Induced Formation of Toxic Tau and Its Biochemical Similarities to Tau in AD Brains

Science.gov (United States)

2017-10-01

produces high quantities of protein (0.1-1.5mg tau from 1.5g of frozen tissue), preserves tau phosphorylation, and removes the vast majority of...disease This project seeks to establish extracellular soluble species of tau as major toxic species responsible for reduction of synaptic...competitive renewal grant is to optimize ultrasound parameters for non- invasive opening of the BBB. Dr. Lewis Brown 5R01MH098786-02 (Andrew J. Dwork

Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain

DEFF Research Database (Denmark)

Liu, Xiaobin; Zeng, Joanne; Zhou, Anni

2011-01-01

/EGFP-transgenic mice show anatomically correct and overlapping expression of both NPS and EGFP. A total number of ~500 NPS/EGFP-positive neurons are present in the mouse brain, located in the pericoerulear region and the Kölliker-Fuse nucleus. NPS and transgene expression is first detectable around E14, indicating...

Tau physics at the LHC with ATLAS

CERN Document Server

Lai, Stan

2009-01-01

The presence of tau leptons in the final state is an important signature in searches for physics beyond the Standard Model. Hadronically decaying tau leptons can be reconstructed over a wide kinematic range at ATLAS. The reconstruction algorithm for hadronically decaying tau leptons and the performance of tau lepton identification is described. A review of physics processes with tau lepton final states is given, ranging from Standard Model processes in early data, such as W and Z boson production, to searches for new phenomena beyond the Standard Model.

Tumor suppressor PTEN affects tau phosphorylation: deficiency in the phosphatase activity of PTEN increases aggregation of an FTDP-17 mutant Tau

Directory of Open Access Journals (Sweden)

Zhang Xue

2006-07-01

Full Text Available Abstract Background Aberrant hyperphosphorylation of tau protein has been implicated in a variety of neurodegenerative disorders. Although a number of protein kinases have been shown to phosphorylate tau in vitro and in vivo, the molecular mechanisms by which tau phosphorylation is regulated pathophysiologically are largely unknown. Recently, a growing body of evidence suggests a link between tau phosphorylation and PI3K signaling. In this study, phosphorylation, aggregation and binding to the microtubule of a mutant frontal temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 tau in the presence of tumor suppressor PTEN, a major regulatory component in PI3K signaling, were investigated. Results Phosphorylation of the human mutant FTDP-17 tau, T40RW, was evaluated using different phospho-tau specific antibodies in the presence of human wild-type or phosphatase activity null mutant PTEN. Among the evaluated phosphorylation sites, the levels of Ser214 and Thr212 phospho-tau proteins were significantly decreased in the presence of wild-type PTEN, and significantly increased when the phosphatase activity null mutant PTEN was ectopically expressed. Fractionation of the mutant tau transfected cells revealed a significantly increased level of soluble tau in cytosol when wild-type PTEN was expressed, and an elevated level of SDS-soluble tau aggregates in the presence of the mutant PTEN. In addition, the filter/trap assays detected more SDS-insoluble mutant tau aggregates in the cells overexpressing the mutant PTEN compared to those in the cells overexpressing wild-type PTEN and control DNA. This notion was confirmed by the immunocytochemical experiment which demonstrated that the overexpression of the phosphatase activity null mutant PTEN caused the mutant tau to form aggregates in the COS-7 cells. Conclusion Tumor suppressor PTEN can alleviate the phosporylation of the mutant FTDP-17 tau at specific sites, and the phosphatase activity

Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

LENUS (Irish Health Repository)

Colgan, N

2015-10-23

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer\\'s disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer\\'s disease.

Neutral Higgs boson searches in the H{yields}{tau}{tau}{yields}{mu}{mu} decay channel

Energy Technology Data Exchange (ETDEWEB)

Bethani, Agni

2013-10-15

This dissertation describes the search for Higgs bosons decaying to a pair of {tau} leptons both decaying to muons. The analysis was performed using events recorded by the CMS detector at the LHC in 2011 and 2012, at center-of-mass energy 7 TeV and 8 TeV respectively. The dataset corresponds to total integrated luminosity of 17 fb{sup -1}, 4.9 fb{sup -1} taken at 7 TeV center-of-mass energy and 12.1 fb{sup -1} at 8 TeV. The results were interpreted in the context of both the Standard Model and the Minimal Supersymmetric Standard Model. Upper limits were set to the Higgs production cross section in the former case and on the (tan {beta}, m{sub A}) plane in the latter. The update of this analysis with more data, combined with other {tau}{tau} final states, lead to the first evidence of the Higgs coupling to {tau} leptons. Included in this document is also the study of the Z boson production followed by Z {yields} {tau}{tau} decay with two muons in the final state. This analysis was performed with 36 pb{sup -1} of data collected in 2010, at center-of-mass energy 7 TeV, by the CMS experiment. The result of this study was the measurement of the Z production cross section in proton-proton collisions. The analysis procedures developed for the Z boson decay to {tau} leptons were used to commission the Higgs boson searches in the same decay channel.

Multi-Scale Characterization of the PEPCK-Cmus Mouse through 3D Cryo-Imaging

Directory of Open Access Journals (Sweden)

Debashish Roy

2010-01-01

Full Text Available We have developed, for the Case 3D Cryo-imaging system, a specialized, multiscale visualization scheme which provides color-rich volume rendering and multiplanar reformatting enabling one to visualize an entire mouse and zoom in to organ, tissue, and microscopic scales. With this system, we have anatomically characterized, in 3D, from whole animal to tissue level, a transgenic mouse and compared it with its control. The transgenic mouse overexpresses the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C in its skeletal muscle and is capable of greatly enhanced physical endurance and has a longer life-span and reproductive life as compared to control animals. We semiautomatically analyzed selected organs such as kidney, heart, adrenal gland, spleen, and ovaries and found comparatively enlarged heart, much less visceral, subcutaneous, and pericardial adipose tissue, and higher tibia-to-femur ratio in the transgenic animal. Microscopically, individual skeletal muscle fibers, fine mesenteric blood vessels, and intestinal villi, among others, were clearly seen.

Measurement of the Lifetime of the $\\tau$ Lepton

CERN Document Server

Acciarri, M; Aguilar-Benítez, M; Ahlen, S P; Alpat, B; Alcaraz, J; Alemanni, G; Allaby, James V; Aloisio, A; Alverson, G; Alviggi, M G; Ambrosi, G; Anderhub, H; Andreev, V P; Angelescu, T; Anselmo, F; Antreasyan, D; Arefev, A; Azemoon, T; Aziz, T; Bagnaia, P; Baksay, L; Ball, R C; Banerjee, S; Banicz, K; Barillère, R; Barone, L; Bartalini, P; Baschirotto, A; Basile, M; Battiston, R; Bay, A; Becattini, F; Becker, U; Behner, F; Berdugo, J; Berges, P; Bertucci, B; Betev, B L; Bhattacharya, S; Biasini, M; Biland, A; Bilei, G M; Blaising, J J; Blyth, S C; Bobbink, Gerjan J; Böck, R K; Böhm, A; Borgia, B; Boucham, A; Bourilkov, D; Bourquin, Maurice; Boutigny, D; Branson, J G; Brigljevic, V; Brock, I C; Buffini, A; Buijs, A; Burger, J D; Burger, W J; Busenitz, J K; Buytenhuijs, A O; Cai, X D; Campanelli, M; Capell, M; Cara Romeo, G; Caria, M; Carlino, G; Cartacci, A M; Casaus, J; Castellini, G; Cavallari, F; Cavallo, N; Cecchi, C; Cerrada-Canales, M; Cesaroni, F; Chamizo-Llatas, M; Chan, A; Chang, Y H; Chaturvedi, U K; Chemarin, M; Chen, A; Chen, G; Chen, G M; Chen, H F; Chen, H S; Chen, M; Chiefari, G; Chien, C Y; Choi, M T; Cifarelli, Luisa; Cindolo, F; Civinini, C; Clare, I; Clare, R; Cohn, H O; Coignet, G; Colijn, A P; Colino, N; Costantini, S; Cotorobai, F; de la Cruz, B; Csilling, Akos; Dai, T S; D'Alessandro, R; De Asmundis, R; De Boeck, H; Degré, A; Deiters, K; Denes, P; De Notaristefani, F; DiBitonto, Daryl; Diemoz, M; Van Dierendonck, D N; Di Lodovico, F; Dionisi, C; Dittmar, Michael; Dominguez, A; Doria, A; Dorne, I; Dova, M T; Drago, E; Duchesneau, D; Duinker, P; Durán, I; Dutta, S; Easo, S; Efremenko, Yu V; El-Mamouni, H; Engler, A; Eppling, F J; Erné, F C; Ernenwein, J P; Extermann, Pierre; Fabre, M; Faccini, R; Falciano, S; Favara, A; Fay, J; Fedin, O; Felcini, Marta; Fenyi, B; Ferguson, T; Fernández, D; Ferroni, F; Fesefeldt, H S; Fiandrini, E; Field, J H; Filthaut, Frank; Fisher, P H; Forconi, G; Fredj, L; Freudenreich, Klaus; Furetta, C; Galaktionov, Yu; Ganguli, S N; García-Abia, P; Gau, S S; Gentile, S; Gerald, J; Gheordanescu, N; Giagu, S; Goldfarb, S; Goldstein, J; Gong, Z F; Gougas, Andreas; Gratta, Giorgio; Grünewald, M W; Gupta, V K; Gurtu, A; Gutay, L J; Hangarter, K; Hartmann, B; Hasan, A; Hatzifotiadou, D; Hebbeker, T; Hervé, A; Van Hoek, W C; Hofer, H; Hoorani, H; Hou, S R; Hu, G; Innocente, Vincenzo; Janssen, H; Jin, B N; Jones, L W; de Jong, P; Josa-Mutuberria, I; Kasser, A; Khan, R A; Kamyshkov, Yu A; Kapinos, P; Kapustinsky, J S; Karyotakis, Yu; Kaur, M; Kienzle-Focacci, M N; Kim, D; Kim, J K; Kim, S C; Kim, Y G; Kinnison, W W; Kirkby, A; Kirkby, D; Kirkby, Jasper; Kiss, D; Kittel, E W; Klimentov, A; König, A C; Korolko, I; Koutsenko, V F; Krämer, R W; Krenz, W; Kuijten, H; Kunin, A; Ladrón de Guevara, P; Landi, G; Lapoint, C; Lassila-Perini, K M; Laurikainen, P; Lebeau, M; Lebedev, A; Lebrun, P; Lecomte, P; Lecoq, P; Le Coultre, P; Lee Jae Sik; Lee, K Y; Leggett, C; Le Goff, J M; Leiste, R; Leonardi, E; Levchenko, P M; Li Chuan; Lieb, E H; Lin, W T; Linde, Frank L; Lista, L; Liu, Z A; Lohmann, W; Longo, E; Lu, W; Lü, Y S; Lübelsmeyer, K; Luci, C; Luckey, D; Luminari, L; Lustermann, W; Ma Wen Gan; Maity, M; Majumder, G; Malgeri, L; Malinin, A; Maña, C; Mangla, S; Marchesini, P A; Marin, A; Martin, J P; Marzano, F; Massaro, G G G; McNally, D; Mele, S; Merola, L; Meschini, M; Metzger, W J; Von der Mey, M; Mi, Y; Mihul, A; Van Mil, A J W; Mirabelli, G; Mnich, J; Molnár, P; Monteleoni, B; Moore, R; Morganti, S; Moulik, T; Mount, R; Müller, S; Muheim, F; Nagy, E; Nahn, S; Napolitano, M; Nessi-Tedaldi, F; Newman, H; Nippe, A; Nowak, H; Organtini, G; Ostonen, R; Pandoulas, D; Paoletti, S; Paolucci, P; Park, H K; Pascale, G; Passaleva, G; Patricelli, S; Paul, T; Pauluzzi, M; Paus, C; Pauss, Felicitas; Peach, D; Pei, Y J; Pensotti, S; Perret-Gallix, D; Petrak, S; Pevsner, A; Piccolo, D; Pieri, M; Pinto, J C; Piroué, P A; Pistolesi, E; Plyaskin, V; Pohl, M; Pozhidaev, V; Postema, H; Produit, N; Prokofev, D; Prokofiev, D O; Rahal-Callot, G; Rancoita, P G; Rattaggi, M; Raven, G; Razis, P A; Read, K; Ren, D; Rescigno, M; Reucroft, S; Van Rhee, T; Riemann, S; Riemers, B C; Riles, K; Rind, O; Ro, S; Robohm, A; Rodin, J; Rodríguez-Calonge, F J; Roe, B P; Röhner, S; Romero, L; Rosier-Lees, S; Rosselet, P; Van Rossum, W; Roth, S; Rubio, Juan Antonio; Rykaczewski, H; Salicio, J; Sánchez, E; Santocchia, A; Sarakinos, M E; Sarkar, S; Sassowsky, M; Sauvage, G; Schäfer, C; Shchegelskii, V; Schmidt-Kärst, S; Schmitz, D; Schmitz, P; Schneegans, M; Schöneich, B; Scholz, N; Schopper, Herwig Franz; Schotanus, D J; Schwenke, J; Schwering, G; Sciacca, C; Sciarrino, D; Sens, Johannes C; Servoli, L; Shevchenko, S; Shivarov, N; Shoutko, V; Shukla, J; Shumilov, E; Shvorob, A V; Siedenburg, T; Son, D; Sopczak, André; Soulimov, V; Smith, B; Spillantini, P; Steuer, M; Stickland, D P; Stone, H; Stoyanov, B; Strässner, A; Strauch, K; Sudhakar, K; Sultanov, G G; Sun, L Z; Susinno, G F; Suter, H; Swain, J D; Tang, X W; Tauscher, Ludwig; Taylor, L; Ting, Samuel C C; Ting, S M; Tonisch, F; Tonutti, M; Tonwar, S C; Tóth, J; Tully, C; Tuchscherer, H; Tung, K L; Ulbricht, J; Uwer, U; Valente, E; Van de Walle, R T; Vesztergombi, G; Vetlitskii, I; Viertel, Gert M; Vivargent, M; Völkert, R; Vogel, H; Vogt, H; Vorobev, I; Vorobyov, A A; Vorvolakos, A; Wadhwa, M; Wallraff, W; Wang, J C; Wang, X L; Wang, Z M; Weber, A; Wittgenstein, F; Wu, S X; Wynhoff, S; Xu, J; Xu, Z Z; Yang, B Z; Yang, C G; Yao, X Y; Ye, J B; Yeh, S C; You, J M; Zalite, A; Zalite, Yu; Zemp, P; Zeng, Y; Zhang, Z; Zhang, Z P; Zhou, B; Zhou, Y; Zhu, G Y; Zhu, R Y; Zichichi, Antonino

1996-01-01

The lifetime of the tau lepton is measured using data collected in 1994 by the L3 detector at LEP. The precise track position information of the Silicon Microvertex Detector is exploited. The tau lepton lifetime is determined from the signed impact parameter distribution for 30 322 tau decays into one charged particle and from the decay length distribution for 3891 tau decays into three charged particles. Combining the two methods we obtain $\\tau_{\\tau}$ = 290.1 $\\pm$ 4.0 fs.

Expression of the human growth hormone variant gene in cultured fibroblasts and transgenic mice

International Nuclear Information System (INIS)

Selden, R.F.; Wagner, T.E.; Blethen, S.; Yun, J.S.; Rowe, M.E.; Goodman, H.M.

1988-01-01

The nucleotide sequence of the human growth hormone variant gene, one of the five members of the growth hormone gene family, predicts that it encodes a growth hormone-like protein. As a first step in determining whether this gene is functional in humans, the authors have expressed a mouse methallothionein I/human growth hormone variant fusion gene in mouse L cells and in transgenic mice. The growth hormone variant protein expressed in transiently transfected L cells is distinct from growth hormone itself with respect to reactivity with anti-growth hormone monoclonal antibodies, behavior during column chromatography, and isoelectric point. Transgenic mice expressing the growth hormone variant protein are 1.4- to 1.9-fold larger than nontransgenic controls, suggesting that the protein has growth-promoting properties

Enhanced Antibody Responses in a Novel NOG Transgenic Mouse with Restored Lymph Node Organogenesis

Directory of Open Access Journals (Sweden)

Takeshi Takahashi

2018-01-01

Full Text Available Lymph nodes (LNs are at the center of adaptive immune responses. Various exogenous substances are transported into LNs and a series of immune responses ensue after recognition by antigen–specific lymphocytes. Although humanized mice have been used to reconstitute the human immune system, most lack LNs due to deficiency of the interleukin (IL-2Rγ gene (cytokine common γ chain, γc. In this study, we established a transgenic strain, NOG-pRORγt-γc, in the NOD/shi-scid-IL-2Rγnull (NOG background, in which the γc gene was expressed in a lymph-tissue inducer (LTi lineage by the endogenous promoter of RORγt. In this strain, LN organogenesis was normalized and the number of human T cells substantially increased in the periphery after reconstitution of the human immune system by human hematopoietic stem cell transplantation. The distribution of human T cells differed between NOG-pRORγt-γc Tg and NOG-non Tg mice. About 40% of human T cells resided in LNs, primarily the mesenteric LNs. The LN-complemented humanized mice exhibited antigen-specific immunoglobulin G responses together and an increased number of IL-21+–producing CD4+ T cells in LNs. This novel mouse strain will facilitate recapitulation of human immune responses.

Neuronal Models for Studying Tau Pathology

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Thorsten Koechling

2010-01-01

Full Text Available Alzheimer's disease (AD is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing -amyloid peptide and neurofibrillary tangles (NFTs, consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD.

Application of TauSpinner for studies on tau-lepton polarization and spin correlations in Z, W and H decays at LHC

CERN Document Server

Kaczmarska, A.; Przedzinski, T.; Richter-Was, E.; Was, Z.

2014-01-01

The tau-lepton plays an important role in the physics program at LHC. Its spin can be used for separation of signal from background or in measuring properties of New Particles decaying to tau leptons. The TauSpinner package represents a tool to modify tau spin effects in any sample containing tau leptons. Generated events, featuring taus produced from intermediate state W, Z, H bosons can be used as an input. The information on the polarization and spin correlations is reconstructed from the kinematics of the tau lepton(s) (nutau in case of W-mediated processes) and tau decay products. By weights, attributed on the event-by-event basis, it enables numerical evaluation and/or modification of the spin effects. We review distributions to monitor spin effects in leptonic and hadronic tau decays with up to three pions, to provide benchmarks for validation of spin content of the event sample and to visualize the tau lepton spin polarization and correlation effects. The demonstration examples for use of TauSpinner l...

Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

Directory of Open Access Journals (Sweden)

Zagozdzon Agnieszka M

2012-05-01

Full Text Available Abstract Background Numerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study. Results A new mouse strain (MMTV-Luc2 mice expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal. Conclusions We have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

LENUS (Irish Health Repository)

Zagozdzon, Agnieszka M

2012-05-30

AbstractBackgroundNumerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study.ResultsA new mouse strain (MMTV-Luc2 mice) expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal.ConclusionsWe have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and\\/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

New Features about Tau Function and Dysfunction

Directory of Open Access Journals (Sweden)

Miguel Medina

2016-04-01

Full Text Available Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future.

New Features about Tau Function and Dysfunction

Science.gov (United States)

Medina, Miguel; Hernández, Félix; Avila, Jesús

2016-01-01

Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future. PMID:27104579

Studies of the Strange Hadronic Tau Decay Tau- to K0(S) Pi- Nu-Tau Using the BaBar Detector

Energy Technology Data Exchange (ETDEWEB)

Lyon, Andrew J.; /Manchester U. /SLAC

2006-01-27

A study of the decay {tau}{sup -} {yields} K{sub S}{sup 0}{pi}{sup -} {nu}{sub {tau}} (K{sub S}{sup 0} {yields} {pi}{sup +}{pi}{sup -}) using the BABAR detector is presented. Using 124.4 fb{sup -1} of data we measure {Beta}({tau}{sup -} {yields} {bar K}{sup 0}{pi}{sup -}{nu}{sub {tau}}) = (0.830 {+-} 0.005(stat) {+-} 0.042(syst))%, which is the world's most precise measurement to date of this branching ratio, and is consistent with the current world average. This preliminary result, unlike most of the {Beta}({tau}{sup -} {yields} {bar K}{sup 0}{pi}{sup -}{nu}{sub {tau}}) measurements already published, is systematics dominated and so the biggest future improvement to this number should come from reducing the systematic uncertainties in the analysis. A study of the K{pi} mass spectrum, from which the strange (K{pi}) spectral function can be measured, reveals excess contributions above the K*(892) tail at higher K{pi} mass. While in the past this has been thought to be due to K*(892) - K*(1410) interference, we find that the K*(1410), whose branching ratio to K{pi} is approximately 7%, seems insufficient to explain the excess mass observed in the data. Instead, we perform a fit using a K*(892) - K*(1680) interference model and find better agreement. The discrepancy that remains could be due to an s-wave contribution to the interference that is not parameterized in the model used, and/or detector smearing that is not accounted for in our fit. We also attempt to find an s-wave contribution to the K{pi} mass spectrum by searching for an sp-interference effect. While we find a hint that such an effect exists, we have neither the confidence in the statistics nor systematics in the higher K{pi} mass region to announce an observation. We conclude that it would be a worthwhile study to pursue.

$\\tau^{-} \\to (\\pi \\pi \\pi )^{-} \

CERN Document Server

Gómez-Dumm, D; Portolés, J; 10.1016/j.nuclphysbps.2004.04.166

2004-01-01

We analyse tau to pi pi pi nu /sub tau / decays within the framework of the resonance effective theory of QCD. We have worked out the relevant Lagrangian that describes the axial-vector current hadronization contributing to these processes, and the new coupling constants that arise have been constrained by imposing the asymptotic behaviour of the corresponding spectral function within QCD. Hence we compare the theoretical framework with the experimental data, obtaining a good quality fit from the ALEPH spectral function and branching ratio. We also get values for the mass and on-shell width of the a/sub 1/(1260) resonance, and provide the tau to pi pi pi nu /sub tau / structure functions that have been measured by OPAL and CLEO-II finding an excellent agreement.

A Tau-Charm Factory at CEBAF

Energy Technology Data Exchange (ETDEWEB)

Seth, K.K. [Northwestern Univ., Evanston, IL (United States)

1994-04-01

It is proposed that a Tau Charm Factory represents a natural extension of CEBAF into higher energy domains. The exciting nature of the physics of charm quarks and tau leptons is briefly reviewed and it is suggested that the concept of a linac-ring collider as a Tau Charm Factory at CEBAF should be seriously studied.

Tetracycline-inducible system for regulation of skeletal muscle-specific gene expression in transgenic mice

Science.gov (United States)

Grill, Mischala A.; Bales, Mark A.; Fought, Amber N.; Rosburg, Kristopher C.; Munger, Stephanie J.; Antin, Parker B.

2003-01-01

Tightly regulated control of over-expression is often necessary to study one aspect or time point of gene function and, in transgenesis, may help to avoid lethal effects and complications caused by ubiquitous over-expression. We have utilized the benefits of an optimized tet-on system and a modified muscle creatine kinase (MCK) promoter to generate a skeletal muscle-specific, doxycycline (Dox) controlled over-expression system in transgenic mice. A DNA construct was generated in which the codon optimized reverse tetracycline transactivator (rtTA) was placed under control of a skeletal muscle-specific version of the mouse MCK promoter. Transgenic mice containing this construct expressed rtTA almost exclusively in skeletal muscles. These mice were crossed to a second transgenic line containing a bi-directional promoter centered on a tet responder element driving both a luciferase reporter gene and a tagged gene of interest; in this case the calpain inhibitor calpastatin. Compound hemizygous mice showed high level, Dox dependent muscle-specific luciferase activity often exceeding 10,000-fold over non-muscle tissues of the same mouse. Western and immunocytochemical analysis demonstrated similar Dox dependent muscle-specific induction of the tagged calpastatin protein. These findings demonstrate the effectiveness and flexibility of the tet-on system to provide a tightly regulated over-expression system in adult skeletal muscle. The MCKrtTA transgenic lines can be combined with other transgenic responder lines for skeletal muscle-specific over-expression of any target gene of interest.

Organotypic brain slice cultures of adult transgenic P301S mice--a model for tauopathy studies.

Directory of Open Access Journals (Sweden)

Agneta Mewes

Full Text Available BACKGROUND: Organotypic brain slice cultures represent an excellent compromise between single cell cultures and complete animal studies, in this way replacing and reducing the number of animal experiments. Organotypic brain slices are widely applied to model neuronal development and regeneration as well as neuronal pathology concerning stroke, epilepsy and Alzheimer's disease (AD. AD is characterized by two protein alterations, namely tau hyperphosphorylation and excessive amyloid β deposition, both causing microglia and astrocyte activation. Deposits of hyperphosphorylated tau, called neurofibrillary tangles (NFTs, surrounded by activated glia are modeled in transgenic mice, e.g. the tauopathy model P301S. METHODOLOGY/PRINCIPAL FINDINGS: In this study we explore the benefits and limitations of organotypic brain slice cultures made of mature adult transgenic mice as a potential model system for the multifactorial phenotype of AD. First, neonatal (P1 and adult organotypic brain slice cultures from 7- to 10-month-old transgenic P301S mice have been compared with regard to vitality, which was monitored with the lactate dehydrogenase (LDH- and the MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assays over 15 days. Neonatal slices displayed a constant high vitality level, while the vitality of adult slice cultures decreased significantly upon cultivation. Various preparation and cultivation conditions were tested to augment the vitality of adult slices and improvements were achieved with a reduced slice thickness, a mild hypothermic cultivation temperature and a cultivation CO(2 concentration of 5%. Furthermore, we present a substantial immunohistochemical characterization analyzing the morphology of neurons, astrocytes and microglia in comparison to neonatal tissue. CONCLUSION/SIGNIFICANCE: Until now only adolescent animals with a maximum age of two months have been used to prepare organotypic brain slices. The current study

Characteristics of Tau and Its Ligands in PET Imaging

Directory of Open Access Journals (Sweden)

Ryuichi Harada

2016-01-01

Full Text Available Tau deposition is one of the neuropathological hallmarks in Alzheimer’s disease as well as in other neurodegenerative disorders called tauopathies. Recent efforts to develop selective tau radiopharmaceuticals have allowed the visualization of tau deposits in vivo. In vivo tau imaging allows the assessment of the regional distribution of tau deposits in a single human subject over time for determining the pathophysiology of tau accumulation in aging and neurodegenerative conditions as well as for application in drug discovery of anti-dementia drugs as surrogate markers. However, tau deposits show complicated characteristics because of different isoform composition, histopathology, and ultrastructure in various neurodegenerative conditions. In addition, since tau radiopharmaceuticals possess different chemotype classes, they may show different binding characteristics with heterogeneous tau deposits. In this review, we describe the characteristics of tau deposits and their ligands that have β-sheet binding properties, and the status of tau imaging in clinical studies.

Measurements of the decays {tau}{sup {minus}}{r_arrow}{ital h}{sup {minus}}{ital h}{sup +}{ital h}{sup {minus}}{nu}{sub {tau}} and {tau}{sup {minus}}{r_arrow}{ital h}{sup {minus}}{ital h}{sup +}{ital h}{sup {minus}}{pi}{sup 0}{nu}{sub {tau}}

Energy Technology Data Exchange (ETDEWEB)

Balest, R.; Cho, K.; Ford, W.T.; Lohner, M.; Park, H.; Rankin, P.; Smith, J.G.; Alexander, J.P.; Bebek, C.; Berger, B.E.; Berkelman, K.; Bloom, K.; Browder, T.E.; Cassel, D.G.; Cho, H.A.; Coffman, D.M.; Crowcroft, D.S.; Dickson, M.; Drell, P.S.; Dumas, D.J.; Ehrlich, R.; Elia, R.; Gaidarev, P.; Garcia-Sciveres, M.; Gittelman, B.; Gray, S.W.; Hartill, D.L.; Heltsley, B.K.; Henderson, S.; Jones, C.D.; Jones, S.L.; Kandaswamy, J.; Katayama, N.; Kim, P.C.; Kreinick, D.L.; Lee, T.; Liu, Y.; Ludwig, G.S.; Masui, J.; Mevissen, J.; Mistry, N.B.; Ng, C.R.; Nordberg, E.; Patterson, J.R.; Peterson, D.; Riley, D.; Soffer, A.; Avery, P.; Freyberger, A.; Lingel, K.; Prescott, C.; Rodriguez, J.; Yang, S.; Yelton, J.; Brandenburg, G.; Cinabro, D.; Liu, T.; Saulnier, M.; Wilson, R.; Yamamoto, H.; Bergfeld, T.; Eisenstein, B.I.; Ernst, J.; Gladding, G.E.; Gollin, G.D.; Palmer, M.; Selen, M.; Thaler, J.J.; Edwards, K.W.; McLean, K.W.; Ogg, M.; Bellerive, A.; Britton, D.I.; Hyatt, E.R.F.; Janicek, R.; MacFarlane, D.B.; Patel, P.M.; Spaan, B.; Sadoff, A.J.; Ammar, R.; Baringer, P.; Bean, A.; Besson, D.; Coppage, D.; Copty, N.; Davis, R.; Hancock, N.; Kotov, S.; Kravchenko, I.; Kwak, N.; Kubota, Y.; Lattery, M.; Momayezi, M.; Nelson, J.K.; Patton, S.; Poling, R.; Savinov, V.; Schrenk, S.; Wang, R.; Alam, M.S.; Kim, I.J.; Ling, Z.; Mahmood, A.H.; O`Neill, J.J.; Severini, H.; Sun, C.R.; Wappler, F.; Crawford, G.; Fulton, R.; Fujino, D.; Gan, K.K.; Honscheid, K.; Kagan, H.; Kass, R.; Lee, J.; Sung, M.; White, C.; Wolf, A.; Zoeller, M.M.; Fu, X.; Nemati, B.; Ross, W.R.; Skubic, P.; Wood, M.; Bishai, M.; Fast, J.; Gerndt, E.; Hinson, J.W.; Miao, T.; Miller, D.H.; Modesitt, M.; Shibata, E.I.; Shipsey, I.P.J.; Wang, P.N.; Gibbons, L.; Johnson, S.D.; Kwon, Y.; Roberts, S.; Thorndike, E.H.; Coan, T.E.; Dominick, J.; Fadeyev, V.; Korolkov, I.; Lambrecht, M.; Sanghera, S.; Shelkov, V.; Skwarnicki, T.; Stroynowski, R.; Volobouev, I.; Wei, G.; Artuso, M.; Gao, M.; Goldberg, M.; He, D.; (CLEO Colla...

1995-11-20

We use a data sample of 2.8{times}10{sup 6} produced {tau}-pair events, obtained with the CLEO II detector, to measure {ital B}{bold (}{tau}{sup {minus}}{r_arrow}{ital h}{sup {minus}}{ital h}{sup +}{ital h}{sup {minus}}({pi}{sup 0}){nu}{sub {tau}}{bold )}, where {ital h} refers to either a charged {pi} or {ital K}. These branching fractions are measured with samples of lepton-tagged and 3 vs 3 events. We find {ital B}({tau}{sup {minus}}{r_arrow}{ital h}{sup {minus}}{ital h}{sup +}{ital h}{sup {minus}}{nu}{sub {tau}})=0.0951{plus_minus}0.0007 m*0.0020 and {ital B}({tau}{sup {minus}}{r_arrow}{ital h}{sup {minus}}{ital h}{sup +}{ital h}{sup {minus}}{pi}{sup 0}{nu}{sub {tau}})=0.0423{plus_minus} .0006{plus_minus}0.0022. We also measure {ital B}({tau}{sup {minus}}{r_arrow}{omega}{ital h}{sup {minus}}{nu}{sub {tau}})=0.0195{plus_minus}0.0007{plus_minus}0.0011 {copyright} {ital 1995} {ital The} {ital American} {ital Physical} {ital Society}.

Study on the property of $\\tau$ hadronic decays

CERN Document Server

Chen, G M

2002-01-01

Using the data collected with the L3 detector at LEP during 1992-1995 run at Z/sup 0/ peak, corresponding to an integrated luminosity of 92.63 pb/sup -1/, the topological and hadronic tau decay branching fractions are measured. Photon conversion, fake photon and backlash are studied and rejected in the analysis. The decay channels are identified using a set of neural networks. By fitting neural network output spectra with the binned maximum likelihood method the branching fractions of tau hadronic decays are determined: BR( tau to h nu )=(12.51 +or- 0.12 +or- 0.13)%, BR( tau to h pi /sup 0/ nu )= (25.38 +or- 0.18 +or- 0.14)% BR( tau to h2 pi /sup 0/ nu )=(8.98 +or- 0.21 +or- 0.19)%, BR( tau to h >or= 3 pi /sup 0/ nu )=(1.77 +or- 0.14 +or- 0.15)% BR( tau to 3h nu )=(9.11 +or- 0.15 +or- 0.08)%, BR( tau to 3h pi /sup 0/ nu )=(4.77 +or- 0.19 +or- 0.10)% , BR( tau to 3h >or = 2 pi /sup 0/ nu )=(0.45 +or- 0.10 +or- 0.11)%. And the topological tau decay branching fractions are B( tau to 1-prong) = 85.14 +or- 0.27 +o...

Comments on the tau heavy lepton

International Nuclear Information System (INIS)

Perl, M.L.

1977-08-01

There is now substantial published evidence for the existence of a new charged particle of mass 1.9 GeV/c which decays through the weak interaction. All this evidence is in agreement with the particle being a new lepton, which is called the tau. Measurements from the data of the SLAC-LBL Magnetic Detector Collaboration of the tau mass, of the mass of the associated neutrino, of the coupling of the tau to the associated neutrinos, and of the decay modes are presented. Also discussed is the evidence for the tau being a sequential heavy lepton

Genetic enrichment of cardiomyocytes derived from mouse ...

African Journals Online (AJOL)

Jane

2011-06-22

Jun 22, 2011 ... Pluripotent embryonic stem cells (ESC) have the ability to differentiate into a ... We describe a simple method to generate relatively pure cardiomyocytes from mouse ... In this study, we described the generation of transgenic.

Kinematic tau reconstruction and search for the Higgs boson in hadronic tau pair decays with the CMS experiment

Energy Technology Data Exchange (ETDEWEB)

Perchalla, Lars

2011-05-11

The thesis prepares a search for the Standard Model Higgs boson in the di-tau channel with the CMS experiment. Based on Monte Carlo simulations, two selections are developed for light Higgs bosons produced by the dominant processes, gluon fusion and vector-boson fusion. Both selections exclusively consider the hadronic tau decay into three charged pions. They rely on an efficient algorithm to identify the tau decay products within the hadronic environment at the LHC. A kinematic fit exploits the topology of the particular decay mode and enables the reconstruction of the entire tau momentum including the neutrino. A set of quality criteria is defined on the obtained observables, which is valid for a broad range of tau energies. This provides an efficient suppression of quark and gluon jets that fake tau decays. The Higgs boson is reconstructed from pairs of tau leptons that pass the quality requirements. The selections derive further background suppression from the event kinematics. In case of the gluon fusion, the selected sample is dominated by off-shell Z{sup 0} bosons that decay into tau pairs. The vector-boson fusion involves two additional quark jets. Their signature and the significant transversal momentum of the Higgs boson allow for a background-free selection. The significance of both selections is discussed for an integrated luminosity of 30 fb{sup -1}. (orig.)

Kinematic tau reconstruction and search for the Higgs boson in hadronic tau pair decays with the CMS experiment

International Nuclear Information System (INIS)

Perchalla, Lars

2011-01-01

The thesis prepares a search for the Standard Model Higgs boson in the di-tau channel with the CMS experiment. Based on Monte Carlo simulations, two selections are developed for light Higgs bosons produced by the dominant processes, gluon fusion and vector-boson fusion. Both selections exclusively consider the hadronic tau decay into three charged pions. They rely on an efficient algorithm to identify the tau decay products within the hadronic environment at the LHC. A kinematic fit exploits the topology of the particular decay mode and enables the reconstruction of the entire tau momentum including the neutrino. A set of quality criteria is defined on the obtained observables, which is valid for a broad range of tau energies. This provides an efficient suppression of quark and gluon jets that fake tau decays. The Higgs boson is reconstructed from pairs of tau leptons that pass the quality requirements. The selections derive further background suppression from the event kinematics. In case of the gluon fusion, the selected sample is dominated by off-shell Z 0 bosons that decay into tau pairs. The vector-boson fusion involves two additional quark jets. Their signature and the significant transversal momentum of the Higgs boson allow for a background-free selection. The significance of both selections is discussed for an integrated luminosity of 30 fb -1 . (orig.)

First Observation of the Decay {tau}{sup {minus}} {r_arrow} K{sup {asterisk}{minus}}{eta}{nu}{sub {tau}}

Energy Technology Data Exchange (ETDEWEB)

Bishai, M.; Chen, S.; Fast, J.; Hinson, J.W.; Menon, N.; Miller, D.H.; Shibata, E.I.; Shipsey, I.P. [Purdue University, West Lafayette, Indiana 47907 (United States); Glenn, S.; Kwon, Y.; Lyon, A.L.; Roberts, S.; Thorndike, E.H. [University of Rochester, Rochester, New York 14627 (United States); Jessop, C.P.; Lingel, K.; Marsiske, H.; Perl, M.L.; Savinov, V.; Ugolini, D.; Zhou, X. [Stanford Linear Accelerator Center, Stanford University, Stanford, California 94309 (United States); Coan, T.E.; Fadeyev, V.; Korolkov, I.; Maravin, Y.; Narsky, I.; Stroynowski, R.; Ye, J.; Wlodek, T. [Southern Methodist University, Dallas, Texas 75275 (United States); Artuso, M.; Dambasuren, E.; Kopp, S.; Moneti, G.C.; Mountain, R.; Schuh, S.; Skwarnicki, T.; Stone, S.; Titov, A.; Viehhauser, G.; Wang, J.C. [Syracuse University, Syracuse, New York 13244 (United States); Bartelt, J.; Csorna, S.E.; McLean, K.W.; Marka, S.; Xu, Z. [Vanderbilt University, Nashville, Tennessee 37235 (United States); Godang, R.; Kinoshita, K.; Lai, I.C.; Pomianowski, P.; Schrenk, S. [Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 (United States); Bonvicini, G.; Cinabro, D.; Greene, R.; Perera, L.P.; Zhou, G.J. [Wayne State University, Detroit, Michigan 48202 (United States); Chan, S.; Eigen, G.; Lipeles, E.; Miller, J.S.; Schmidtler, M.; Shapiro, A.; Sun, W.M.; Urheim, J.; Weinstein, A.J.; Wuerthwein, F. [California Institute of Technology, Pasadena, California 91125 (United States); Jaffe, D.E.; Masek, G.; Paar, H.P.; Potter, E.M.; Prell, S.; Sharma, V. [University of California, San Diego, La Jolla, California 92093 (United States); Asner, D.M.; Gronberg, J.; Hill, T.S.; Lange, D.J.; Morrison, R.J.; Nelson, H.N.; Nelson, T.K.; Roberts, D. [University of California, Santa Barbara, California 93106 (United States); Behrens, B.H.; Ford, W.T.; Gritsan, A.; Krieg, H.; Roy, J.; Smith, J.G. [Univ. of Colorado, Boulder, Colorado 80309-0390 (United States)

1999-01-01

The decay {tau}{sup {minus}}{r_arrow}K{sup {asterisk}{minus}}{eta}{nu}{sub {tau}} has been observed with the CLEOthinspthinspII detector. The K{sup {asterisk}{minus}} is reconstructed in two decay channels, K{sup {asterisk}{minus}}{r_arrow}K{sub S}{pi}{sup {minus}}{r_arrow} {pi}{sup {minus}}{pi}{sup +}{pi}{sup {minus}} and K{sup {asterisk}{minus}}{r_arrow}K{sup {minus}}{pi}{sup 0} . The {eta} is reconstructed from the decay {eta}{r_arrow}{gamma}{gamma} . The measured branching fraction is B({tau}{sup {minus}}{r_arrow}K{sup {asterisk}{minus}} {eta}{nu}{sub {tau}})=(2.9{plus_minus} 0.8{plus_minus}0.4){times}10{sup {minus}4} . We also measure the inclusive branching fractions without requiring the K{sup {asterisk}} resonance, B({tau}{sup {minus}}{r_arrow}K{sub S}{pi}{sup {minus}}{eta}{nu}{sub {tau}})=(1.10 {plus_minus}0.35{plus_minus}0.11){times}10{sup {minus}4} and B({tau}{sup {minus}}{r_arrow}K{sup {minus}}{pi}{sup 0}{eta}{nu}{sub {tau}})=(1.77 {plus_minus}0.56{plus_minus}0.71){times}10{sup {minus}4} . The results indicate that the K{sup {asterisk}{minus}} resonance dominates the K{sub S}{pi}{sup {minus}} mass spectrum. {copyright} {ital 1999} {ital The American Physical Society}

Measurement of the tau lifetime with the DELPHI detector

CERN Document Server

Andreazza, Attilio

2005-01-01

The tau lepton lifetime has been measured with the $e^{+}e^{-}$ to tau /sup +/ tau /sup -/ events collected by the DELPHI detector at LEP in the years 1991-1995. Three different methods have been exploited, using both one-prong and three-prong tau decay channels. These are combined with previously published DELPHI results to provide a tau lifetime measurement of tau /sub tau /=290.9+or-1.4/sub stat/+or-1.0/sub sys/ fs, using the full LEP1 data sample.

Lymphoma induction by heterocyclic amines in Eu-pim-1 transgenic mice

DEFF Research Database (Denmark)

Sørensen, Ilona Kryspin; Kristiansen, E.; Mortensen, Alicja

1997-01-01

The usefulness of transgenic E mu-pim-1 mice bearing in their genome the pim-1 oncogene supplemented with an upstream immunoglobulin enhancer and a downstream murine leukaemia virus long terminal repeat, as sensitive test organisms was studied in two short-term carcinogenicity studies. The mice...... to bacteria and cultured mammalian cells. PhIP is a potent mouse lymphomagen, while IQ is a liver, lung and forestomach carcinogen in mice. We found that transgenic E mu-pim-1 mice are highly susceptible to PhIP induced lymphomagenesis but do not respond to IQ treatment. PhIP feeding of E mu-pim-1 mice...... not only increased the total number of T-cell lymphomas but also decreased the latency time compared to either transgenic or wild-type controls. The effect was most pronounced in the treated female E mu-pim-1 mice, which showed a higher incidence of PhIP induced T-cell lymphomas than transgenic males...

Measurement of the inclusive branching fraction tau- → nu/sub tau/π-π0 + neutral meson(s)

International Nuclear Information System (INIS)

Moses, W.W.

1986-12-01

This dissertation measures an inclusive branching fraction of (13.9 +- 2.0/sub -2.4//sup +2.1/)% for the decay tau - → nu/sub tau/π - π 0 + nh 0 where h 0 is a π 0 or an eta and n ≥ 1. The data sample, obtained with the TPC detector facility at PEP, corresponds to an integrated luminosity of 72 pb -1 at 29 GeV center of mass energy. The measured value for this branching fraction is somewhat greater than the theoretical prediction and, taking errors into account, resolves the present difference between the inclusive and the sum of the exclusive tau - branching fractions into one charged prong. In addition, a lower limit of 8.3% (95% CL) is placed on the branching fraction B(tau - → nu/sub tau/π - π 0 π 0 )

Search for tau decays to the eta meson

International Nuclear Information System (INIS)

Skwarnicki, T.

1987-12-01

Using a sample of 530,000 tau leptons collected by the Crystal Ball experiment at the e + e - storage ring DORIS II, we have searched for tau decays to the eta meson. No eta signal is found in the inclusive analysis, tau → eta X, of 1-prong decays, leading to the upper limits, BR(tau - → nu π - eta) - → π - π 0 eta) - → nu π - π 0 π 0 eta) - → nu π - eta eta) - → nu π - eta and tau - → nu π - π 0 eta, are also not found in the exclusive analyses, while BR(tau - → nu π - π 0 ) = (22.7 +- 0.9 +- 3.0)% and BR(tau - → nu π - π 0 π 0 ) = (7.0 +- 0.7 +- 1.4)% are measured in accord with the expectations. The hadronic final state, π - π 0 π 0 , is reconstructed in tau decays for the first time. The results are preliminary. 21 refs., 10 figs

Pomegranate from Oman Alleviates the Brain Oxidative Damage in Transgenic Mouse Model of Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Selvaraju Subash

2014-10-01

Full Text Available Oxidative stress may play a key role in Alzheimer’s disease (AD neuropathology. Pomegranates (石榴 Shí Liú contain very high levels of antioxidant polyphenolic substances, as compared to other fruits and vegetables. Polyphenols have been shown to be neuroprotective in different model systems. Here, the effects of the antioxidant-rich pomegranate fruit grown in Oman on brain oxidative stress status were tested in the AD transgenic mouse. The 4-month-old mice with double Swedish APP mutation (APPsw/Tg2576 were purchased from Taconic Farm, NY, USA. Four-month-old Tg2576 mice were fed with 4% pomegranate or control diet for 15 months and then assessed for the influence of diet on oxidative stress. Significant increase in oxidative stress was found in terms of enhanced levels of lipid peroxidation (LPO and protein carbonyls. Concomitantly, decrease in the activities of antioxidant enzymes was observed in Tg2576 mice treated with control diet. Supplementation with 4% pomegranate attenuated oxidative damage, as evidenced by decreased LPO and protein carbonyl levels and restoration in the activities of the antioxidant enzymes [superoxide dismutase (SOD, catalase, glutathione peroxidase (GPx, glutathione (GSH, and Glutathione S transferase (GST]. The activities of membrane-bound enzymes [Na+ K+-ATPase and acetylcholinesterase (AChE] were altered in the brain regions of Tg2576 mouse treated with control diet, and 4% pomegranate supplementation was able to restore the activities of enzymes to comparable values observed in controls. The results suggest that the therapeutic potential of 4% pomegranate in the treatment of AD might be associated with counteracting the oxidative stress by the presence of active phytochemicals in it.

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

Science.gov (United States)

Schreurs, A.-S.; Torres, S.; Truong, T.; Kumar, A.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

2014-01-01

Exposure to musculoskeletal disuse and radiation result in bone loss; we hypothesized that these catabolic treatments cause excess reactive oxygen species (ROS), and thereby alter the tight balance between bone resorption by osteoclasts and bone formation by osteoblasts, culminating in bone loss. To test this, we used transgenic mice which over-express the human gene for catalase, targeted to mitochondria (MCAT). Catalase is an anti-oxidant that converts the ROS hydrogen peroxide into water and oxygen. MCAT mice were shown previously to display reduced mitochondrial oxidative stress and radiosensitivity of the CNS compared to wild type controls (WT). As expected, MCAT mice expressed the transgene in skeletal tissue, and in marrow-derived osteoblasts and osteoclast precursors cultured ex vivo, and also showed greater catalase activity compared to wildtype (WT) mice (3-6 fold). Colony expansion in marrow cells cultured under osteoblastogenic conditions was 2-fold greater in the MCAT mice compared to WT mice, while the extent of mineralization was unaffected. MCAT mice had slightly longer tibiae than WT mice (2%, P less than 0.01), although cortical bone area was slightly lower in MCAT mice than WT mice (10%, p=0.09). To challenge the skeletal system, mice were treated by exposure to combined disuse (2 wk Hindlimb Unloading) and total body irradiation Cs(137) (2 Gy, 0.8 Gy/min), then bone parameters were analyzed by 2-factor ANOVA to detect possible interaction effects. Treatment caused a 2-fold increase (p=0.015) in malondialdehyde levels of bone tissue (ELISA) in WT mice, but had no effect in MCAT mice. These findings indicate that the transgene conferred protection from oxidative damage caused by treatment. Unexpected differences between WT and MCAT mice emerged in skeletal responses to treatment.. In WT mice, treatment did not alter osteoblastogenesis, cortical bone area, moment of inertia, or bone perimeter, whereas in MCAT mice, treatment increased these

Transgenic Mouse Model for Reducing Oxidative Damage in Bone

Science.gov (United States)

Schreurs, Ann-Sofie; Torres, S.; Truong, T.; Moyer, E. L.; Kumar, A.; Tahimic, Candice C. G.; Alwood, J. S.; Limoli, C. L.; Globus, R. K.

2016-01-01

Bone loss can occur due to many challenges such age, radiation, microgravity, and Reactive Oxygen Species (ROS) play a critical role in bone resorption by osteoclasts (Bartell et al. 2014). We hypothesize that suppression of excess ROS in skeletal cells, both osteoblasts and osteoclasts, regulates skeletal growth and remodeling. To test our hypothesis, we used transgenic mCAT mice which overexpress the human anti-oxidant catalase gene targeted to the mitochondria, the main site for endogenous ROS production. mCAT mice have a longer life-span than wildtype controls and have been used to study various age-related disorders. To stimulate remodeling, 16 week old mCAT mice or wildtype mice were exposed to treatment (hindlimb-unloading and total body-irradiation) or sham treatment conditions (control). Tissues were harvested 2 weeks later for skeletal analysis (microcomputed tomography), biochemical analysis (gene expression and oxidative damage measurements), and ex vivo bone marrow derived cell culture (osteoblastogenesis and osteoclastogenesis). mCAT mice expressed the transgene and displayed elevated catalase activity in skeletal tissue and marrow-derived osteoblasts and osteoclasts grown ex vivo. In addition, when challenged with treatment, bone tissues from wildtype mice showed elevated levels of malondialdehyde (MDA), indicating oxidative damage) whereas mCAT mice did not. Correlation analysis revealed that increased catalase activity significantly correlated with decreased MDA levels and that increased oxidative damage correlated with decreased percent bone volume (BVTV). In addition, ex-vivo cultured osteoblast colony growth correlated with catalase activity in the osteoblasts. Thus, we showed that these transgenic mice can be used as a model to study the relationship between markers of oxidative damage and skeletal properties. mCAT mice displayed reduced BVTV and trabecular number relative to wildtype mice, as well as increased structural model index in the

Recombineering strategies for developing next generation BAC transgenic tools for optogenetics and beyond.

Science.gov (United States)

Ting, Jonathan T; Feng, Guoping

2014-01-01

The development and application of diverse BAC transgenic rodent lines has enabled rapid progress for precise molecular targeting of genetically-defined cell types in the mammalian central nervous system. These transgenic tools have played a central role in the optogenetic revolution in neuroscience. Indeed, an overwhelming proportion of studies in this field have made use of BAC transgenic Cre driver lines to achieve targeted expression of optogenetic probes in the brain. In addition, several BAC transgenic mouse lines have been established for direct cell-type specific expression of Channelrhodopsin-2 (ChR2). While the benefits of these new tools largely outweigh any accompanying challenges, many available BAC transgenic lines may suffer from confounds due in part to increased gene dosage of one or more "extra" genes contained within the large BAC DNA sequences. Here we discuss this under-appreciated issue and propose strategies for developing the next generation of BAC transgenic lines that are devoid of extra genes. Furthermore, we provide evidence that these strategies are simple, reproducible, and do not disrupt the intended cell-type specific transgene expression patterns for several distinct BAC clones. These strategies may be widely implemented for improved BAC transgenesis across diverse disciplines.

Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates.

Science.gov (United States)

Russell, Claire L; Mitra, Vikram; Hansson, Karl; Blennow, Kaj; Gobom, Johan; Zetterberg, Henrik; Hiltunen, Mikko; Ward, Malcolm; Pike, Ian

2017-01-01

Aberrant tau phosphorylation is a hallmark in Alzheimer's disease (AD), believed to promote formation of paired helical filaments, the main constituent of neurofibrillary tangles in the brain. While cerebrospinal fluid (CSF) levels of total tau and tau phosphorylated at threonine residue 181 (pThr181) are established core biomarkers for AD, the value of alternative phosphorylation sites, which may have more direct relevance to pathology, for early diagnosis is not yet known, largely due to their low levels in CSF and lack of standardized detection methods. To overcome sensitivity limitations for analysis of phosphorylated tau in CSF, we have applied an innovative mass spectrometry (MS) workflow, TMTcalibratortrademark, to enrich and enhance the detection of phosphoproteome components of AD brain tissue in CSF, and enable the quantitation of these analytes. We aimed to identify which tau species present in the AD brain are also detectable in CSF and which, if any, are differentially regulated with disease. Over 75% coverage of full-length (2N4R) tau was detected in the CSF with 47 phosphopeptides covering 31 different phosphorylation sites. Of these, 11 phosphopeptides were upregulated by at least 40%, along with an overall increase in tau levels in the CSF of AD patients relative to controls. Use of the TMTcalibratortrademark workflow dramatically improved our ability to detect tau-derived peptides that are directly related to human AD pathology. Further validation of regulated tau peptides as early biomarkers of AD is warranted and is currently being undertaken.

Light induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apoptotic bcl-2 related gene.

Science.gov (United States)

Shinoda, K; Nakamura, Y; Matsushita, K; Shimoda, K; Okita, H; Fukuma, M; Yamada, T; Ohde, H; Oguchi, Y; Hata, J; Umezawa, A

2001-10-01

EAT/mcl-1 (EAT), an immediate early gene, functions in a similar way to bcl-2 in neutralising Bax mediated cytotoxicity, suggesting that EAT is a blocker of cell death. The aim of this study was to determine the effect of overexpression of the human EAT gene on light induced retinal cell apoptosis. EAT transgenic mice incorporating the EF-1alpha promoter were utilised, and expression of human EAT was detected by RT-PCR. Light damage was induced by raising mice under constant illumination. Two groups of animals, EAT transgenic mice (n=14) and littermates (n=13), were examined by ERG testing and histopathology at regular time points up to 20 weeks of constant light stimulation. Electrophysiological and histopathological findings were evaluated by established systems of arbitrary scoring as scores 0-2 and scores 0-3, respectively. The mean score (SD) of ERG response was significantly lower in EAT transgenic mice (0.79 (0.89)) than in littermates (1.69 (0.48)) (pstatistical significance (p=0.1156), the estimated incidence of electrophysiological retinal damage was higher in EAT mice (0.0495/mouse/week; 95% confidence interval (CI) 0.0347-0.0500) than in littermates (0. 0199/mouse/week; 95% CI 0.0035-0.0364). The mean scores (SD) for histopathological retinal degeneration were 2.31 (0.63) in littermates and 1.43 (1.22) in EAT transgenic mice (p=0.065). However, Kaplan-Meier curves for histopathological failure in two groups of mice showed that retinal photoreceptor cells were preserved significantly against constant light in the littermate compared with transgenic mice (p=0.0241). The estimated incidence of histopathological retinal damage was 0.0042/mouse/week in the littermates (95% CI 0-0.0120) and 0.0419/mouse/week in the EAT mice (95% CI 0.0286-0.0500). Retinal photoreceptor cell apoptosis under constant light stimulation is likely to be accelerated in transgenic retina overexpressing EAT.

Muscle-directed gene therapy for phenylketonuria (PKU): Development of transgenic mice with muscle-specific phenylalanine hydroxylase expression

Energy Technology Data Exchange (ETDEWEB)

Harding, C.O.; Messing, A.; Wolff, J.A. [Univ. of Wisconsin, Madison, WI (United States)

1994-09-01

Phenylketonuria (PKU) is an attractive target for gene therapy because of shortcomings in current therapy including lifelong commitment to a difficult and expensive diet, persistent mild cognitive deficits in some children despite adequate dietary therapy, and maternal PKU syndrome. Phenylalanine hydroxylase (PAH) is normally expressed only in liver, but we propose to treat PKU by introducing the gene for PAH into muscle. In order to evaluate both the safety and efficacy of this approach, we have a developed a trangenic mouse which expresses PAH in both cardiac and skeletal muscle. The transgene includes promoter and enhancer sequences from the mouse muscle creatine kinase (MCK) gene fused to the mouse liver PAH cDNA. Mice which have inherited the transgene are healthy, active, and do not exhibit any signs of muscle weakness or wasting. Ectopic PAH expression in muscle is not detrimental to the health, neurologic function, or reproduction of the mice. Pah{sup enu2} hyperphenylalaninemic mice, a model of human PAH deficiency, bred to carry the transgene have substantial PAH expression in cardiac and skeletal muscle but none in liver. Muscle PAH expression alone does not complement the hyperphenylalaninemic phenotype of Pah{sup enu2} mice. However, administration of reduced tetrahydrobiopterin to transgenic Pah{sup enu2} mice is associated with a 25% mean decrease in serum phenylalanine levels. We predict that ectopic expression of PAH in muscle along with adequate muscle supplies of reduced biopterin cofactor will decrease hyperphenylalaninemia in PKU.

A Study of Three-Prong $\\tau$ Decays with Charged Kaons

CERN Document Server

Abbiendi, G.; Alexander, G.; Allison, John; Anderson, K.J.; Anderson, S.; Arcelli, S.; Asai, S.; Ashby, S.F.; Axen, D.; Azuelos, G.; Ball, A.H.; Barberio, E.; Barlow, Roger J.; Batley, J.R.; Baumann, S.; Bechtluft, J.; Behnke, T.; Bell, Kenneth Watson; Bella, G.; Bellerive, A.; Bentvelsen, S.; Bethke, S.; Betts, S.; Biebel, O.; Biguzzi, A.; Bloodworth, I.J.; Bock, P.; Bohme, J.; Boeriu, O.; Bonacorsi, D.; Boutemeur, M.; Braibant, S.; Bright-Thomas, P.; Brigliadori, L.; Brown, Robert M.; Burckhart, H.J.; Capiluppi, P.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, David G.; Chrisman, D.; Ciocca, C.; Clarke, P.E.L.; Clay, E.; Cohen, I.; Conboy, J.E.; Cooke, O.C.; Couchman, J.; Couyoumtzelis, C.; Coxe, R.L.; Cuffiani, M.; Dado, S.; Dallavalle, G.Marco; Dallison, S.; Davis, R.; De Jong, S.; de Roeck, A.; Dervan, P.; Desch, K.; Dienes, B.; Dixit, M.S.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Estabrooks, P.G.; Etzion, E.; Fabbri, F.; Fanfani, A.; Fanti, M.; Faust, A.A.; Feld, L.; Ferrari, P.; Fiedler, F.; Fierro, M.; Fleck, I.; Frey, A.; Furtjes, A.; Futyan, D.I.; Gagnon, P.; Gary, J.W.; Gaycken, G.; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Gibson, W.R.; Gingrich, D.M.; Glenzinski, D.; Goldberg, J.; Gorn, W.; Grandi, C.; Graham, K.; Gross, E.; Grunhaus, J.; Gruwe, M.; Hajdu, C.; Hanson, G.G.; Hansroul, M.; Hapke, M.; Harder, K.; Harel, A.; Hargrove, C.K.; Harin-Dirac, M.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Herten, G.; Heuer, R.D.; Hildreth, M.D.; Hill, J.C.; Hobson, P.R.; Hocker, James Andrew; Hoffman, Kara Dion; Homer, R.J.; Honma, A.K.; Horvath, D.; Hossain, K.R.; Howard, R.; Huntemeyer, P.; Igo-Kemenes, P.; Imrie, D.C.; Ishii, K.; Jacob, F.R.; Jawahery, A.; Jeremie, H.; Jimack, M.; Jones, C.R.; Jovanovic, P.; Junk, T.R.; Kanaya, N.; Kanzaki, J.; Karlen, D.; Kartvelishvili, V.; Kawagoe, K.; Kawamoto, T.; Kayal, P.I.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Kim, D.H.; Klier, A.; Kobayashi, T.; Kobel, M.; Kokott, T.P.; Kolrep, M.; Komamiya, S.; Kowalewski, Robert V.; Kress, T.; Krieger, P.; von Krogh, J.; Kuhl, T.; Kyberd, P.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Lauber, J.; Lawson, I.; Layter, J.G.; Lellouch, D.; Letts, J.; Levinson, L.; Liebisch, R.; Lillich, J.; List, B.; Littlewood, C.; Lloyd, A.W.; Lloyd, S.L.; Loebinger, F.K.; Long, G.D.; Losty, M.J.; Lu, J.; Ludwig, J.; Lui, D.; Macchiolo, A.; Macpherson, A.; Mader, W.; Mannelli, M.; Marcellini, S.; Marchant, T.E.; Martin, A.J.; Martin, J.P.; Martinez, G.; Mashimo, T.; Mattig, Peter; McDonald, W.John; McKenna, J.; Mckigney, E.A.; McMahon, T.J.; McPherson, R.A.; Meijers, F.; Mendez-Lorenzo, P.; Merritt, F.S.; Mes, H.; Meyer, I.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Mohr, W.; Montanari, A.; Mori, T.; Nagai, K.; Nakamura, I.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oakham, F.G.; Odorici, F.; Ogren, H.O.; Okpara, A.; Oreglia, M.J.; Orito, S.; Pasztor, G.; Pater, J.R.; Patrick, G.N.; Patt, J.; Perez-Ochoa, R.; Petzold, S.; Pfeifenschneider, P.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Poffenberger, P.; Poli, B.; Polok, J.; Przybycien, M.; Quadt, A.; Rembser, C.; Rick, H.; Robertson, S.; Robins, S.A.; Rodning, N.; Roney, J.M.; Rosati, S.; Roscoe, K.; Rossi, A.M.; Rozen, Y.; Runge, K.; Runolfsson, O.; Rust, D.R.; Sachs, K.; Saeki, T.; Sahr, O.; Sang, W.M.; Sarkisian, E.K.G.; Sbarra, C.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schieck, J.; Schmitt, S.; Schoning, A.; Schroder, Matthias; Schumacher, M.; Schwick, C.; Scott, W.G.; Seuster, R.; Shears, T.G.; Shen, B.C.; Shepherd-Themistocleous, C.H.; Sherwood, P.; Siroli, G.P.; Skuja, A.; Smith, A.M.; Snow, G.A.; Sobie, R.; Soldner-Rembold, S.; Spagnolo, S.; Sproston, M.; Stahl, A.; Stephens, K.; Stoll, K.; Strom, David M.; Strohmer, R.; Surrow, B.; Talbot, S.D.; Taras, P.; Tarem, S.; Teuscher, R.; Thiergen, M.; Thomas, J.; Thomson, M.A.; Torrence, E.; Towers, S.; Trefzger, T.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Van Kooten, Rick J.; Vannerem, P.; Verzocchi, M.; Voss, H.; Wackerle, F.; Wagner, A.; Waller, D.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wermes, N.; Wetterling, D.; White, J.S.; Wilson, G.W.; Wilson, J.A.; Wyatt, T.R.; Yamashita, S.; Zacek, V.; Zer-Zion, D.

2000-01-01

From an analysis of the ionisation energy loss of charged particles selected from a sample of 147926 e+e- -> tau+tau- candidates recorded in the OPAL detector at e+e- centre-of-mass energies near the Z0 resonance, we determine the branching ratios: BR(tau- -> nu_tau K- pi- pi+ (pi0)) = 0.343 +- 0.073 +- 0.031 % BR(tau- -> nu_tau K- pi- K+ (pi0)) = 0.159 +- 0.053 +- 0.020 % where the (pi0) notation refers to decay modes with or without an accompanying pizero. The tau- -> nu_tau K- pi- pi+ (pi0) final states occurring through tau- -> nu_tau K- K_s (pi0) are treated as background in this analysis. We also examine the resonant structure of tau- -> nu_tau K- pi- pi+ candidates. Under the assumption that the resonant structure is dominated by the K_1 resonances, we determine the ratio of the BR (tau- -> K_1(1270)) to the sum of the BRs (tau -> K_1(1270) and (tau -> K_1(1400)) to be 0.71 +- 0.16 +- 0.11. In all results, the first uncertainties are statistical and the second are systematic.

Proceedings of the tau-charm factory workshop

International Nuclear Information System (INIS)

Beers, L.V.

1989-06-01

This report contains papers on the following main topics: machine physics; tau physics; D and D s physics; J/Ψ and charmonium physics; tau charm factories; workshop summary; accelerator physics; tau physics; charmed meson physics; J/Ψ and charmonium physics; and detector

An extensive phenotypic characterization of the hTNFα transgenic mice

Directory of Open Access Journals (Sweden)

Tugusheva Marina

2007-12-01

Full Text Available Abstract Background Tumor necrosis factor alpha (TNFα is implicated in a wide variety of pathological and physiological processes, including chronic inflammatory conditions, coronary artery disease, diabetes, obesity, and cachexia. Transgenic mice expressing human TNFα (hTNFα have previously been described as a model for progressive rheumatoid arthritis. In this report, we describe extensive characterization of an hTNFα transgenic mouse line. Results In addition to arthritis, these hTNFα transgenic mice demonstrated major alterations in body composition, metabolic rate, leptin levels, response to a high-fat diet, bone mineral density and content, impaired fertility and male sexual function. Many phenotypes displayed an earlier onset and a higher degree of severity in males, pointing towards a significant degree of sexual dimorphism in response to deregulated expression of TNFα. Conclusion These results highlight the potential usefulness of this transgenic model as a resource for studying the progressive effects of constitutively expressed low levels of circulating TNFα, a condition mimicking that observed in a number of human pathological conditions.

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.

Science.gov (United States)

Lu, Jiaxiong; Guan, Shan; Zhao, Yanling; Yu, Yang; Woodfield, Sarah E; Zhang, Huiyuan; Yang, Kristine L; Bieerkehazhi, Shayahati; Qi, Lin; Li, Xiaonan; Gu, Jerry; Xu, Xin; Jin, Jingling; Muscal, Jodi A; Yang, Tianshu; Xu, Guo-Tong; Yang, Jianhua

2017-08-01

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB. Copyright © 2017 Elsevier B.V. All rights reserved.

Tau decays: A theoretical perspective

International Nuclear Information System (INIS)

Marciano, W.J.

1992-11-01

Theoretical predictions for various tau decay rates are reviewed. Effects of electroweak radiative corrections are described. Implications for precision tests of the standard model and ''new physics'' searches are discussed. A perspective on the tau decay puzzle and 1-prong problem is given

Tau Polarization Measurement in the L3 Detector

International Nuclear Information System (INIS)

Garcia, P.

1996-01-01

The Polarization asymmetry (A p ) measurement can be obtained from the energy spectra of the tau lepton (tau) decay products. This measurement provides a precise determination of the weak mixing angel (sin''2 tilde char theta w ), one of the Standard Model fundamental parameters. Tau leptons are produced at LEP in e''+e''-yields tilde char f interactions at a center of mass energy of the order of the Z boson mass. In order to get A p we have calculated the analytical formulae of the tau decay products energy spectra, including radiative corrections, for all of the one prong tau decay channels. We have also extended this analytical formalism to the detector level, including the selection criteria effectsand the detector resolution (calibration) in the analytical expressions.Detailed studies have been performed concerning our measurement using this formalism. From the data collected with the L3 detector between 1991 and 1994, which corresponds to an integrated luminosity of 118.8 pb''1 at a center of mass energy of the order of the Z mass, we have identified and selected the following tau decay channel samples: tau yields e nu tilde char nu, tau yields mu nu tilde char nu, tau yields pi/K nu y tau yields p/K*nu. From the analysis of these samples we get the tau polarization asymmetry measurement: A p =3D0.143+-0.014+-0.010, which corresponds to a value of sin''2 tilde char theta w =3D0.2320+-0.0018+-0.0013. (Author) 24 refs

Cardiac Dysfunction in HIV-1 Transgenic Mouse: Role of Stress and BAG3.

Science.gov (United States)

Cheung, Joseph Y; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Tilley, Douglas G; Gao, Erhe; Koch, Walter J; Rabinowitz, Joseph; Klotman, Paul E; Khalili, Kamel; Feldman, Arthur M

2015-08-01

Since highly active antiretroviral therapy improved long-term survival of acquired immunodeficiency syndrome (AIDS) patients, AIDS cardiomyopathy has become an increasingly relevant clinical problem. We used human immunodeficiency virus (HIV)-1 transgenic (Tg26) mouse to explore molecular mechanisms of AIDS cardiomyopathy. Tg26 mice had significantly lower left ventricular (LV) mass and smaller end-diastolic and end-systolic LV volumes. Under basal conditions, cardiac contractility and relaxation and single myocyte contraction dynamics were not different between wild-type (WT) and Tg26 mice. Ten days after open heart surgery, contractility and relaxation remained significantly depressed in Tg26 hearts, suggesting that Tg26 mice did not tolerate surgical stress well. To simulate heart failure in which expression of Bcl2-associated athanogene 3 (BAG3) is reduced, we down-regulated BAG3 by small hairpin ribonucleic acid in WT and Tg26 hearts. BAG3 down-regulation significantly reduced contractility in Tg26 hearts. BAG3 overexpression rescued contractile abnormalities in myocytes expressing the HIV-1 protein Tat. We conclude: (i) Tg26 mice exhibit normal contractile function at baseline; (ii) Tg26 mice do not tolerate surgical stress well; (iii) BAG3 down-regulation exacerbated cardiac dysfunction in Tg26 mice; (iv) BAG3 overexpression rescued contractile abnormalities in myocytes expressing HIV-1 protein Tat; and (v) BAG3 may occupy a role in pathogenesis of AIDS cardiomyopathy. © 2015 Wiley Periodicals, Inc.

Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism

Energy Technology Data Exchange (ETDEWEB)

Cole, Toby B.; Walter, Betsy J.; Shih, Diana M.; Tward, Aaron D.; Lusis, Aldons J.; Timchalk, Chuck; Richter, Rebecca J.; Costa, Lucio G.; Furlong, Clement E.

2005-08-01

The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. Methods Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. Results Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6?12 h, with PON1R192, PON1Q192, and PON1? /? mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose?response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. Conclusion These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.

Caspase-2 cleavage of tau reversibly impairs memory.

Science.gov (United States)

Zhao, Xiaohui; Kotilinek, Linda A; Smith, Benjamin; Hlynialuk, Chris; Zahs, Kathleen; Ramsden, Martin; Cleary, James; Ashe, Karen H

2016-11-01

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Measurement of the $\\tau$ lepton lifetime

CERN Document Server

Buskulic, Damir; De Bonis, I; Décamp, D; Ghez, P; Goy, C; Lees, J P; Lucotte, A; Minard, M N; Odier, P; Pietrzyk, B; Ariztizabal, F; Chmeissani, M; Crespo, J M; Efthymiopoulos, I; Fernández, E; Fernández-Bosman, M; Gaitan, V; Garrido, L; Martínez, M; Orteu, S; Pacheco, A; Padilla, C; Palla, Fabrizio; Pascual, A; Perlas, J A; Sánchez, F; Teubert, F; Colaleo, A; Creanza, D; De Palma, M; Farilla, A; Gelao, G; Girone, M; Iaselli, Giuseppe; Maggi, G; Maggi, M; Marinelli, N; Natali, S; Nuzzo, S; Ranieri, A; Raso, G; Romano, F; Ruggieri, F; Selvaggi, G; Silvestris, L; Tempesta, P; Zito, G; Huang, X; Lin, J; Ouyang, Q; Wang, T; Xie, Y; Xu, R; Xue, S; Zhang, J; Zhang, L; Zhao, W; Bonvicini, G; Cattaneo, M; Comas, P; Coyle, P; Drevermann, H; Engelhardt, A; Forty, Roger W; Frank, M; Hagelberg, R; Harvey, J; Jacobsen, R; Janot, P; Jost, B; Kneringer, E; Knobloch, J; Lehraus, Ivan; Markou, C; Martin, E B; Mato, P; Minten, Adolf G; Miquel, R; Oest, T; Palazzi, P; Pater, J R; Pusztaszeri, J F; Ranjard, F; Rensing, P E; Rolandi, Luigi; Schlatter, W D; Schmelling, M; Schneider, O; Tejessy, W; Tomalin, I R; Venturi, A; Wachsmuth, H W; Wiedenmann, W; Wildish, T; Witzeling, W; Wotschack, J; Ajaltouni, Ziad J; Bardadin-Otwinowska, Maria; Barrès, A; Boyer, C; Falvard, A; Gay, P; Guicheney, C; Henrard, P; Jousset, J; Michel, B; Monteil, S; Pallin, D; Perret, P; Podlyski, F; Proriol, J; Rossignol, J M; Saadi, F; Fearnley, Tom; Hansen, J B; Hansen, J D; Hansen, J R; Hansen, P H; Nilsson, B S; Kyriakis, A; Simopoulou, Errietta; Siotis, I; Vayaki, Anna; Zachariadou, K; Blondel, A; Bonneaud, G R; Brient, J C; Bourdon, P; Passalacqua, L; Rougé, A; Rumpf, M; Tanaka, R; Valassi, Andrea; Verderi, M; Videau, H L; Candlin, D J; Parsons, M I; Focardi, E; Parrini, G; Corden, M; Delfino, M C; Georgiopoulos, C H; Jaffe, D E; Antonelli, A; Bencivenni, G; Bologna, G; Bossi, F; Campana, P; Capon, G; Chiarella, V; Felici, G; Laurelli, P; Mannocchi, G; Murtas, F; Murtas, G P; Pepé-Altarelli, M; Dorris, S J; Halley, A W; ten Have, I; Knowles, I G; Lynch, J G; Morton, W T; O'Shea, V; Raine, C; Reeves, P; Scarr, J M; Smith, K; Smith, M G; Thompson, A S; Thomson, F; Thorn, S; Turnbull, R M; Becker, U; Braun, O; Geweniger, C; Graefe, G; Hanke, P; Hepp, V; Kluge, E E; Putzer, A; Rensch, B; Schmidt, M; Sommer, J; Stenzel, H; Tittel, K; Werner, S; Wunsch, M; Beuselinck, R; Binnie, David M; Cameron, W; Colling, D J; Dornan, Peter J; Konstantinidis, N P; Moneta, L; Moutoussi, A; Nash, J; San Martin, G; Sedgbeer, J K; Stacey, A M; Dissertori, G; Girtler, P; Kuhn, D; Rudolph, G; Bowdery, C K; Brodbeck, T J; Colrain, P; Crawford, G; Finch, A J; Foster, F; Hughes, G; Sloan, Terence; Whelan, E P; Williams, M I; Galla, A; Greene, A M; Kleinknecht, K; Quast, G; Raab, J; Renk, B; Sander, H G; Wanke, R; Van Gemmeren, P; Zeitnitz, C; Aubert, Jean-Jacques; Bencheikh, A M; Benchouk, C; Bonissent, A; Bujosa, G; Calvet, D; Carr, J; Diaconu, C A; Etienne, F; Thulasidas, M; Nicod, D; Payre, P; Rousseau, D; Talby, M; Abt, I; Assmann, R W; Bauer, C; Blum, Walter; Brown, D; Dietl, H; Dydak, Friedrich; Ganis, G; Gotzhein, C; Jakobs, K; Kroha, H; Lütjens, G; Lutz, Gerhard; Männer, W; Moser, H G; Richter, R H; Rosado-Schlosser, A; Schael, S; Settles, Ronald; Seywerd, H C J; Saint-Denis, R; Wolf, G; Alemany, R; Boucrot, J; Callot, O; Cordier, A; Courault, F; Davier, M; Duflot, L; Grivaz, J F; Heusse, P; Jacquet, M; Kim, D W; Le Diberder, F R; Lefrançois, J; Lutz, A M; Musolino, G; Nikolic, I A; Park, H J; Park, I C; Schune, M H; Simion, S; Veillet, J J; Videau, I; Abbaneo, D; Azzurri, P; Bagliesi, G; Batignani, G; Bettarini, S; Bozzi, C; Calderini, G; Carpinelli, M; Ciocci, M A; Ciulli, V; Dell'Orso, R; Fantechi, R; Ferrante, I; Fidecaro, F; Foà, L; Forti, F; Giassi, A; Giorgi, M A; Gregorio, A; Ligabue, F; Lusiani, A; Marrocchesi, P S; Messineo, A; Rizzo, G; Sanguinetti, G; Sciabà, A; Spagnolo, P; Steinberger, Jack; Tenchini, Roberto; Tonelli, G; Triggiani, G; Vannini, C; Verdini, P G; Walsh, J; Betteridge, A P; Blair, G A; Bryant, L M; Cerutti, F; Gao, Y; Green, M G; Johnson, D L; Medcalf, T; Mir, L M; Perrodo, P; Strong, J A; Bertin, V; Botterill, David R; Clifft, R W; Edgecock, T R; Haywood, S; Edwards, M; Maley, P; Norton, P R; Thompson, J C; Bloch-Devaux, B; Colas, P; Emery, S; Kozanecki, Witold; Lançon, E; Lemaire, M C; Locci, E; Marx, B; Pérez, P; Rander, J; Renardy, J F; Roussarie, A; Schuller, J P; Schwindling, J; Trabelsi, A; Vallage, B; Johnson, R P; Kim, H Y; Litke, A M; McNeil, M A; Taylor, G; Beddall, A; Booth, C N; Boswell, R; Cartwright, S L; Combley, F; Dawson, I; Köksal, A; Letho, M; Newton, W M; Rankin, C; Thompson, L F; Böhrer, A; Brandt, S; Cowan, G D; Feigl, E; Grupen, Claus; Lutters, G; Minguet-Rodríguez, J A; Rivera, F; Saraiva, P; Smolik, L; Stephan, F; Apollonio, M; Bosisio, L; Della Marina, R; Giannini, G; Gobbo, B; Ragusa, F; Rothberg, J E; Wasserbaech, S R; Armstrong, S R; Bellantoni, L; Elmer, P; Feng, Z; Ferguson, D P S; Gao, Y S; González, S; Grahl, J; Harton, J L; Hayes, O J; Hu, H; McNamara, P A; Nachtman, J M; Orejudos, W; Pan, Y B; Saadi, Y; Schmitt, M; Scott, I J; Sharma, V; Turk, J; Walsh, A M; Wu Sau Lan; Wu, X; Yamartino, J M; Zheng, M; Zobernig, G

1996-01-01

The mean lifetime of the \\tau lepton is measured in a sample of 25700 \\tau pairs collected in 1992 with the ALEPH detector at LEP. A new analysis of the 1-1 topology events is introduced. In this analysis, the dependence of the impact parameter sum distribution on the daughter track momenta is taken into account, yielding improved precision compared to other impact parameter sum methods. Three other analyses of the one- and three-prong \\tau decays are updated with increased statistics. The measured lifetime is 293.5 \\pm 3.1 \\pm 1.7 \\fs. Including previous (1989--1991) ALEPH measurements, the combined \\tau lifetime is 293.7 \\pm 2.7 \\pm 1.6 \\fs.

Gtl2lacZ, an insertional mutation on mouse chromosome 12 with parental origin-dependent phenotype.

Science.gov (United States)

Schuster-Gossler, K; Simon-Chazottes, D; Guenet, J L; Zachgo, J; Gossler, A

1996-01-01

We have produced a transgenic mouse line, Gtl2lacZ (Gene trap locus 2), that carries an insertional mutation with a dominant modified pattern of inheritance:heterozygous Gtl2lacZ mice that inherited the transgene from the father show a proportionate dwarfism phenotype, whereas the penetrance and expressivity of the phenotype is strongly reduced in Gtl2lacZ mice that inherited the transgene from the mother. On a mixed genetic background this pattern of inheritance was reversible upon transmission of the transgene through the germ line of the opposite sex. On a predominantly 129/Sv genetic background, however, transgene passage through the female germ line modified the transgene effect, such that the penetrance of the mutation was drastically reduced and the phenotype was no longer obvious after subsequent male germ line transmission. Expression of the transgene, however, was neither affected by genetic background nor by parental legacy. Gtl2lacZ maps to mouse Chromosome 12 in a region that displays imprinting effects associated with maternal and paternal disomy. Our results suggest that the transgene insertion in Gtl2lacZ mice affects an endogenous gene(s) required for fetal and postnatal growth and that this gene(s) is predominantly paternally expressed.

A Search for B+ --> tau + nu tau Recoiling Against B- --> D0 l- nu-bar l X

CERN Document Server

Sekula, S J

2003-01-01

We present a search for the decay B sup + -> tau sup +nu subtau in 88.9 x 10 sup 6 UPSILON(4S) decays recorded with the BABAR detector at the SLAC B-Factory. A sample of semi-exclusive, semi-leptonic B decays (B sup - -> D sup 0 (ell) sup - (bar nu) sub e sub l sub l X), where X is either a photon, pi sup 0 , or nothing, is used to identify the daughter particles that are associated with the other B meson in each event. These particles are searched for evidence of a one-prong leptonic B sup + -> tau sup +nu subtau decay. For this data sample we set a preliminary upper limit on the branching fraction of BETA(B sup + -> tau sup +nu subtau) tau sup +nu subtau to give a combined preliminary limit of BETA(B sup + -> tau sup +nu subtau) < 4.1 x 10 sup - sup 4.

Tau Identification at CMS in Run II

CERN Document Server

Ojalvo, Isabel

2016-01-01

During LHC Long Shutdown 1 necessary upgrades to the CMS detector were made. CMS also took the opportunity to improve further particle reconstruction. A number of improvements were made to the Hadronic Tau reconstruction and Identification algorithms. In particular, electromag- netic strip reconstruction of the Hadron plus Strips (HPS) algorithm was improved to better model signal of pi0 from tau decays. This modification improves energy response and removes the tau footprint from isolation area. In addition to this, improvement to discriminators combining iso- lation and tau life time variables, and anti-electron in MultiVariate Analysis technique was also developed. The results of these improvements are presented and validation of Tau Identification using a variety of techniques is shown.

Genome scan identifies a locus affecting gamma-globin expression in human beta-cluster YAC transgenic mice

Energy Technology Data Exchange (ETDEWEB)

Lin, S.D.; Cooper, P.; Fung, J.; Weier, H.U.G.; Rubin, E.M.

2000-03-01

Genetic factors affecting post-natal g-globin expression - a major modifier of the severity of both b-thalassemia and sickle cell anemia, have been difficult to study. This is especially so in mice, an organism lacking a globin gene with an expression pattern equivalent to that of human g-globin. To model the human b-cluster in mice, with the goal of screening for loci affecting human g-globin expression in vivo, we introduced a human b-globin cluster YAC transgene into the genome of FVB mice . The b-cluster contained a Greek hereditary persistence of fetal hemoglobin (HPFH) g allele resulting in postnatal expression of human g-globin in transgenic mice. The level of human g-globin for various F1 hybrids derived from crosses between the FVB transgenics and other inbred mouse strains was assessed. The g-globin level of the C3HeB/FVB transgenic mice was noted to be significantly elevated. To map genes affecting postnatal g-globin expression, a 20 centiMorgan (cM) genome scan of a C3HeB/F VB transgenics [prime] FVB backcross was performed, followed by high-resolution marker analysis of promising loci. From this analysis we mapped a locus within a 2.2 cM interval of mouse chromosome 1 at a LOD score of 4.2 that contributes 10.4% of variation in g-globin expression level. Combining transgenic modeling of the human b-globin gene cluster with quantitative trait analysis, we have identified and mapped a murine locus that impacts on human g-globin expression in vivo.

Yeast as a Model System to Study Tau Biology

Directory of Open Access Journals (Sweden)

Ann De Vos

2011-01-01

Full Text Available Hyperphosphorylated and aggregated human protein tau constitutes a hallmark of a multitude of neurodegenerative diseases called tauopathies, exemplified by Alzheimer's disease. In spite of an enormous amount of research performed on tau biology, several crucial questions concerning the mechanisms of tau toxicity remain unanswered. In this paper we will highlight some of the processes involved in tau biology and pathology, focusing on tau phosphorylation and the interplay with oxidative stress. In addition, we will introduce the development of a human tau-expressing yeast model, and discuss some crucial results obtained in this model, highlighting its potential in the elucidation of cellular processes leading to tau toxicity.

The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology

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Jui-Heng Tseng

2017-08-01

Full Text Available The initiating events that promote tau mislocalization and pathology in Alzheimer’s disease (AD are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.

Cardiac disease and arrhythmogenesis: Mechanistic insights from mouse models

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Lois Choy

2016-09-01

Full Text Available The mouse is the second mammalian species, after the human, in which substantial amount of the genomic information has been analyzed. With advances in transgenic technology, mutagenesis is now much easier to carry out in mice. Consequently, an increasing number of transgenic mouse systems have been generated for the study of cardiac arrhythmias in ion channelopathies and cardiomyopathies. Mouse hearts are also amenable to physical manipulation such as coronary artery ligation and transverse aortic constriction to induce heart failure, radiofrequency ablation of the AV node to model complete AV block and even implantation of a miniature pacemaker to induce cardiac dyssynchrony. Last but not least, pharmacological models, despite being simplistic, have enabled us to understand the physiological mechanisms of arrhythmias and evaluate the anti-arrhythmic properties of experimental agents, such as gap junction modulators, that may be exert therapeutic effects in other cardiac diseases. In this article, we examine these in turn, demonstrating that primary inherited arrhythmic syndromes are now recognized to be more complex than abnormality in a particular ion channel, involving alterations in gene expression and structural remodelling. Conversely, in cardiomyopathies and heart failure, mutations in ion channels and proteins have been identified as underlying causes, and electrophysiological remodelling are recognized pathological features. Transgenic techniques causing mutagenesis in mice are extremely powerful in dissecting the relative contributions of different genes play in producing disease phenotypes. Mouse models can serve as useful systems in which to explore how protein defects contribute to arrhythmias and direct future therapy.

Bacterial magnetic particles improve testes-mediated transgene efficiency in mice.

Science.gov (United States)

Wang, Chao; Sun, Guanghong; Wang, Ye; Kong, Nana; Chi, Yafei; Yang, Leilei; Xin, Qiliang; Teng, Zhen; Wang, Xu; Wen, Yujun; Li, Ying; Xia, Guoliang

2017-11-01

Nano-scaled materials have been proved to be ideal DNA carriers for transgene. Bacterial magnetic particles (BMPs) help to reduce the toxicity of polyethylenimine (PEI), an efficient gene-transferring agent, and assist tissue transgene ex vivo. Here, the effectiveness of the BMP-PEI complex-conjugated foreign DNAs (BPDs) in promoting testes-mediated gene transfer (TMGT) in mouse was compared with that of liposome-conjugated foreign DNAs. The results proved that through testes injection, the clusters of BPDs successfully reached the cytoplasm and the nuclear of spermatogenesis cell, and expressed in testes of transgene founder mice. Additionally, the ratio of founder mice obtained from BPDs (88%) is about 3 times higher than the control (25%) (p mice from BPD group were significantly improved, as compared with the control (p mice within the first filial was significantly higher in BPDs compared with the control (73.8% versus 11.6%, p mice in vivo.

Study of 3-prong hadronic {tau} decays with charged kaons

Energy Technology Data Exchange (ETDEWEB)

Richichi, S. J. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Severini, H. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Skubic, P. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Undrus, A. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Bishai, M. [Purdue University, West Lafayette, Indiana 47907 (United States); Chen, S. [Purdue University, West Lafayette, Indiana 47907 (United States); Fast, J. [Purdue University, West Lafayette, Indiana 47907 (United States); Hinson, J. W. [Purdue University, West Lafayette, Indiana 47907 (United States); Menon, N. [Purdue University, West Lafayette, Indiana 47907 (United States); Miller, D. H. [Purdue University, West Lafayette, Indiana 47907 (United States)] (and others)

1999-12-01

Using a sample of 4.7 fb{sup -1} integrated luminosity accumulated with the CLEO-II detector at the Cornell Electron Storage Ring (CESR), we have measured the ratios of the branching fractions B({tau}{sup -}{yields}K{sup -}h{sup +}{pi}{sup -}{nu}{sub {tau}})/B({tau}{sup -}{yields}h{sup -}h{sup +}h{sup -}{nu}{sub {tau}})=(5.16(+= - )0.20{+-}0.50)x10{sup -2}, B({tau}{sup -}{yields}K{sup -}h{sup +}{pi}{sup -}{pi}{sup 0}{nu}{sub {tau}})/B({tau}{sup -}{yields}h{sup -}h{sup +}h{sup -}{pi}{sup 0}{nu}{sub (t= a u))=(2.54{+-}0.44{+-}0.39)x10{sup -2}, B({tau}{sup -}{yields}K{sup -}K{sup +}{pi}{sup -}{nu}{sub {tau}})/B({tau}{sup -}{yields}h{sup -}h{sup +}h{sup -}{nu}{sub {tau}})=(1.52(+= - )0.14{+-}0.29)x10{sup -2}, and the upper limit B({tau}{sup -}{yields}K{sup -}K{sup +}{pi}{sup -}{pi}{sup 0}{nu}{sub {tau}})/B({tau}{sup -}{yields}h{sup -}h{sup +}h{sup -}{pi}{sup 0}{nu}{sub (t= a u))<0.0154 at 95% C.L. Coupled with additional experimental information, we use our results to extract information on the structure of three-prong tau decays to charged kaons. (c) 1999 The American Physical Society.

Viscoelasticity of amyloid plaques in transgenic mouse brain studied by Brillouin microspectroscopy and correlative Raman analysis

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Sara Mattana

2017-11-01

Full Text Available Amyloidopathy is one of the most prominent hallmarks of Alzheimer’s disease (AD, the leading cause of dementia worldwide, and is characterized by the accumulation of amyloid plaques in the brain parenchyma. The plaques consist of abnormal deposits mainly composed of an aggregation-prone protein fragment, β-amyloid 1-40/1-42, into the extracellular matrix. Brillouin microspectroscopy is an all-optical contactless technique that is based on the interaction between visible light and longitudinal acoustic waves or phonons, giving access to the viscoelasticity of a sample on a subcellular scale. Here, we describe the first application of micromechanical mapping based on Brillouin scattering spectroscopy to probe the stiffness of individual amyloid plaques in the hippocampal part of the brain of a β-amyloid overexpressing transgenic mouse. Correlative analysis based on Brillouin and Raman microspectroscopy showed that amyloid plaques have a complex structure with a rigid core of β-pleated sheet conformation (β-amyloid protein surrounded by a softer ring-shaped region richer in lipids and other protein conformations. These preliminary results give a new insight into the plaque biophysics and biomechanics, and a valuable contrast mechanism for the study and diagnosis of amyloidopathy.

Tau electron atoms at RHIC

International Nuclear Information System (INIS)

Weiss, M.S.

1985-01-01

An amusement ancillary to the proposed quark-gluon plasma production hypothesized from a relativistic heavy ion collider (RHIC is a sufficient quantity of tau electrons to potentially admit the study of its exotic atoms. In this paper the given wealth of nuclear phenomena is derived from muonic atoms assume a tau atom is more forthcoming of information due to the lower orbits entirely contained within the nucleus. It is the purpose of this brief note to discuss the production mechanism at a RHIC and to delineate some of the more obvious properties of the tau atom. As in the case of the mu, more exotic phenomena derived from resonance ''accidents'' with nuclear transitions takes place, but it would be presumptions to discuss them at this time. Given the complete containment in nuclear matter of the tau lepton in its innermost atomic orbits. An experiment performed with such an exotic species results in the measurement of its lifetime

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy

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Petrica-Adrian Panaite

2013-05-01

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1. Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding

Identification of Secretory Odontoblasts Using DMP1-GFP Transgenic Mice

Science.gov (United States)

Balic, Anamaria; Mina, Mina

2011-01-01

Terminal differentiation of odontoblasts from dental papilla is a long process involving several intermediate steps and changes in the transcriptional profile and expression of proteins secreted by cells in the odontoblast lineage. Transgenic mouse lines in which GFP expression is under the control of tissue-and stage specific promoters have provided powerful experimental tools for identification and isolation of cells at specific stages of differentiation along a lineage. Our previous studies showed utilization of pOBCol3.6GFP and pOBCol2.3GFP animals for identification of odontoblasts at early and late stages of polarization respectively. In the present study we used the DMP1-GFP transgenic animal as an experimental model to examine its expression during the differentiation of odontoblasts from progenitor cells in vivo and in vitro. Our observations showed that DMP1-GFP transgene is first activated in secretory/functional odontoblasts engaged in secretion of predentin and then transiently expressed at high levels in newly differentiated odontoblasts. Expression of DMP1-GFP was down-regulated in highly differentiated odontoblasts. The temporal and spatial pattern of expression of DMP1-GFP transgene closely mimics the expression of endogenous DMP1. This transgenic animal will facilitate studies of gene expression and biological functions in secretory/functional odontoblasts. PMID:21172466

Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model

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Sangmook Lee

2012-01-01

Full Text Available We used a nontransgenic cellular tauopathy model in which individual giant neurons in the lamprey CNS (ABCs overexpress human tau isoforms cell autonomously to characterize the still poorly understood consequences of disease-associated tau processing in situ. In this model, tau colocalizes with endogenous microtubules and is nontoxic when expressed at low levels, but is misprocessed by a toxicity-associated alternative pathway when expressed above levels that saturate dendritic microtubules, causing abnormally phosphorylated, vesicle-associated tau to accumulate in ABC distal dendrites. This causes localized microtubule loss and eventually dendritic degeneration, which is preceded by tau secretion to the extracellular space. This sequence is reiterated at successively more proximal dendritic locations over time, suggesting that tau-induced dendritic degeneration is driven by distal dendritic accumulation of hyperphosphorylated, vesicle-associated tau perpetuated by localized microtubule loss. The implications for the diagnosis and treatment of human disease are discussed.

Search for {phi} mesons in {tau} lepton decay

Energy Technology Data Exchange (ETDEWEB)

Avery, P.; Prescott, C.; Yang, S.; Yelton, J. [University of Florida, Gainesville, Florida 32611 (United States); Brandenburg, G.; Briere, R.A.; Liu, T.; Saulnier, M.; Wilson, R.; Yamamoto, H. [Harvard University, Cambridge, Massachusetts 02138 (United States); Browder, T.E.; Li, F.; Rodriguez, J.L. [University of Hawaii at Manoa, Honolulu, Hawaii 96822 (United States); Bergfeld, T.; Eisenstein, B.I.; Ernst, J.; Gladding, G.E.; Gollin, G.D.; Karliner, I.; Palmer, M.; Selen, M.; Thaler, J.J. [University of Illinois, Champaign-Urbana, Illinois 61801 (United States); Edwards, K.W.; Ogg, M. [Carleton University, Ottawa, Ontario, K1S 5B6 (CANADA); Bellerive, A.; Britton, D.I.; Janicek, R.; MacFarlane, D.B.; McLean, K.W.; Patel, P.M. [McGill University, Montreal, Quebec, H3A 2T8 (CANADA); Sadoff, A.J. [Ithaca College, Ithaca, New York 14850 (United States); Ammar, R.; Baringer, P.; Bean, A.; Besson, D.; Coppage, D.; Copty, N.; Davis, R.; Hancock, N.; Kotov, S.; Kravchenko, I.; Kwak, N. [University of Kansas, Lawrence, Kansas 66045 (United States); Anderson, S.; Kubota, Y.; Lattery, M.; ONeill, J.J.; Patton, S.; Poling, R.; Riehle, T.; Smith, A.; Savinov, V. [University of Minnesota, Minneapolis, Minnesota 55455 (United States); Alam, M.S.; Athar, S.B.; Kim, I.J.; Ling, Z.; Mahmood, A.H.; Severini, H.; Timm, S.; Wappler, F. [State University of New York at Albany, Albany, New York 12222 (United States); Duboscq, J.E.; Fulton, R.; Fujino, D.; Gan, K.K.; Honscheid, K.; Kagan, H.; Kass, R.; Lee, J.; Sung, M.; Undrus, A.; White, C.; Wanke, R.; Wolf, A.; Zoeller, M.M. [Ohio State University, Columbus, Ohio 43210 (United States); Nemati, B.; Richichi, S.J.; Ross, W.R.; Skubic, P.; Wood, M. [University of Oklahoma, Norman, Oklahoma 73019 (United States); Bishai, M.; Fast, J.; Gerndt, E.; Hinson, J.W.; Miller, D.H.; Shibata, E.I.; Shipsey, I.P.; Yurko, M. [Purdue University, West Lafayette, Indiana 47907 (United States); Gibbons, L.; Johnson, S.D.

1997-02-01

We report results from a direct search for {tau}{sup {minus}}{r_arrow}{phi}h{sup {minus}}{nu}{sub {tau}}(h{sup {minus}}={pi}{sup {minus}}or K{sup {minus}}) using 3.1 fb{sup {minus}1} of data collected with the CLEO II detector. We find model-dependent upper limits on the branching fractions in the range B({tau}{sup {minus}}{r_arrow}{phi}{pi}{sup {minus}}{nu}{sub {tau}}){lt}(1.2{minus}2.0){times}10{sup {minus}4} and B({tau}{sup {minus}}{r_arrow}{phi}K{sup {minus}}{nu}{sub {tau}}){lt}(5.4{minus}6.7){times}10{sup {minus}5} at 90{percent} confidence level. {copyright} {ital 1997} {ital The American Physical Society}

Heart-specific expression of laminopathic mutations in transgenic zebrafish.

Science.gov (United States)

Verma, Ajay D; Parnaik, Veena K

2017-07-01

Lamins are key determinants of nuclear organization and function in the metazoan nucleus. Mutations in human lamin A cause a spectrum of genetic diseases that affect cardiac muscle and skeletal muscle as well as other tissues. A few laminopathies have been modeled using the mouse. As zebrafish is a well established model for the study of cardiac development and disease, we have investigated the effects of heart-specific lamin A mutations in transgenic zebrafish. We have developed transgenic lines of zebrafish expressing conserved lamin A mutations that cause cardiac dysfunction in humans. Expression of zlamin A mutations Q291P and M368K in the heart was driven by the zebrafish cardiac troponin T2 promoter. Homozygous mutant embryos displayed nuclear abnormalities in cardiomyocyte nuclei. Expression analysis showed the upregulation of genes involved in heart regeneration in transgenic mutant embryos and a cell proliferation marker was increased in adult heart tissue. At the physiological level, there was deviation of up to 20% from normal heart rate in transgenic embryos expressing mutant lamins. Adult homozygous zebrafish were fertile and did not show signs of early mortality. Our results suggest that transgenic zebrafish models of heart-specific laminopathies show cardiac regeneration and moderate deviations in heart rate during embryonic development. © 2017 International Federation for Cell Biology.

Human iPSC-Derived Neuronal Model of Tau-A152T Frontotemporal Dementia Reveals Tau-Mediated Mechanisms of Neuronal Vulnerability

Directory of Open Access Journals (Sweden)

M. Catarina Silva

2016-09-01

Full Text Available Frontotemporal dementia (FTD and other tauopathies characterized by focal brain neurodegeneration and pathological accumulation of proteins are commonly associated with tau mutations. However, the mechanism of neuronal loss is not fully understood. To identify molecular events associated with tauopathy, we studied induced pluripotent stem cell (iPSC-derived neurons from individuals carrying the tau-A152T variant. We highlight the potential of in-depth phenotyping of human neuronal cell models for pre-clinical studies and identification of modulators of endogenous tau toxicity. Through a panel of biochemical and cellular assays, A152T neurons showed accumulation, redistribution, and decreased solubility of tau. Upregulation of tau was coupled to enhanced stress-inducible markers and cell vulnerability to proteotoxic, excitotoxic, and mitochondrial stressors, which was rescued upon CRISPR/Cas9-mediated targeting of tau or by pharmacological activation of autophagy. Our findings unmask tau-mediated perturbations of specific pathways associated with neuronal vulnerability, revealing potential early disease biomarkers and therapeutic targets for FTD and other tauopathies.

The use of transgenic animals to study lipoprotein metabolism

Energy Technology Data Exchange (ETDEWEB)

Rubin, E.M.; Plump, A.S.

1993-12-01

The application of transgenic technology to lipoprotein metabolism and atherosclerosis was first reported in 1988. Today, a large percentage of the genes involved in lipoprotein metabolism have been overexpressed in mice, and a substantial number of these same genes have been disrupted by homologous recombination in embryonic stem (ES) cells. The utility of animal models of lipoprotein metabolism and atherosclerosis is far-reaching given the complex nature of these systems. There are at least 17 known genes directly involved in lipoprotein metabolism and likely dozens more may be involved. This massive network of interacting factors has necessitated the development of in vivo systems which can be subject to genetic manipulation. The power of overexpression is obvious: elucidating function in a relatively controlled genetic environment in which the whole system is present and operational. The not-so-obvious problem with transgenics is ``background,`` or for purposes of the current discussion, the mouse`s own lipoprotein system. With the advent of gene knockout, we have been given the ability to overcome ``background.`` By recreating the genetic complement of the mouse we can alter a system in essentially any manner desired. As unique tools, and in combination with one another, the overexpression of foreign genes and the targeted disruption or alteration of endogenous genes has already and will continue to offer a wealth of information on the biology of lipoprotein metabolism and its effect on atherosclerosis susceptibility.

Electroweak and Higgs Measurements Using Tau Final States

CERN Document Server

INSPIRE-00258006; McNulty, Ronan

Spin correlations for $\\tau$ lepton decays are included in the PYTHIA 8 event generation software with a framework which can be expanded to include the decays of particles other than the $\\tau$ lepton. The spin correlations for the decays of $\\tau$ leptons produced from electroweak and Higgs bosons are calculated. Decays of the $\\tau$ lepton using sophisticated resonance models are included in PYTHIA 8 for all channels with experimentally observed branching fractions greater than $0.04\\%$. The mass distributions for the decay products of these channels calculated with PYTHIA 8 are validated against the equivalent distributions from the HERWIG++ and TAUOLA event generators. The technical implementation of the $\\tau$ lepton spin correlations and decays in PYTHIA 8 is described. A measurement of the inclusive ${Z \\rightarrow \\tau\\tau}$ cross-section using ${1.0~\\mathrm{fb}^{-1}}$ of data from $pp$ collisions at $\\sqrt{s} = 7~\\mathrm{Te\\kern -0.1em V}$ collected with the LHCb detector is presented. Reconstructed ...

Utrophin up-regulation by an artificial transcription factor in transgenic mice.

Directory of Open Access Journals (Sweden)

Elisabetta Mattei

2007-08-01

Full Text Available Duchenne Muscular Dystrophy (DMD is a severe muscle degenerative disease, due to absence of dystrophin. There is currently no effective treatment for DMD. Our aim is to up-regulate the expression level of the dystrophin related gene utrophin in DMD, complementing in this way the lack of dystrophin functions. To this end we designed and engineered several synthetic zinc finger based transcription factors. In particular, we have previously shown that the artificial three zinc finger protein named Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from the utrophin promoter "A". Here we report on the characterization of Vp16-Jazz-transgenic mice that specifically over-express the utrophin gene at the muscular level. A Chromatin Immunoprecipitation assay (ChIP demonstrated the effective access/binding of the Jazz protein to active chromatin in mouse muscle and Vp16-Jazz was shown to be able to up-regulate endogenous utrophin gene expression by immunohistochemistry, western blot analyses and real-time PCR. To our knowledge, this is the first example of a transgenic mouse expressing an artificial gene coding for a zinc finger based transcription factor. The achievement of Vp16-Jazz transgenic mice validates the strategy of transcriptional targeting of endogenous genes and could represent an exclusive animal model for use in drug discovery and therapeutics.

JINR tau-charm factory design study

International Nuclear Information System (INIS)

Perel'shtejn, E.; Aleksandrov, V.; Antropov, V.

1993-01-01

The review on tau-charm factory in JINR (Dubna) is presented. The structure scheme of tau-charm factory is described. The problems on injection complex are discussed: the composition, the working regime and parameters. The magnetic lattice of a booster is described. A versatile magnet lattice is used in tau-charm collider. It can realize both conventional flat beam scheme and monochromatization scheme. The results of chromaticity correction in high emittance lattice are presented. The list of parameters of tau-charm collider is given. The technical proposal of magnetic elements of booster and collider and their power supplies is made, as well as RF power supply in collider and vacuum system in its periodic cell. 12 refs.; 12 figs.; 3 tabs

arXiv Higgs boson measurements in $WW$, $\\tau\\tau$ and $\\mu\\mu$ channels with CMS

CERN Document Server

INSPIRE-00205539

2017-01-01

This note presents a search for the Standard Model (SM) Higgs boson in $WW$, $\\tau\\tau$ and $\\mu\\mu$ decay channels with proton-proton collision data collected by the CMS experiment at the LHC. The results have been derived using different amounts of luminosities for different channels.

Neprilysin-Like Activity Correlates with CSF-Tau and Phospho-Tau in Patients with Alzheimer's Disease

DEFF Research Database (Denmark)

Sorensen, Katrine Christa Nordskov; Simonsen, Anja Hviid; Holmetoft, Ulla Bachmann

2013-01-01

the level and enzyme activity of NEP in serum and CSF, using a sandwich enzyme-linked immunosorbent assay and a fluorescence resonance energy transfer assay, respectively, in patients with AD, frontotemporal dementia (FTD), Creutzfeldt-Jakob disease (CJD), and depression. Results were correlated...... activity was seen. However, NEP concentration was lower and the specific activity was higher in FTD compared to AD. Aβ42 levels in CSF did not correlate with NEP concentration or activity in the AD, CJD, or depression groups, but NEP-like activity and Aβ42 levels correlated significantly in the FTD group....... In AD and depression, the NEP-like activity in CSF correlated with levels of p-tau, and, in the AD group, it also was correlated with t-tau levels. Our results suggest that the relation between the specific activity of NEP and t-tau and p-tau is a characteristic trait of AD. The correlation between NEP...

A surgical approach appropriate for targeted cochlear gene therapy in the mouse.

Science.gov (United States)

Jero, J; Tseng, C J; Mhatre, A N; Lalwani, A K

2001-01-01

Therapeutic manipulations of the mammalian cochlea, including cochlear gene transfer, have been predominantly studied using the guinea pig as the experimental model. With the significant developments in mouse genomics and the availability of mutant strains of mice with well-characterized hearing loss, the mouse justifiably will be the preferred animal model for therapeutic manipulations. However, the potential advantages of the mouse model have not been fully realized due to the surgical difficulty of accessing its small cochlea. This study describes a ventral approach, instead of the routinely used postauricular approach in other rodents, for accessing the mouse middle and inner ear, and its application in cochlear gene transfer. This ventral approach enabled rapid and direct delivery of liposome-transgene complex to the mouse inner ear while avoiding blood loss, facial nerve morbidity, and mortality. Transgene expression at 3 days was detected in Reissner's membrane, spiral limbus, spiral ligament, and spiral ganglion cells, in a pattern similar to that previously described in the guinea pig. The successful access and delivery of material to the mouse cochlea and the replication of gene expression seen in the guinea pig demonstrated in this study should promote the use of the mouse in future studies investigating targeted cochlear therapy.

HIGH ANGULAR RESOLUTION RADIO OBSERVATIONS OF THE HL/XZ TAU REGION: MAPPING THE 50 AU PROTOPLANETARY DISK AROUND HL TAU AND RESOLVING XZ TAU S INTO A 13 AU BINARY

International Nuclear Information System (INIS)

Carrasco-Gonzalez, Carlos; Anglada, Guillem; RodrIguez, Luis F.; Curiel, Salvador

2009-01-01

We present new 7 mm and archive 1.3 cm high angular resolution observations of the HL/XZ Tau region made with the Very Large Array. At 7 mm, the emission from HL Tau seems to arise in a clumpy disk with radius of the order of 25 AU. The 1.3 cm emission from XZ Tau shows the emission from a binary system with 0.''3 (42 AU) separation, known from previous optical/IR observations. However, at 7 mm, the southern radio component resolves into a binary with 0.''09 (13 AU) separation, suggesting that XZ Tau is actually a triple star system. We suggest that the remarkable ejection of gas from the XZ Tau system observed with the Hubble Space Telescope may be related to a periastron passage of this newly discovered close binary system.

Age-related changes in body composition of bovine growth hormone transgenic mice.

Science.gov (United States)

Palmer, Amanda J; Chung, Min-Yu; List, Edward O; Walker, Jennifer; Okada, Shigeru; Kopchick, John J; Berryman, Darlene E

2009-03-01

GH has a significant impact on body composition due to distinct anabolic and catabolic effects on lean and fat mass, respectively. Several studies have assessed body composition in mice expressing a GH transgene. Whereas all studies report enhanced growth of transgenic mice as compared with littermate controls, there are inconsistencies in terms of the relative proportion of lean mass to fat mass in these animals. The purpose of this study was to characterize the accumulation of adipose and lean mass with age and according to gender in a bovine (b) GH transgenic mouse line. Weight and body composition measurements were assessed in male and female bGH mice with corresponding littermate controls in the C57BL/6J genetic background. Body composition measurements began at 6 wk and continued through 1 yr of age. At the conclusion of the study, tissue weights were determined and triglyceride content was quantified in liver and kidney. Although body weights for bGH mice were significantly greater than their corresponding littermate controls at all time points, body composition measurements revealed an unexpected transition midway through analyses. That is, younger bGH mice had relatively more fat mass than nontransgenic littermates, whereas bGH mice became significantly leaner than controls by 4 months in males and 6 months in females. These results reveal the importance in timing and gender when conducting studies related to body composition or lean and fat tissue in GH transgenic mice or in other genetically manipulated mouse strains in which body composition may be impacted.

Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.

Science.gov (United States)

Wu, Xiaoli; Sandhu, Sumit; Nabi, Zinnatun; Ding, Hao

2012-10-01

Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic.

Genetic human prion disease modelled in PrP transgenic Drosophila.

Science.gov (United States)

Thackray, Alana M; Cardova, Alzbeta; Wolf, Hanna; Pradl, Lydia; Vorberg, Ina; Jackson, Walker S; Bujdoso, Raymond

2017-09-20

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrP Sc , an abnormal isomer of the normal host protein PrP C , in the brain of affected individuals. PrP Sc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host. © 2017 The Author(s).

Creating Transgenic shRNA Mice by Recombinase-Mediated Cassette Exchange

Science.gov (United States)

Premsrirut, Prem K.; Dow, Lukas E.; Park, Youngkyu; Hannon, Gregory J.; Lowe, Scott W.

2014-01-01

RNA interference (RNAi) enables sequence-specific, experimentally induced silencing of virtually any gene by tapping into innate regulatory mechanisms that are conserved among most eukaryotes. The principles that enable transgenic RNAi in cell lines can also be used to create transgenic animals, which express short-hairpin RNAs (shRNAs) in a regulated or tissue-specific fashion. However, RNAi in transgenic animals is somewhat more challenging than RNAi in cultured cells. The activities of promoters that are commonly used for shRNA expression in cell culture can vary enormously in different tissues, and founder lines also typically vary in transgene expression due to the effects of their single integration sites. There are many ways to produce mice carrying shRNA transgenes and the method described here uses recombinase-mediated cassette exchange (RMCE). RMCE permits insertion of the shRNA transgene into a well-characterized locus that gives reproducible and predictable expression in each founder and enhances the probability of potent expression in many cell types. This procedure is more involved and complex than simple pronuclear injection, but if even a few shRNA mice are envisioned, for example, to probe the functions of several genes, the effort of setting up the processes outlined below are well worthwhile. Note that when creating a transgenic mouse, one should take care to use the most potent shRNA possible. As a rule of thumb, the sequence chosen should provide >90% knockdown when introduced into cultured cells at single copy (e.g., on retroviral infection at a multiplicity of ≤0.3). PMID:24003198

infrared spectra of T Tau stars and related objects

International Nuclear Information System (INIS)

Shanin, G.I.; Shevchenko, V.S.; Shcherbakov, A.G.

1975-01-01

Four T Tau stars and related objects (RY Tau, T Tau, AB Aur and V1057 Cyg) have been included in the authors' spectroscopic programme since 1973. The present paper is concerned with the spectroscopic observations made at the Crimea with the single stage image tube S1. Tentative atomic line identifications are given for programme stars. Ca II and O I emission line equivalent widths and profiles are presented for RY Tau, T Tau and AB Aur. The lambda 10830 A line of neutral helium has shown P Cyg-type features for T Tau and V 1057 Cyg. (Auth.)

Study of tau-pair production at HERA

Energy Technology Data Exchange (ETDEWEB)

Abramowicz, H. [Tel Aviv Univ. (Israel). School of Physics; Max Planck Institute for Physics, Munich (Germany); Adamczyk, L. [AGH-Univ. of Science and Technology, Cracow (Poland). Faculty of Physics and Applied Computer Science; Adamus, M. [Institute for Nuclear Studies, Warsaw (PL)] (and others)

2010-12-15

A study of events containing two tau leptons with high transverse momentum has been performed with the ZEUS detector at HERA, using a data sample corresponding to an integrated luminosity of 0.33 fb{sup -1}. The tau candidates were identified from their decays into electrons, muons or hadronic jets. The number of tau-pair candidates has been compared with the prediction from the Standard Model, where the largest contribution is expected from Bethe-Heitler processes. The total visible cross section was extracted. Standard Model expectations agree well with the measured distributions, also at high invariant mass of the tau pair. (orig.)

Measurement of the Strange Spectral Function in Hadronic $\\tau$ Decays

CERN Document Server

Abbiendi, G.; Akesson, P.F.; Alexander, G.; Allison, John; Amaral, P.; Anagnostou, G.; Anderson, K.J.; Arcelli, S.; Asai, S.; Axen, D.; Azuelos, G.; Bailey, I.; Barberio, E.; Barillari, T.; Barlow, R.J.; Batley, R.J.; Bechtle, P.; Behnke, T.; Bell, Kenneth Watson; Bell, P.J.; Bella, G.; Bellerive, A.; Benelli, G.; Bethke, S.; Biebel, O.; Boeriu, O.; Bock, P.; Boutemeur, M.; Braibant, S.; Brigliadori, L.; Brown, Robert M.; Buesser, K.; Burckhart, H.J.; Campana, S.; Carnegie, R.K.; Carter, A.A.; Carter, J.R.; Chang, C.Y.; Charlton, D.G.; Ciocca, C.; Csilling, A.; Cuffiani, M.; Dado, S.; De Roeck, A.; De Wolf, E.A.; Desch, K.; Dienes, B.; Donkers, M.; Dubbert, J.; Duchovni, E.; Duckeck, G.; Duerdoth, I.P.; Etzion, E.; Fabbri, F.; Feld, L.; Ferrari, P.; Fiedler, F.; Fleck, I.; Ford, M.; Frey, A.; Gagnon, P.; Gary, John William; Gaycken, G.; Geich-Gimbel, C.; Giacomelli, G.; Giacomelli, P.; Giunta, Marina; Goldberg, J.; Gross, E.; Grunhaus, J.; Gruwe, M.; Gunther, P.O.; Gupta, A.; Hajdu, C.; Hamann, M.; Hanson, G.G.; Harel, A.; Hauschild, M.; Hawkes, C.M.; Hawkings, R.; Hemingway, R.J.; Herten, G.; Heuer, R.D.; Hill, J.C.; Hoffman, Kara Dion; Horvath, D.; Igo-Kemenes, P.; Ishii, K.; Jeremie, H.; Jovanovic, P.; Junk, T.R.; Kanaya, N.; Kanzaki, J.; Karlen, D.; Kawagoe, K.; Kawamoto, T.; Keeler, R.K.; Kellogg, R.G.; Kennedy, B.W.; Klein, K.; Klier, A.; Kluth, S.; Kobayashi, T.; Kobel, M.; Komamiya, S.; Kramer, T.; Krieger, P.; von Krogh, J.; Kruger, K.; Kuhl, T.; Kupper, M.; Lafferty, G.D.; Landsman, H.; Lanske, D.; Layter, J.G.; Lellouch, D.; Lettso, J.; Levinson, L.; Lillich, J.; Lloyd, S.L.; Loebinger, F.K.; Lu, J.; Ludwig, A.; Ludwig, J.; Mader, W.; Marcellini, S.; Martin, A.J.; Masetti, G.; Mashimo, T.; Mattig, Peter; McKenna, J.; McPherson, R.A.; Meijers, F.; Menges, W.; Menke, S.; Merritt, F.S.; Mes, H.; Michelini, A.; Mihara, S.; Mikenberg, G.; Miller, D.J.; Moed, S.; Mohr, W.; Mori, T.; Mutter, A.; Nagai, K.; Nakamura, I.; Nanjo, H.; Neal, H.A.; Nisius, R.; O'Neale, S.W.; Oh, A.; Okpara, A.; Oreglia, M.J.; Orito, S.; Pahl, C.; Pasztor, G.; Pater, J.R.; Pilcher, J.E.; Pinfold, J.; Plane, David E.; Poli, B.; Pooth, O.; Przybycien, M.; Quadt, A.; Rabbertz, K.; Rembser, C.; Renkel, P.; Roney, J.M.; Rosati, S.; Rozen, Y.; Runge, K.; Sachs, K.; Saeki, T.; Sarkisyan, E.K.G.; Schaile, A.D.; Schaile, O.; Scharff-Hansen, P.; Schieck, J.; Schorner-Sadenius, T.; Schroder, Matthias; Schumacher, M.; Scott, W.G.; Seuster, R.; Shears, T.G.; Shen, B.C.; Sherwood, P.; Skuja, A.; Smith, A.M.; Sobie, R.; Soldner-Rembold, S.; Spano, F.; Stahl, A.; Strom, David M.; Strohmer, R.; Tarem, S.; Tasevsky, M.; Teuscher, R.; Thomson, M.A.; Torrence, E.; Toya, D.; Tran, P.; Trigger, I.; Trocsanyi, Z.; Tsur, E.; Turner-Watson, M.F.; Ueda, I.; Ujvari, B.; Vollmer, C.F.; Vannerem, P.; Vertesi, R.; Verzocchi, M.; Voss, H.; Vossebeld, J.; Waller, D.; Ward, C.P.; Ward, D.R.; Watkins, P.M.; Watson, A.T.; Watson, N.K.; Wells, P.S.; Wengler, T.; Wermes, N.; Wetterling, D.; Wilson, G.W.; Wilson, J.A.; Wolf, G.; Wyatt, T.R.; Yamashita, S.; Zer-Zion, D.; Zivkovic, Lidija

2004-01-01

Tau Lepton decays with open strangeness in the final state are measured with the OPAL detector at LEP to determine the strange hadronic spectral function of the tau lepton. The decays tau- -> (Kpi)-nu tau, (Kpipi)-nu tau and (Kpipipi)-nu tau with final states consisting of neutral and charged kaons and pions have been studied. The invariant mass distributions of 93.4% of these final states have been experimentally determined. Monte Carlo simulations have been used for the remaining 6.6% and for the strange final states including eta mesons. The reconstructed strange final states, corrected for resolution effects and detection efficiencies, yield the strange spectral function of the tau lepton. The moments of the spectral function and the ratio of strange to non-strange moments, which are important input parameters for theoretical analyses, are determined. Furthermore, the branching fractions B(tau- -> K-pi0nu tau) = (0.471+-0.059stat+-0.023sys)% and B(tau- -> K-pi+pi-nu tau) = (0.415+-0.053stat+-0.040sys)% ha...

Cannabinoid Receptor 2 Participates in Amyloid-β Processing in a Mouse Model of Alzheimer's Disease but Plays a Minor Role in the Therapeutic Properties of a Cannabis-Based Medicine.

Science.gov (United States)

Aso, Ester; Andrés-Benito, Pol; Carmona, Margarita; Maldonado, Rafael; Ferrer, Isidre

2016-01-01

The endogenous cannabinoid system represents a promising therapeutic target to modify neurodegenerative pathways linked to Alzheimer's disease (AD). The aim of the present study was to evaluate the specific contribution of CB2 receptor to the progression of AD-like pathology and its role in the positive effect of a cannabis-based medicine (1:1 combination of Δ9-tetrahidrocannabinol and cannabidiol) previously demonstrated to be beneficial in the AβPP/PS1 transgenic model of the disease. A new mouse strain was generated by crossing AβPP/PS1 transgenic mice with CB2 knockout mice. Results show that lack of CB2 exacerbates cortical Aβ deposition and increases the levels of soluble Aβ40. However, CB2 receptor deficiency does not affect the viability of AβPP/PS1 mice, does not accelerate their memory impairment, does not modify tau hyperphosphorylation in dystrophic neurites associated to Aβ plaques, and does not attenuate the positive cognitive effect induced by the cannabis-based medicine in these animals. These findings suggest a minor role for the CB2 receptor in the therapeutic effect of the cannabis-based medicine in AβPP/PS1 mice, but also constitute evidence of a link between CB2 receptor and Aβ processing.

Pathogenesis of axonal dystrophy and demyelination in alphaA-crystallin-expressing transgenic mice.

NARCIS (Netherlands)

Rijk, A. van; Sweers, M.A.; Merkx, G.F.M.; Lammens, M.M.Y.; Bloemendal, H.

2003-01-01

We recently described a transgenic mouse strain overexpressing hamster alphaA-crystallin, a small heat shock protein, under direction of the hamster vimentin promoter. As a result myelin was degraded and axonal dystrophy in both central nervous system (especially spinal cord) and peripheral nervous

A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice.

Science.gov (United States)

Martín, V; Pascual, E; Avia, M; Rangel, G; de Molina, A; Alejo, A; Sevilla, N

2016-01-06

Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Evaluation of chromatic cues for trapping Bactrocera tau.

Science.gov (United States)

Li, Lei; Ma, Huabo; Niu, Liming; Han, Dongyin; Zhang, Fangping; Chen, Junyu; Fu, Yueguan

2017-01-01

Trapping technology based on chromatic cues is an important strategy in controlling Tephritidae (fruit flies). The objectives of this present study were to evaluate the preference of Bactrocera tau for different chromatic cues, and to explore an easy method to print and reproduce coloured paper. Chromatic cues significantly affected the preference of adult B. tau. Wavelengths in the 515-604 nm range were the suitable wavelengths for trapping B. tau. Different-day-old B. tau had different colour preferences. Virtual wavelengths of 595 nm (yellow) and 568 nm (yellowish green) were the optimum wavelengths for trapping 5-7-day-old B. tau and 30-32-day-old B. tau respectively. The trap type and height significantly influenced B. tau attraction efficiency. The number of B. tau on coloured traps hung perpendicular to plant rows was not significantly higher than the number on traps hung parallel to plant rows. The quantisation of colour on the basis of Bruton's wavelength to RGB function can serve as an alternative method for printing and reproducing coloured paper, but a corrected equation should be established between the theoretical wavelength and actual wavelength of coloured paper. Results show that a compound paper coloured yellow (595 nm) and yellowish green (568 nm) installed at 60 and 90 cm above the ground shows the maximum effect for trapping B. tau. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

Directory of Open Access Journals (Sweden)

Sara Calafate

2015-05-01

Full Text Available Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer’s disease (AD. Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology.

Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation.

Science.gov (United States)

Calafate, Sara; Buist, Arjan; Miskiewicz, Katarzyna; Vijayan, Vinoy; Daneels, Guy; de Strooper, Bart; de Wit, Joris; Verstreken, Patrik; Moechars, Diederik

2015-05-26

Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of tauopathies, including Alzheimer's disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that, in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation. These findings can have implications for synaptic repair therapies, which may turn out to have adverse effects by promoting propagation of Tau pathology. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Methods in Molecular Biology Mouse Genetics: Methods and Protocols | Center for Cancer Research

Science.gov (United States)

Mouse Genetics: Methods and Protocols provides selected mouse genetic techniques and their application in modeling varieties of human diseases. The chapters are mainly focused on the generation of different transgenic mice to accomplish the manipulation of genes of interest, tracing cell lineages, and modeling human diseases.

AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging.

Science.gov (United States)

Ordoñez-Gutierrez, Lara; Fernandez-Perez, Ivan; Herrera, Jose Luis; Anton, Marta; Benito-Cuesta, Irene; Wandosell, Francisco

2016-09-06

Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis)

DEFF Research Database (Denmark)

Darusman, Huda Shalahudin; Sajuthi, D; Kalliokoski, O

2013-01-01

In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aβ42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid.......In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aβ42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid....